Medicinal Theory+Practicals

The number of hosts involved in the life cycle of Plasmodium are:
a. None of the options

b. 3
C. 2
d. 3
6-Chloro-2-methoxy-9-(diethyl amino isopentyl)amino acridine is the chemical

name of:
a. Mepacrine
b. Azacrine
c. Pamaquine
In the structure of Quinine, group is attached at 6'-position in quinoline

nucleus.
a. Methyl
b. Methoxy
c. Ethyl
d. Ethoxy
Folic acid can help to synthesize

in livings.
a. Proteins
b. Enzymes
c. Carbohydrates
d. DNA
Methyl Penicillin is commonly
known as:
a. Penicillin-G
b. Penicillin-K
c. Penicillin-V
d. None of the options
Cephalothin belongs to:

a. Second generation
b. Forth generation
c. Third generation
d. First generation
Beta lactamase resistant by cephalosporins depend upon:

a. Steric factors
b. Both steric factor and polar substituents in side chain
c. Polar substituents in amino adipoyl side chain
Which one of the following is
derivative?
a. Erythromycin
b. Kenamycin
c. Amikacin
d. Gentamycin
Uptake of tetracycline by bacteria require:

a. ADP and calcium
b. ADP and Magnesium
c. ATP and calcium
d. ATP and Magnesium
Cephalosporins-N has following components:

a. Alpha lactam ring, thiazolidine ring and amino-acyl group
b. Alpha lactam ring, thiazolidine ring and amino adipoyl side chain
c. Beta lactam ring, thiazolidine ring and amino adipoyl side chain
d. beta lactam ring, thiazolidine ring and amino-acyl group
Cefamendole belongs to:

a. Second generation
b. Third generation
c. Fourth generation
d. First generation
Acid-salts of tetracylines are formed through protonation of group on carbon-
2.
a. Enol
b. Keto
c. Carboxamide
d. Amide
Dioxolane is used in the synthesis of .............. antiviral drug.

b. Arildon
c. Acyclovir
d. Ribavirin
Which one is used to synthesize

Ribavirin drug?
a. Pyridine
b. Dioxolane
c. Triazole carboxylate
d. Phosphoric acid
Sulfonamides can block:

a. Dihydrofolate synthetase
b. Dihydrofolate reductase
c. Nuclease
d. Dihydropteroate synthetase
9-[(2-Hydroxy ethoxy) methyl] guanine is the chemical name of:
a. Ribavirin
b. Acyclovir
c. Mefanemic acid
d. Arildon
Tromantadine HCL is used to treat:

a. Bacterial diseases
b. Metabolic disorder
c. Fungal diseases
d. Viral diseases
Amodiaquine chemically belongs to:

a. Cinchona alkaloids
b. 8-Amino Quinolines
c. 9-Amino acridines
d. 4-Amino Quinolines
The degradation by hydrolysis is influenced by:

a. Temperature
b. None of the options
c. Light
d. pH
The antiviral drug that inhibits the early stages of viral replication are:
a. Amantadine and Ribavirin
b. Amantadine and interferon
c. Amantadine and arildon
d. Amantadine and methisazone
2-Ethoxy-1-naphthyl penicillin is the chemical name of:

b. Naficillin
c. Penicillin-G
d. Methicillin
Sulfonamides being structural analogue of ............... inhibit the pathway of

folic acid synthesis and growth of bacteria becomes arrested.
a. PABA
b. PAFA
C. PASA
The reduction of methacycline in the presence of rancy nickel produces:

a. Oxytetracycline
b. Chlortetracycline
c. Tetracycline
Derivatives of Erythromycin have been developed to improve:
a. Water stability
b. Bitter taste
c. Lipid stability
d. Acid stability
The antimalarials which eradicate the organisms before entering the RBCs
are called:
a. Erthrocytic Schizontocides
b. Tissue Schizontocides
c. None of the options
d. Sporontocides
The natural source of Penicillins is/are:

a. Penicillium notatum and P. crysogenum
b. Penicillium crysogenum
c. Penicillium notatum
Identify the group at position-2 of tetracyclines and is crucial for

antimicrobial activity and best if left unsubstitueted or monosubstitueted.
a. Keto group
b. Hydroxyl group
c. Dimethyl amine group
d. Carboxamide group
The example of tetracyclines having pyrrolidine as mono substituent at
position-2 (carboxamide group) is:
a. Rolitetracycline
b. Chlortetracycline
c. Minocycline
d. Doxycycline
The addition of amino group in penicillin-G at CH2 (methylene) group of

amide chain results into:
a. Amoxicillin
b. Ampicillin
c. Cloxacillin
d. Carbenacillin
Chemically tetracyclines are:

a. Amphoteric
b. Acidic
c. Neutral
d. Basic
During folic acid synthesis in microbes, is converted into pyrophosphate.

a. Dihydropterin
c. Tetrahydro folic acid
d. Dihydroxymethyl dihydropterin
Which one of the Kenamycin is
more active:
a. Type-D
b. Type-B
c. Type-C
d. Type-A
3-Metanilamide-5-chloro pyrimide (sulfonamides derivative) is 16-times

effective more active against:
a. Plasmodium ovalae
b. Plasmodium falciparum
c. Plasmodium gallinaecum
d. Plasmodium vivax
Dimethylated substitution of sulfadiazine is known as:

a. Sulfadimidine
b. Sulfamerazine
c. Sulfanilamide
d. Sulfaisoxozole
Doxycycline is one of the efficient tetracyclines because it:

a. Stable
b. Resistant to epimerization and chemical degradation
c. Not show epimerization
d. Can form salts
The cell wall of bacteria has mucopeptide component which is also know as:
a. All of the options
b. Techoic acid
c. Lipoproteins
d. Murein sacculus
6-Methoxy-8-(dimethyl amino isopentyl)amino quinoline is the chemical name

of:
a. Pentaquine
b. Pamaquine
c. Primaquine
d. Quinine
During life cycle of Plasmodium, merozoites are released by/;

b. Erythrocytes
c. Saliva of mosquito
d. Stomach of mosquito
Chemically Proguanil belongs

to:
b. 4-Amino quinolines
c. 8-Amino quinolines
d. 9-Amino acridines
Chloramphenicol is not produced by:
a. Streptomyces omiyamensis
b. Streptomyces chloromyceticus
c. Streptomyces griseus
d. Streptomyces venezualae
What will be the degraded structure after complete oxidation in the presence
of Potassium permanganate?
a. All of the options
b. Pyridine Tricarboxylic acid
c. Quininone
d. Quinotoxin
Demethlation of Santaquine results in:

a. Chloroquine
b. Amodiaquine
c. Mepacrine
d. Hydroxy Chloroquine
Pro-drugs of sulfonamides can be formed by reaction of sulfonamides with

dicarboxylic acids like:
a. Phthalic acid
b. Succinic acid
c. None of the options
d. Both succinic acid and phthalic acid
Peptidoglycan component of cell wall of bacteria consists of:
a. N-acetyl glucosamine, N-acetyl muramic acid, lactic acid and lipids
b. N-acetyl glucosamine, N-acetyl muramic acid and amino acids
c. N-acetyl glucosamine, N-acetyl muramic acid, lactic acid and amino acids
Identify the organisms having obligate parasitic condition, operational

characteristic of an exogenous submicroscopic unit and capable of
multiplication only inside specific cells.
a. Viruses
b. Yeast
c. Protozoa
d. Bacteria
2,6-Dimethoxy phenyl penicillin is the chemical name of:

a. Methicillin
b. Penicillin-G
c. Carbenacillin
d. Penicillin-V
The number of naturally occurring cephalosporins are:

a. 4
b. 2
C.3
d.5
In 4-amino quinolines, the effective position for acidic substitution is:
a.6
b.7
c.5
d.2
During folic acid synthesis in microbes, Dihydrofolic acid is synthesized by

reaction between dihydropteroate and
a.Glutamic acid
b. Aspartic acid
c None of the options
d PABA
The pro-drugs of cephalosporins to increase the bioavailabilty can be achieved

by modification of……...group.
b. Carboxylic
c. Thiopyrone
d Beta lactam
During cell wall synthesis in bacteria, cross-linking is controlled by.

a Transamidase and Ligase
b. Amidase and Ligase
c. Transamidase and transpeptidase
d Transemidase and synthetase
How many positions are available on tetracyclines for formation of effective
analogues?
a.3
b.2
c.4
d.5
The oxidation of C-3 vinyl part in Quinine gives inactive analogue, known as:
a.Quininone
b.Quinetenine
c.cinchonine
d.Quinotoxins
Replacement of benzyl group in penicillin-G with dimethoxy benzene results

into the formation of Penicillinase resistant
a.Cloxacilin
b Methicillin
c.carbenicillin
d.Dicloxacilin
4,4-Diamino diphenyl sulfone is the chemical name of:

a. Sulfanilamide
b. Clofazimine
c Ripampin
d. Dapsone
The addition of amino group in penicillin-G at CH2 (methylene) group of
amide chain results into
a Cloxacillin
b.Ampicillin
c.Amoxicillin
d .Carbenacin
The toxin and degraded portion left after digestion of haeme during life cycle
of Plasmodiun in RBC is:
a.All of the options

b. Porphyrin
c. Ferritoxin
d.Ferriprotophyrin-IX
Which one is used to synthesize Ribavirin drug?

a Phosphoric acid
b. Triazole carboxylate
c.Dioxolane
d. Pyridine
The methylated form of ampicillin is known as:
b. Ampicillin
c Amoxicillin
d. Penicillin-G
1.During life cycle of Plasmodium, merozoites are released by:
a. Erythrocytes
b. Saliva of mosquito
c. Stomach of mosquito
2.The malaria is caused by:
a. Male Anopheles
b. Female Anopheles
c. Plasmodium vivax
d. Plasmodiun pneumonia
3.Biguanides include:
b. Chloroquine and Santaquine
c. Quine and Cinchonine
d. Mepacrine and Azacrine
4. 3-vinyl-6'-methoxy-9 rubanol is the chemical name of:
a. Mepacrine
b. Quinine
C. Cinchonine
d. Pamaquine
5. Primaquine chemically belongs to:
a. Cinchona alkaloids
b. 4-Amino quinolines
c. Biguanides
d. 8-Amino quinolones
6. 3-membered lactone ring is known as:
a. Alpha Lactam
b. Beta Lactam
c Alpha Lactim
d. Beta Lactim
7. The penicillin which is dibasic acid, acid labile and not taken orally, is known as:
a. Methacillin
b. Carbenicin
c. Ampicin
d.Amoxicillin
8. Phenoxy methyl penicillin is also known as:
b. Penicillin-G
c. Penicillin-V
d. Penicillin-K
9. The number of asymmetrical carbon atoms in Penicillins are:
b. 2
c.3
d. 4
10. In folic acid synthesis, Trimethoprim can block:
b. Dihydrofolate synthase
c. Dihydrofolate reductase
d. Dihydropterin pyrophosphokinase
11. Follic acid is essential for the synthesis of?
a. Pyrimidines
b. Purines
c. Proteins
d. Nucleoside
12. The addition of methyl group in pyrimidine of sulfadiazine will result in
a. Sulfamerazine
b. Sulfamethoxazole
c. Sulfacetamide
d. Sulfadimidine
13. Who suggested the significant curative properties of Prontosil?
a. Garhard Domagk
b. Alfard Harshey
c.Trefuel
d. Marshal
14. Penicillin allergy may be caused by unpurified and amorphous:
a. Penicillin-G and V
b. Penicillin-G
c. Carbenicillin
d. Ampicillin
15. Ribavirin, a purine nucleoside analogue is phosphorylated to triphosphate by:
a. Thimidine kinase
b. Polymerase
c. Guanosine monophosphate kinase
d. Adenoxine kinase
16. Cefazolin is the example of:
a. 4th generation
b. 3nd generation
c. 1st generation
d. 2nd generation
17. Acyclovir drug can inhibit the synthesis of:
a. Protein
b. Nucleic acid
c. All of these
d. Translocation
18. The replacement of "S" by "O" in cephalosporin, can lead to the formation of
a. Cefodoxine
b. Latamoxef
c.Loracarbef
19. The epimerization in Tetracyclines may occur due to the change in orientation of:
a. Ketonic group
b. Dimethyl amino group
c. Hydroxyl group
d. Carboxamide group
20. Oxime formation is taken place during the formation of:
a. Roxithromycin
b. Azithromycin
c. Gentamycin
d. Clarithromycin
21. Derivatives of Erythromycin have been developed to improve:
a. Bitter taste
b. Water stability
c. Lipid stability
d. Acid stability
22. The active form of Chloramphenicol is:
a. D-threo form
b. D-Erythro form
c. L-threo form
d. L-Erythro form
23. Methoxy form of Erythromycin is also known as:
a. Clarithromycin
b. Roxithromycin
c. Azithromycin
d. Gentamycin
24. Two dimethyl anino groups are present in:
a. Minocycline
b. Doxycycline
c. Methacycline
d. Chlortetracycline
25. Streptomycin-C possess the number of sugars:
a. 5
b. 2
C.3
d. 4
26. Micromonospora purpurea
yields:
a. Streptomycin
b. Tobramycin
c. Gentamycin
d. Neomycin
27. Which one of the following is
derivative?
a. Erythromycin
b. Amikacin
c. Gentamycin
d. Kenamycin
28. Tetracyclines Binds to for Protein synthesis inhibition.
a. Cell membrane
b.DNA
C.30S Ribosome
d.50S Ribosome
29. Seldomycin Belongs to
a. Miscellaneous
b.Tetracyclines
c.Macrolides
d.Aminoglycosides
30.Chemically tetracyclines are:
a.Basic
b.Neutral
c.Acidic
d.Amphoteric
31. Gray baby syndrome is the adverse effect of:

a. Erythromycin
b. Chloramphenicol
c.Penicillins
d.Streptomycin
32. Chloramphenicol palmitate pro-drug is used to:
a. mask bitter taste
b. increase water solubility
c. increase shelf life
d. increase stability
33. Chloramphenicol is not produced by:

a.streptomyces chloromyceticus
b.streptomyces venezualae
c.streptomyces omiyamensis
d.streptomyces griseus
34. Chemically Debakicin is:
a.3,4-dideoxy kenamycin-C
b.None of the options
c.3,5--diddeoxy kenamycin-B
d.3,4-dideoxy kenamycin-A
35. During isolation of Erythromycin from its natural source, which of the following type of
Erythromycin is obtained in lesser quantity?
a. Type-B
b. Type-C
c. Type-D
d. Type-A
36. The type of Gentamycin which is resistant to acetyltransferase is:

a.None
b.C2
c.C1
d.C3
37. Number of basic groups present in Streptomycin are:

a.5
b.2
c.4
d.3
38. Which one is the strict condition that has to maintain during salt formation of
Chloramphenicol with HCL
a.Hydrous
b.Pressure
c.Temperature
d.Anhydrous
39. Streptomycin Belongs to
A. Aminoglycosides
B. Miscellaneous
C. Macrolides
D. Tetracycline
40. Chemically Netilmicin is:

a. 1-Ethyl-sisomicin
b. 1-N-methyl-sisomicin
c. 1-N-ethyl-sisomicin
d. 1-methyl-sisomicin
41.Fanconi's syndrome is due to the degradation of:

a. Tetracyclines
b. Chloramphenicol
c. Macrolides
d. Aminoglycosides
42. Streptomyces fradiae yields:
a. Chloramphenicol
b. Tobramycin
c. Gentamycin
d. Neomycin
43.Cephalosporins can undergo the degradation process to form desacetyl 7-
aminocehalosporanic acid lactone in the presence of:
a. Lactamase
b. Strong acidic condition
c. Acylase
d. alkaline condition
44.During folic acid synthesis in microbes, …….. is converted into pyrophosphate.

a. Tetrahydro folic acid
c. Dihydropterin
d. Dihydroxymethyl dihydropterin
Antibiotics
Introduction
The term chemotherapy can be defined as the treatment of diseases caused due to infective
parasites or organisms without causing destruction of their host. Modern chemotherapy began
with the work of Paul Ehlrich (1854-1915) (Fig. 56.1). Due to his pioneer discoveries in this field,
he is regarded as "Father of Chemo therapy"
. The second phase of revolution emerged in the 1930s (following the discovery of the British
bacteriologist Alexander Fleming (Fig. 56.2) when he tested the filtrate of a broth culture of a
penicilium mold for its antibacterial activity.
• The term antibiotic has its origin in the word antibiosis (i.e. against the life); the latter being
first time used by Vuillemin in 1889 in an attempt to describe the concept of survival of the
fittest.
• Although the discovery of penicillin is named after Sir Fleming in 1928, it was not until 1940 at
Oxford that Florey and Chain and their associates isolated it and described its properties in
detail, and thus turning Fleming's discovery of practical significance.
• Among the many attempts to define the term antibiotic, the most appropriate one may be
stated as,
"An antibiotic is a chemical compound derived from or metabolically produced by
microorganism and that in high dilution antagonizes the growth and/or the survival of one or
more species of microorganism".
 The probable points of differences amongst the antibiotics maybe physical, chemical
and pharmacological properties, anti bacterial spectra and mechanism of action.
• With advances made by the medical chemists to modify naturally occurring antibiotics and to
prepare synthetic analogues, it has become necessary to permit the inclusion of semisynthetic
and synthetic derivatives in the definition. Therefore, a substance is classified as an antibiotics,
if the following conditions are met.
1. It is the product of metabolism.
2. It is a synthetic product, produced as a structurally similar with naturally occurring
antibiotics.
3. It antagonizes the growth or survival of one or more species of micro-organisms.
4. It is affective in low concentration.
Antibiotics are substances produced by various species of microorganisms (bacteria, fungi,
actinomycetes) that suppress the growth of other microorganisms and eventually may destroy
them. The discovery of antibiotics in 1930 has made it possible to cure disease such as
pneumonia, meningitis, microbial disease and infection.
Classification
Antibiotics are classified based on their mechanism of action and by its chemical nature.
Classification Based on Mechanism of Action
1. Agents that inhibit the synthesis of bacterial cell wall: These include the penicillin’s and
cephalosporins that are structurally similar and dissimilar agents, such as cycloserine,
vancomycin, bacitracin and the imidazole antifungal agents.
2. Agents that act directly on the cell membrane of the microorganisms, affecting
permeability, and leading to leakage of intracellular compounds: These include polymyxin,
polyene antifungal agents, nystatin, and amphotericin B that bind to cell wall sterols.
3. Agents that affect the function of 30s and 50s ribosomal subunits to cause reversible
inhibition of protein synthesis: These include tetracyclines, erythromycins, chloramphenicol,
and clindamycin.
4. Agents that bind to the 30s ribosomal subunit and alter protein synthesis: These include
aminoglycosides that leads to cell deaths eventually.
5. Agents that affect nucleic acid metabolism: Such as rifamycin’s, which inhibit DNA
dependent RNA polymerase.
Classification Based Upon Mode of Action

1. Drugs that interfere in the biosynthesis of bacterial cell wall, e.g
penicillins, cephalosporins, cycloserine, bacitracin and vancomycin.
2. Drugs that interfere in the functioning of cytoplasmic membrane, e.g.
polymixins, amphotericin B and nystatin.
3. Drugs that interfere in the protein biosynthesis, e.g.
erythromycin, lincomycins, tetracyclines, and chloramphenicol.
4. Drugs that interfere in the nucleic acid biosynthesis, e. g.
actinomycin, griseofulvin and rifampin.
CLASSIFICATION OF ANTIBIOTICS
Flow chart 56.1: Classification of antibiotics
ANTIBIOTICS
1. Based upon spectrum of action
 Broad-spectrum antibiotics Cephalosporin, rifamycin tetracycline

 Antibiotics against gram +ve micro-organism: Polymixin, sulfomyxan
 Antibiotics against mycobacteria Streptomycin, rifampin
 Antibiotics against fungi: Griseofulvin, pollyne antibiotics
 Antibiotics used in neoplasia(cancer): Actinomycin, doxorubicin plicamycin
 Antibiotics against Gram-ve microbes: Bacitracin, polymyxin
2. Based upon Source from which it is obtained
 Natural source: Totracyclin, polymixin streptomycin

 Semisynthetic: Penicillin G
 Synthetic source: Chloramphenicol
3. Based upon mode of action
 Drugs that interfere in cell wall synthesis: Penicillin, cephalosporin cycloserine,

bacitracin
 Drugs that interfere in cytoplasmic membrane functioning: Amphotericin B, Nystatin
 Drug that Interfere in blo synthesis of the protein: chloramphenicol, vancomycin,
tetracycline
 Drugs that interfero in nuceic acid biosynthesis: Actinomycin griseofulvin, rifampin
4. Based upon chemical nature
 B-lactam antibiotics Penicillin, cephlosporin

 Aminoglycoside antibiotic Streptomycin, gentamicin
 Tetracycline antibiotics: Chlortetracycline oxytetracycline
 Macrolide antibiotics: Erythromycin. olondomycin
 Peptide antibiotic: Bacitracin, polymixin
 Unclassified antibiotics: Chloramphenicol
Peptide antibiotics
Bacitracin (Reaction)
Macrolide antibiotics
Olendomycin (structure)
Unclassifieds
OH OH
Cl
HN,
nA_ 'CI
Chloramphenicol
0
Depending Upon the Sources from which Antibiotics is Obtained

Natural
These antibiotics are obtained from the large-scale fermentation of microorganisms, e.g.
bacitracin, and polymixin are obtained from some bacilli while streptomycin, tetracyclines, etc,
from Streptomyces species.
Semisynthetic
The observation that 6-aminopenicillanic acid can be obtained from cultures of P.
chrysogenum that were depleted of side chain precursors led to the development of this class.
For example, during the commercial production of benzyl penicillin (penicillin G), phenylacetic
acid is added to the medium in order to achieve predominance of the product.
Synthetic
This class includes antibiotics which are having purely synthetic origin. For example
chloramphenicol, a broad-spectrum antibiotic initially isolated from a fermented media in 1947
and later was produced synthetically on a commercial basis.
Beta-Lactam Antibiotics (Penicillins)

Even though penicillin had been discovered in 1928, and is a member of B-lactam antibiotic, the
term B-lactam antibiotic has to wait till 1942 to get registered in the dictionary of medicinal
chemists. Thanks to Prof. Howard W. Florey and Dr. Ernst B. Chain, working at that time at the
William Dunn School of Pathology, Oxford with their sincere efforts, isolated and characterised
the basic structure of the penicillins. This work was supplimented by the efforts of the chemests
Dr. Abraham and Dr.Heatley. The clinical effectiveness of penicillin was first tested on February,
1941 in the form of a sodium salt.
 Thus long after the antibiotic projected its appearance on the screen of research, the
structure of penicillin was determined.
 Thus penicillins can be considered as the amido derivatives of the 6-aminopenicillanic
acid.
 In the basic skeleton, a thiazolidine ring (A) is fused with a beta lactam ring (B) which is a
4-membered cyclic amide.
Acyl Side Ueta ..J.,.'tetam Thhlzolidi.J1t

C'hflirt.
Ring Ring
,,,H
N c,COOH
General Structure of Penicillins
Basic skeleton of Penicillin

Chloramphenicol
Introduction
Chloramphenicol also known as chloromycetin is a dextrorotatory broad spectrum anti-biotics
originally produced from several streptomycetes and also by actinomycete namely:
S.venezualae, S.omiyamesis, and S.chloromyceticus.
O 1
Cl
II
H NH-c-CH-CI
02N-0-~
_
C-C-CH2·0H
I I
OH H
chloramphenicol
it has been reported to be the drug of choice for the treatment of typhus and typhoid fever. It
is isolated from Salmonella venezuelae by Ehrlich et al in 1947. It contains chlorine and is
obtained from an actinomycete, and thus, named as chloromycetin. It is specifically
recommended for the treatment of serious infections caused by H. influenzae, S. typhi
(typhoid), S. pneumoniae, and N. meningitides. Its ability to penetrate the CNS presents an
alternative therapy for meningitis and exhibits antirickettsial activity.
However, Chloramphenicol of permanent interest owing to the following reasons:
 It is a naturally occurring aromatic nitro-compound.
 It can exert its effect against viral diseases as well as those due to bacterial invasive and
opens up the whole field of the chemotherapy of virus and rickettsial infections in man
including typhus, salmonella, septicemia, whooping cough, gastroenteritis, typhoid and
paratyphoid.
 It can be synthesized on industrial scale.
Chemistry of chloramphenicol
O Cl
II / (±) 0
H NH-c-CH-CI H
Cl00H
02N-o-~
_
C-C-CH2·0H
I I
OH Cl
OH H
dichloro acetic acid
chloramphenicol
The determination of the structure of chloramphenicol was relatively simple. When the
antibiotics was treated with acid (H+) OR base (OH-) two products were obtained. The acid was
identified as di chloroacetic acid, the base formed a tri-acetyl derivative having two O-acetyl
group and one N- acetyl group. The antibiotic could be reconstituted by reacting the base with
methyl dichloroacetate. It was clear from these result that acidic/ basic conditions hydrolyzed
an amide linkage. Oxidation of the base with periodic acid gave p-nitro benzaldehyde ammonia
and formaldehyde.
Structure activity relationship (SAR) of chloramphenicol

Chloramphenicol possess two chiral/ asymmetrical carbon atoms in the acyl amino propane diol
chain.
~ 0
II /
Cl
~H-c-CH-CI 02 N
-0-OH
H H
C-C-CH ·OH
02N
-0- C-C-CH
I I
OH H
2
·OH I 0
II I
2
Cl
NH-c-CH-CI
D-(-) Threo isomer L-(+) erythro isomer
Cl
0 0H H
-0-
1
II 0 N I I
9H ~H-c-CH-CI 2 ~-c -cH 2-oH
02N
-0- C-C-CH
I
H
I
H
2
·OH
1
0
II /
Cl
NH-c-CH-CI
D-(-) erythro isomer L(+)- Threo isomer
Thus, there are two pairs of enantiomers have similar functional group on same side that on
different side. The biological activity resides almost exclusively in the D- threo isomer, whereas
the L-threo and D-and L- erythro isomers are virtually inactive.
Effect of NO2 group
 About 90% of the biological activity lie in the NO2 group. Many attempts have been
made to replace the nitro-group with other organic radical without sacrificing biological
activity. Among the substituents are CN2, CONH2, CO2H, CO2R, SO2NHR, OH, NH2, OR,
N(CH3)3, NHR, R, Br, Cl, I, F, SO2, SR, C6H5, and various heterocyclic groups. However,
toxicity of compound is increased.
 The O-and m-nitro isomer of chloramphenicol has been synthesized. Shifting of the
nitro-group from the para reduces the antibacterial activity of the compound to a
marked degree. Several di and tri substituted benzene analogs have also been prepared.
Effect on phenyl group
 The phenyl group has been replaced with other aromatic or aliphatic group such as
naphthalene, thionyl, furyl, nitrofuryl, pyridyl and cyclohexyl. Only the nitrothienyl
compound has been reported to have appreciable biological activity but less than
chloramphenicol.
Effect on propane-diol side chain
 The stereo relationship inherent in propanediol side chain appear to be extremely
important in determining the activity of the four stereoisomers, only the D-threo
compound has appreciable activity. The primary alcohol group also seems to be
required since its replacement with hydrogen or alkyl leads to compounds which are
much less potent. The same holds true for the benzyl hydroxyl group.
Effect on dichloroacetyl group
The replacement of the dichloroacetyl group with various acyl and aryl groups has led to some
interesting findings.
 The dibromo acetyl derivative is the most active of this group of analogue in vitro, but it
is only about 80% as potent as antibiotics agent against most organism. The
dichloroacetyl group thus, appears to be the choice acyl group just as the nitro group is
the most effective para substituent on its benzene ring.
 If di-chlor (-CHCl2) is replaced by tri-floro (-CF3) the activity is 1.7 times as
chloramphenicol against E-coli.
Degradation of chloramphenicol
Chloramphenicol is very stable in bulk state and in solid dosage forms. In solutions however, it
slowly undergoes various hydrolytic and photo reactions depending on Ph, heat and light.
Hydrolysis
Attack by either alkali / acid produces dichloracetic acid with an optically active base.
O Cl
II / 0
H NH-c-CH-CI H+
02N-o-~ C-C-CH 2 ·OH --------1► Cl00H +
_ 1 1 oH
OH H Cl
dichloro acetic acid base
chloramphenicol
The base was shown to have a primary amino group and on treatment with methyl
dichloroacetate to base regenerates chloramphenicol.
Reaction with periodic acid (HIO4)
It results into the formation of nitro benzaldehyde, ammonia and formaldehyde. Formaldehyde
further oxidizes into formic acid.
O Cl
II I
H NH-c-CH-CI
O2 N - o - ~ C-C-CH2·0H
I I
02N-O-CHO + NH3 + 2HCHO
- OH H
chloramphenicol
! oxidation
HCOOH
Reaction with mineral acid (HCl)

When chloramphenicol is treated with one equivalent HCl under strictly anhydrous condition,
the dichloroacetyl group shifts from nitrogen to oxygen of the benzyl alcohol group. The ester
amine hydrochloride is very water soluble and the product is converted to chloramphenicol in
vivo.
O Cl
II I
H NH-c-CH-CI
0 N - 0 - ~ C-C-CH2·0H HCI
2 - OH
I
HI --------~
anhydrous condition
chloramphenicol
Mechanism of action
Chloramphenicol is either bacteriocidal or more commonly bacteriostatic depending upon the
organism.it is a broad-spectrum antibiotic which acts as protein synthesis inhibitors by
inhibiting the peptidyl transferase at 50S ribosomal subunit of bacterial ribosome.
Properties
Chloramphenicol is a white or greyish-white or yellowish-white crystalline powder or fine
crystals, slightly soluble in water, soluble in alcohol and propylene glycol. It was the first, and
still is the only therapeutically important antibiotic to be produced in competition with
microbiological processes. It contains a nitrobenzene moiety and is a derivative of di-
chloroacetic acid.
Therapeutic uses
 It is a primarily used against typhoid fever and similar salmonellal infections.
 It is also employed in acute infections dur to heamophillus influenzae including
meningitis attributed to ampicillin resistant strains.
 It has also been used to eradicate vibrios from patients with cholera.
 It is employed for rickettsia infection like typhus and rocky infection spotted fever.
 It is used topically extensively for superficial conjunctival infections and blepharitis
essentially caused by E. coli, H.influenzae, Moraxella lacunata, Streptococcus
hemolyticus and S.aures. However, it is still be drug of choice for the typhoid fever.
Note: the prodrug of chloramphenicol, chloramphenicol palmitate (USP) which is a tasteless
product is slowly intended for pediatric usage preferably because the parent drug has a distinct
bitter taste.
Adverse drug reaction

Anemias
Hemolytic anemia occurs in patients with low levels of glucose-6-phosphate dehydrogenase
reversible and aplastic anemia may also occur.
Gray baby syndrome
Neonates have less ability to glucoronidate the chloramphenicol and have under developed
renal functions. So, drug accumulate in body and interferes with mitochondrial ribosomes. This
leads to poor feeding, CVS collapse, depressed breathing, cyanosis and death.
And others include:
 Bone marrow depression
 GIT, nausea, vomiting, diarrhea
 Hypersensitivity: skin rashes, urticaria
 Synthesis of chloramphenicol
Synthesis of chloramphenicol
Q
OH H H
I I I
CH-C-C-OH
~I
~o
condensation
6 N0214__r_ed_u_c_ti_o_n_ _
V20sfPd
HO-C-H
I
H-C-NH
I 2
CH2-0H
benzaldehyde 1-phenyl-2-nitro-1,3-propandiol DI-three
i·c: D)
~
~ '<
.c ii>
C:
al -
5·
CJ::::,
nitration
0
II
H3C-C-O-C-H
Q 0
~
I II
H-y-NH-C-CH3
CH2-0-C-CH 3
II
0
I acetylated three isomer
0
I
D)
::::,
C.
D)
C.
C.
I
C")
r
0 Cl
II I
H NH2 H NH-c-CH-CI
02N
-0- C-C-CH 2 ·OH
I
OH H
I
0 N - o - ~ C-C-CH ·OH
2 - I I
OH H
2
chloramphenicol
Macrolide antibiotics
Introduction
The term macrolide is derived from its characteristic large (14-membered) lactone (cyclic ester)
ring. The clinically important members of this antibiotic family have two / more characteristics
sugar attached to this ring. One of these sugars usually carries a substituted amino group, so
their overall chemical character is weakly basic.
More than 3-dozen such compounds are known but only few are medicinally used (two
erythromycins and oleandomycin are medically used).
Mode of action
Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by binding
irreversibly to a site on the 50S subunits of the bacterial ribosome. Thus, inhibiting the
translocation steps of protein synthesis at varying stages of peptide chain elongation (hinder
the translocation of elongated peptide chain back from ‘A’ site to ‘P’ site). The macrolides
inhibit ribosomal peptidyl transferase activity. Some macrolides also inhibit the translocation of
the ribosome along with the mRNA template.
Therapeutic uses
The macrolide antibacterial agents are extremely useful chemotherapeutic agent for the
treatment of a variety of infections disorders and diseases caused by a host of gram positive
bacterial pathogen. These agents are exemplified by erythromycin are generally effective
against streptococcus, staphylococcus, chlamydia, legionella and mycoplasma. As a result, the
macrolides are commonly administered for respiratory, skin, tissue and genitourinary infection
caused by these pathogens.
Chemistry
The macrolide antibiotics have three common chemical characteristics
a) A large lactone rings formed by alpha and gamma hydroxy acid..
b) A ketone rings
c) A glycosidically linked amino sugar
Erythromycin
Isolation and chemistry
0
,,, ,, \ \
.,,, HO N-
.,, ''OH
o-
erythromycin
The production of erythromycin by a Streptomyces erythreus, stain was first described by

McGuire and co-worker.
Erythromycin was extracted at pit 9 from fermentation filtrates with amyl acetate / butanol.
The antibiotic was purified by re-extraction into water at PH 5 and the free base was
precipitated by adjusting the PH to the alkaline side.
Studies of the degradation product of erythromycin showed that the molecule consisted of
three structural units connected by glycoside bonds. These moieties were the di-methylamino
sugar (Desosamine) a methoxy-desoxy-methylose, cladinose and a long chain keto-macrocyclic
lactone, Erythronolide.
Resistance against macrolide

Following are mechanism of bacterial resistance against antibiotics.
1. Developed bacterial resistance is primarlry caused by bacteria possesnig R-factor
enzyme that methylate a specific guanine residue on their own m-RNA making them
somewhat less efficient protein biosynthesize but compartevly poor binders of
macrolide. The erythromycin producing so the organism utilize the same ribosomal
methylation technique to protect itself against the toxic effects of its own metabolite.
2. A second mechanism of reistance is associated with the mutation of adenine to guanine
that occours in particular part of m-RNA this change result in a 10,000 fold reduction of
binding capacity of erthyromycin to r-RNA.
3. Some bacterial strains however appear to be resistante to macrolide because of the
operation of an active efflux process in which the drug is expelled from the cell at the
cost of energy. (lack of penetrate ability)
Acid degradation of erythromycin
Erythromycin is unstable in acidic media of stomach and acid-catalyzed dehydration (of it)
initiates as a sequence of reactions. The C-6 hydroxyl (-OH) group reversibly attacks the C-9
ketone, giving rise to a hemi-ketal intermediate. Dehydration prevents the regeneration of the
parent erythromycin and the C-12 hydroxyl group can subsequently add to produce a Spiro-
ketal species. Since neither to hemiketal nor the spiroketal exhibits the significant antibacterial
activity, unprotected erythromycin is inactivated subsequently in the stomach. Furthermore,
evidence suggest that the hemiketal may be largely responsible for the GIT (prokinetic) adverse
effects associated with oral erythromycin.
After the formation of spiroketal species, Cladinose group is cleaved from the macrocycle and
more harsh conditions lead to release of Desosamine part.
Cl}Um>m~in Cllt»W!) (Qocll~
X\~ (OesoS.,.,.,..,.
-!L.
(Ca.GJIIOSel
s ~ • flnKUVe>
-- ft>I
T
O~:!lc:a:a.e .. n
- 0
Types of erythromycin:
Erythromycin-A differs from erythromycin-B only at C-12, at which a Hydrolysis has replaced the
hydroxyl OH group. The B analogue is more acid-stable but only about 80% of activity of erythromycin-
A. Erythromycin C differs from erythromycin A by the replacement of the methoxy-group (at C-3) on the
cladinose moiety by a H-atom. It appears to be as active as erythromycin but is present in every small
amount in fermentation liquor.
erythromycin
erythromycin-a erythromycin-b erythromycin-c
as normal H at C-12 methoxy-group (at C-3)
acetal: a functional group consisting of more acid-stable but 80% on cladinose by H-atom
two OR groups bonded to the same C of activity of erythromycin same action but less in function
they are often used as protecting groups
for aldehydes/ketones
a ketone/aldehyde reacts reversibly with two equivalent of an alcohol in the presence of an acid catalyst
to yield an acetal, R, C(OR), (sometimes called a ketal if derived from a ketone)
Coliform bacteria: gram –ve, non spore forming, aerobic or facultatively anaerobic bacterium that
ferments lactose and produces acid and gas ; significant numbers may indicates water pollution.
SAR of macrolide antibiotics (Derivatization)

Many strategies have been utilized to improve the acid stability of erythromycins.
a- The first approach involved the addition of hydroxylamine (NH2OH) to the ketone to
form oxime (R2CNOH) e. g Roxithromycin.
N,,O..___,,......O~0./
I
·,,o o-
o~H
roxithromycin
b- The second approach involves an alteration of the C-6 hydroxyl (-OH) group which is the
nucleophile functionality and initiates erythromycin degradation. Modification that
removes the nucleophilic nature of this hydroxyl group, can retain antibacterial
properties if the size of the group is kept small so as not to affect the ribosomal binding
e. g clarithromycin.
Clarithromycin
H3C"'".
HsCf"..
 Clarithromycin is the 6-methyl ether of the erythromycin. The simple methylation of the
C-6 hydroxyl group of erythromycins creates a semi-synthetic derivative that fully
retains the antibacterial properties of the parent antibiotic, with markedly increased
acid stability and oral bioavailability and reduced the GI-side effects associated with
erythromycin.
 Clarithromycin is well absorbed following oral administration (bioavailability 50---55%).
Extensive oxidation and hydrolysis occurs in the liver. The major metabolite is the 14-
hydroxyl derivative, which retains antibacterial activity.
Some of the microbiological properties of clarithromycin also appears to be superior to those of
erythromycin.
1- It exhibits greater potency against M. pneumoniae, legionella species, chlamydia
pneumoniae, H. influenza and M. catarrhalis than does erythromycin.
2- It is also significantly more active than erythromycin against A. streptococci, S.
pneumoniae etc. in vivo because of its superior oral bioavailability. However, it is more
expensive.
3- Adverse reaction to clarithromycin are rare.
 The azides (e. g azithromycin) are semi-synthetic 15-membered congeners in which N-
atom has been introduced to expand a 14-membered precursor, and thus leads to an
extended spectrum of action e. g Azithromycin which is a semi-synthetic derivative of
erythromycin, prepared by Beckman rearrangement of the corresponding 6-oxime,
followed by N-methylation and reduction of the resulting ring-expended lactam.
Removal of the 9-keto group coupled with incorporation of a weakly basic tertiary
amine nitrogen into the macrolide ring increases the stability of azithromycin to acid
catalyzed degradation. These changes also increase the lipid-solubility of the molecule,
thereby conferring unique pharmacokinetic and microbiological properties. The oral
bioavailability of it is good.
 The spectrum of antibacterial activity of azithromycin is similar to that observed for
erythromycin and clarithromycin but with some interesting difference generally it is
more active against gram-negative bacteria and less active against gram-positive
bacteria than its close relatives.
Aminoglycoside antibiotics
Introduction
The aminoglycoside antibiotics contain one or more amino sugars such as glucosamine /
neosamine linked by glycosidic linkages to a basic (amines or guanidine) six membered carbon
ring. These are broad-spectrum antibiotics; in general, they have greater activity against gram-
negative than gram-positive bacteria.
The aminoglycoside can produce severe adverse effects, which include nephrotoxicity,
ototoxicity, and neuro effects. These properties have limited the use of aminoglycoside
chemotherapy to serious systemic indications. Some aminoglycosides can be administered for
ophthalmic and topical purposes.
Mode of action
The aminoglycosides exhibit bactericidal effects because of several phenomena. Ribosomal
binding on 30s and 50s subunits as well as the interface produces misreading; this disturbs the
normal protein synthesis. Cell membrane damage also plays an integral part in ensuring
bacterial cell death.
Examples
Name Source
Gentamycin Micromonospora purpura
Neomycin Streptomyces fradiae
Streptomycin Streptomyces griseus
Tobramycin Streptomyces tenebrarius
Framycetin Streptomyces decaris
Kanamycin Streptomyces kanamyeleticus
Amikacin It is 1-L-(-) 4-amino-2-hydroxy butyryl
kanamycin
Microbial resistance
The development of strains of Enterobacteriaceae resistant to antibiotics is a well-recognized,
serious medical problem. Nosocomial (hospital acquired) infections caused by these organisms
are often resistant to antibiotic therapy. Research has established clearly that multidrug
resistance among gram-negative bacilli to a variety of antibiotics occurs and can be transmitted
to previously non-resistant strains of the same species of bacteria. Resistance is transferred
from one bacterium to another by extrachromosomal-R factor (DNA) that self-replicate and are
transfer by conjugation (direct contact). The amino glycoside antibiotics, because of their
potent bactericidal action against gram-negative bacilli, are now preferred for the treatment of
many serious infections caused by coliform bacteria. A pattern of bacterial resistance to each of
aminoglycoside antibiotics, however, has developed as their clinical use. Consequently, there
are bacterial strains resistant to streptomycin, kanamycin and gentamycin strains carrying R-
factors for resistance to these antibiotics synthesize enzymes capable of acetylation,
phosphorylating adenylating by amino or hydroxyl groups of aminoglycosides.
Resistance of individual aminoglycoside to specific inactivating enzymes can be understood, in
large measure, by using clinical principles.
1- First, one can assume that if the target functional group is absenting in a position of the
structure normally attacked by an inactivating enzyme, than antibiotic will be resistance
to the enzyme.
2- Second, steric factors may confer resistance to attack at functionalities, otherwise
susceptible to enzymatic attack. e. g conversion of a primary amine group to a
secondary amine inhibit N-acetylation by certain aminoglycoside acetyl transferases.
At least nine different types of aminoglycoside inactivating enzymes have been identified and
partially characterized. Aminoglycoside inactivating enzymes include amino acetyltransferases
(ACC), which acetylate the 6’-NH2 of ring-I, the 3-NH2 of ring-II or 2’-NH2 of ring-I (in
kanamycin-B) phosphotransferases (ADH) with phosphorylate the 3’-OH of ring-I or the 2’-OH of
ring-III and nucleotidyltransferases (ANT) which adenylate the 2”- OH of ring-III, the 4’-OH of
ring-I or the 4”-OH of ring-III.
- - - - - Deoxystreptamine
kanosamine - - - substituted glucose

 The gentamycin and tobramycin lack a 3’-hydroxyl group in ring-I and consequently are
not inactivated by the phosphotransferase enzymes that phosphorylate that group in
the kanamycin-B.
 Gentamycin-C1 is resistant to acetyltransferase that acetylates the 6’-amino group
in ring-I of kanamycin-B.
 All gentamycin is resistant to the nucleotidyltransferase enzyme that adenylates to
secondary equatorial 4”-hydroxyl group of kanamycin because the 4”-hydroxyl (OH)
group in gentamycin is tertiary and is oriented axially.
 Removal of functional groups susceptible to attacking an aminoglycoside occasionally
can lead to derivatives that resist enzymatic inactivation and retain activity e. g 3’-
deoxy, 4”-deoxy and 3’,4’, -dideoxykenamycins are more similar to the gentamycin and
tobramycin in their pattern of activity against clinical isolate that resist one / more of
the aminoglycoside inactivating enzyme.
But the development of amikacin the 1-N-L-(-) amino-alpha-hydroxybutyric acid (L-AHBA)
derivative of kanamycin keep most of intrinsic potency of kanamycin-A and is resistant to
virtually all aminoglycoside inactivating enzyme known, except the amino-acetyltransferase
that
a) Acetylates the 6’-amino group and the
b) Nucleotidyltransferase that adenylates the 4’-hydroxyl group of ring-I. the cause of
amikacins resistance to enzymatic inactivation is not known, but it has been suggested
that introduction of the L-AHBA-group into the kanamycin-A markedly decreases its
affinity for the inactivating enzyme.
Structure activity relationship of kanamycin

It is convenient to discuss sequentially aminoglycoside SARs in term of substituents in ring I, II
and III.
Ring-I
 RING-I is crucially important for the characteristics broad spectrum antibacterial activity
and it is the primary target for bacterial inactivating enzymes.
 Amino function at 6’ and 2’ are particularly important as kanamycin-B (6’-amino, 2’-
amino) is more active than kanamycin-A (6’-amino, 2’-hydroxyl) which in turn more
active than kanamycin-C (6’-hydroxyl, 2’-amino).
 Methylation at either the 6’-carbon or 6’-aminoo positions does not lower appreciable
antibacterial activity and confers resistance to enzymatic acetylation of the 6’-amino
group.
 Removal of 3’-hydroxyl or the 4’-hydroxyl group or both in the kanamycin (e. g 3’, 4’-
didexykenamycin-B or dibekacin) does not reduce antibacterial potency.
 The gentamycin also lacks oxygen function at thee positions, as to sisomicin and
netilmicin, which also have a 4’, 5’-double bonds. None of these derivatives is
inactivated by increase phosphotransferase enzymes that phosphorylate the 3’-hydroxyl
group. Evidently 3’-phosphorlated derivatives have very low affinity for aminoglycoside
binding sites in bacterial resistance guanidine groups and the more weakly basic
methylamino group. The streptomycin molecule consists of 3-independent units i. e
streptidine, streptose sugar (5-C) and glucosamine sugar (6-C) joined by glycosidic bond.
2) Ring 2
 Few modifications of ring 2 ( deoxystreptamine) functional groups are possible without

appreciable loss of activity in most of the aminoglycoside. The amino group of kanamycin can be
acylated e.g (amikacin), however e- activity largely retained netilmicin (1-N- ethyl sisomicin
)retains the antibacterial potency of sisomicin and is resistance to several additional bacteria
inactivity enzymes .
 2-hydroxysisomicin is claimed to beresistant to bacterial strains that aceteylate the 2-hydroxy
group of ring 3 whereas 3-deaminosisomicin exhibits good activity against bacterial strains that
elaborate 3-acetylating enzymes.
3) Ring 3
 Ring 3 functional groups appears to besome what less sensitive to structural changes than those
of either ring-1 or ring-2.
 Although the 2-deoxygentamicin are significantly less active than 2-hydroxy counterparts the 2-
amins derivative (seldomycin) arehighly active.
 The 3-amino group of gentamycin may be primary or secondary e- high antibacterial potency
furthermore the 4-hydroxyl group may be axial or equatorial e- little change in potency.
SAR of streptomycin
Isolation: In 1944 schatz, bugie and waksmon described the isolation of a new antibiotics in
crude form from two culture of Streptomyces griscus. Although streptomycin could be
extracted fromaqous solution with organic solvenst the active material was obserbed by
activated by carbons, alumina or ion exchange resins and could be eluted under proper
condition. The antibiotic was at first purified by chromatography it acid salt on carbon or
alumina columns.
Chemistry: streptomycin acts as a triacidic base through the effect of its two strongly basic
guanidine group of the more weakly basic methyl amino group. The streptomycin molecule
consist of 3-independent units, streptidine, streptase sugar (5-C) and glucosamine sugar (c-6)
joined by glycosidic bond.
Streptodine
 Guanidine group act as antimalarial and bacterial action against infection of respiratory
tract.
 If one of the guanidine group is lost, there is decrease in the bacterial activity but
increase in the toxicity.
 Due to the presence of two guanidine groups toxicity is decreased but no change in the
therapeutic activity.
 When one of these two guanidine groups are converted into urea-group, toxicity is
increased and loss of biological activity occur. Similarly, if two groups are converted into
urea, there is future increase in toxicity and loss of biological activity.
 If guanidine groups are converted into primary amine, no change in the biological
activity but toxicity to urinary bladder is increased.
Streptose group (5-C-sugar)
 If aldehyde group at P-3 is converted into keto-group 50% biological activity lost.
 If terminal CH3-group at P-4 is converted into primary alcohol, toxicity and activity both
falls. Such compound having (-CH2OH group) at P-4 is called hydroxy-streptomycin
which is also active moiety. Similarly, if aldehyde group at P-3 is also converted into
CH3OH, compound is called as dihydrostreptomycin which has same antimicrobial
activity.
Glucosamine sugar
 If methyl amine at P-2 is converted into ethylamine (C2H5-NH-) toxicity of compound is
increased.
 If primary alcohol (-CH2OH) at P-4 is converted in other basic alkyl alcohol, absolute loss
of activity occurs.
Streptomycin-B (mannosidostreptomycin)
It consists of a molecule of streptomycin-A linked glycosidically to D-manose through 3,4-C
hydroxy of N-methyl-L-glucosamine this mean it consist of three sugars.
Streptomycin-C
This consist of total four sugars molecules.
Therapeutic uses
 Streptomycin is chiefly employed in the treatment of tuberculosis in conjunction witth
other drugs such as isoniazid and rifampicin.
 Streptomycin and penicillin exert a synergistic action against bacteria and are usually
employed together in the treatment of subacute bacterial endocarditis caused by
streptococcus faecalis.
 It exerts bacteriostatic action in low concentration and bacteriocidal in high
concentration against a plethora of gram-negative and gram-positive organisms.
 A combination with a tetracycline, may be employed in the treatment of brucellosis and
infection produced by pseudomonas mallei.
Toxicity
 Streptomycin causes very quick hemolysis, prolong use of it, causes the damaging of
VIII-cranial nerve which results into the deafness. Either or both of the branches of
nerve may be involved. Damage to the auditory branch is associated with permanent
impairment of the sense of hearing, vestibular damage with equilibrium problem.
Kanamycin
----Deoxystreptamine
kanosamine - - - substituted glucose
Kanamycin A R1 NH2 R2 OH
Kanamycin B R1 NH2 R2 NH2
Kanamycin C R1 OH R2 NH2
Isolation
Kanamycin was isolated in 1957 by Umezawa and co-workers from Streptomyces
kanamyceticus.
Chemical structure
Chromatography shower that S. kanamyceticus elaborates three closely related structures
Kanamycin A, B and C. commercially available Kanamycin is almost pure. Kanamycin-A the least
toxic of three forms. The Kanamycin differ only in the sugar moieties attached to the glycosidic
oxygen on the 4-position of the central deoxy-streptamine. The kanosamine fragment leaked
glycosidically to the 6-position of deoxy-streptamine is 3-amino-3-deoxy-D-glucose (3-D-
glucosamine) in all three Kanamycins. They differ in the substituted D-glucoses attached
glycosidically to the 4-position of deoxy-streptamine ring.
 Kanamycin-A contains 6-amino-6-deoxy-D-glucose.
 Kanamycin-B contains 2, 6-diamino-2, 6-dideoxy-D-glucose.
 Kanamycin-C contains 2, amino-2 deoxy-D-glucose.
Properties
 Kanamycin is basic and forms salt of acids through its amino-group. It is water soluble as
the free base, but it is used in therapy as the sulfate salt, which is vary soluble. It is
stable to both heat and chemical.
 Of possible inactivation of either agents Kanamycin and penicillin salts should not be
combined in the same solution.
Uses
 It is effective against some Mycoplasma and gram-positive bacteria, for instance,
staphylococcus pyrogens and staphylococcus epidermicls.
Side effect
 Like streptomycin, Kanamycin may cause decreased or complete loss of heaving. One
development of such symptoms, it’s are should be stopped immediately.
Tetracycline
Introduction
Among the most important broad-spectrum antibiotics are members of the tetracycline family
nine such compounds tetracycline, tetracycline, oxytetracycline, chlortetracycline,
demeclocycline, meclocycline, methacycline, doxycycline, and minocycline have been
introduced into medical use. Several other possess antibiotics activity. The tetracyclines are
obtained by fermentation procedure from Streptomyces spp. Or by chemical transformation of
the natural products.
Their chemical identities have been established by degradation studies. The important member
of the group are derivatives of an octa-hydro-naphthacene i. e, a hydrocarbon made up of a
system of four fused rings.
~
~
naphthacene
cco anthracene
h' co h'
naphtalene
General properties
Following are the general characteristics feature of all the members of tetracycline family.
1- The antibiotic spectra and chemical properties of these compounds are quite similar
but not identical. They are broad-spectrum bacteriostatic antibiotics.
2- Amphoteric antibiotics
The tetracyclines are amphoteric compounds i. e forming salts with either acids or bases. In
neutral solutions, these substances exist mainly as zwitterions.
3- Solubility
 The acid-salts of tetracyclines, which are formed through protonation of an enol group
on C-2, exist as crystalline compound that are vary soluble in water. However, these
amphoteric antibiotics will crystallize out of aqueous solutions of their salts unless they
are dully stabilized by an excess of an acid.
 The hydrochloride salts are used most commonly for oral administration and usually are
encapsulate because they are bitter.
 Water soluble salts may also be obtained from bases such as sodium/ potassium
hydroxide, but they are not stable in aqueous solution.
 Water insoluble salts are formed with divalent (ca++,Mg++ salts) and polyvalent (Fe+++)
metal: calcium salt give tasteless product that may be employed to prepare suspension
for liquid oral dosage forms.
4- Epimerization
NH
2
OHO OHO 0 OHO OHO 0

natural (more active)
epimer (less active)
 an interesting property of the tetracyclines is their ability to undergo epimerization at C-
4 in solution having intermediate PH range. These isomers are called epi-tetracyclines.
The four epi-tetracyclines have been isolated and characterized. They exhibit much less
activity than the corresponding natural isomers, thus accounting for an apparent
decrease in the therapeutic value of compound.
5- Acidic and alkaline degradation
It has been observed that the strong acids and bases attack the tetracyclines having a hydroxyl
group (-OH) at C-6, thereby causing a considerable loss in activity through the modification of
the C-ring.
Strong acid produces a dehydration through a reduction involving the -OH group at C-6 and the
H atom at C-5a. the double bond thus generated between position C-5a and C-6, induces a shift
in a position of the double bond between the C-11 and C-11a, thereby forming the relatively
more energetically favored resonate system of the naphthalene group found in the inactive
anhydrotetracycline.
ACID
tetracycline
6-anhydrotetracycline
The strong bases (solution of the PH above 8.5) promote a reaction between the -OH group at
C-6 and carbonyl moiety at C-11, thereby causing the bond between C-11 and C-11a atoms to
cleave and eventually form the lactone ring which results into inactive iso-tetracyclines.
tetracyclin
isotetracyclin
6- Chelate formation
Stable chelate complexes are formed by the tetracyclines with many metals including calcium,
magnesium, and iron. Such chelates are usually very insoluble in water, accounting for the
impairment in absorption of most (if not all) tetracyclines in the presence of milk, calcium,
magnesium, and aluminium containing antacids and iron salts. Soluble alkalinizes such as
NaHCO3, also decreases the gastrointestinal absorption of tetracyclines.
Me
The affinity of tetracyclines for calcium causes them to be incorporated into newly forming
bones and teeth as tetracycline calcium orthophosphate complexes. Deposits of these
antibiotics in tooth cause yellow discoloration that darkens (photochemical reaction) over time.
Tetracyclines are distributed into the milk of lactating mothers and will cross the placental
barrier into the fetus. The possible effect of these agents on bones and teeth of the child should
be considered before they are used during pregnancy or in children under eight years of age.
SAR of Tetracyclines
Generic name R1 R2 R3 R4
Tetracycline H CH3 OH H
Chlortetracycline Cl CH3 OH H
Oxytetracycline H CH3 OH OH
Demeclocycline Cl H OH H
Methacycline H CH3 H OH
Doxycycline H H CH3 OH
Minocycline N(CH3)2 H H H
The key structural feature is a linearly fused tetracyclic nucleus and each ring needs to be six
membered and purely carbocyclic. A tetracyclic backbone skeleton is essential for activity. The
D-ring needs to be aromatic and the A-ring must be appropriately substituted at each of its
carbon atoms for notable activity. The B-ring and the C-ring tolerate certain substituent
changes as long as the keto-enol systems (at C-11, 12, 12a) remain intact and conjugated to the
phenolic D-ring. Aromatization of either D ring or C ring is determinantal. The A-ring must also
contain a conjugated keto enol system. Specifically, the A-ring contains a tricarbonyl derived
keto-enol array at positions C-1, 2, and -3. Other structural requirements for good antibacterial
activity include a basic amine function at C-4 position of the A-ring.
C-1 SUBSTITUENTS
The keto-enol system of A- ring is indispensable for antibacterial activity. No variation at C-1
position has been successful.
C-2 SUBSTITUENTS
The carboxamide moiety is present in all naturally occurring tetracycline and this group is
crucial for antibacterial activity. The amide is best for left unsubstituted or mono-substitution is
acceptable in the form of activated alkyl-amino-methyl amide (Mannich bases). An example
includes rolitetracycline large alkyl group on the carboxamide that may alter the normal keto-
enol equilibrium of the C-1, 2, and 3 conjugated systems and diminishes inherent antibacterial
activity. The replacement of carboxamide group or dehydration of carboxamide to the
corresponding nitrile results in a loss of activity.
CH 3
H3C-r.f
OH
NH-NC)
OH 0 0
Rolitetracycline
C-3 SUBSTITUENTS
In conjugation with the C-position, the keto-enol conjugated system is imperative for
antibacterial activity.
C-4 SUBSTITUENTS
The naturally occurring tetracyclines contain α-C-4 dimethyl amino substituent that favorably
contributes to the keto-enolic character of the R-rind. Replacement of dimethyl amino group
with hydrazone oxime or hydroxyl group leads to pronounced Loss of activity, probably due to
increase in heteroatom basicity.
C-4a SUBSITUENTS
The α-hydrogen at C-4a position of tetracyclines is necessary for useful antibacterial activity.
C-5 SUBSITUENTS
Alkylation of the C-5 hydroxyl group results in loss of activity. Naturally occurring antibacterial
tetracyclines have an unsubstituted methylene moiety at the C-5 position. However,
oxytetracycline contains C-5 α-hydroxyl group, was found to be a potent compound, and has
been modified chemically to some semisynthetic tetracyclines. Alkylation of the C-5 hydroxyl
group results in loss of activity. Ester formation is only acceptable if the free oxytetracycline
can be liberated in vivo; only small alkyl esters are useful.
C-5a SUBSITUENTS
The configuration of the naturally occurring tetracycline places the C-5a H- atom in an α-
configuration. Epimerization is detrimental to antibacterial activity.
C-6 SUBSITUENTS
The C-6 position is tolerant to a variety of substituents. The majority of tetracyclines have α-
methyl group and α β-hydroxyl group at this position. Demeclocycline is a naturally occurring C-
6 demethylated chlortetracycline with an excellent activity. The C-6 methyl group contributes
little to the activity of tetracycline. Similarly, the C-6 hydroxyl group also appears to offer little
in term of antimicrobial activity. Removal of this group affords doxycycline which is a superb
antibacterial.
C-7 and C-9 SUBSTITUENTS
The nature of the aromatic D-ring predisposes the C-7 position to electrophilic substitution and
nitro and halogen groups have been introduced. some C-7 nitro tetracyclines are among the
most potent of all the tetracycline in vitro, but these compounds are potentially toxic and
carcinogenic. Halogenated derivatives are less active.
C-10 SUBSTITUENTS
The C-10 phenolic moiety is necessary for antibacterial activity.
C-11 SUBSTITUENTS
The C-11 carbonyl moiety is a part of one of the conjugated keto-enol system required for
C-11a SUBSTITUENTS
In general, few modifications at the C-11a position of tetracycline have been tolerated. This is
probably due to the detrimental effects exerted upon the keto-enol system, which is vital for
magnesium cation binding and subsequently to uptake by the bacterial cell.
C-12 SUBSTITUENTS
As with the C-11 position, the C-12 position is part of the keto-enol system vital for drug uptake,
binding of observed antibacterial activity.
C-12a SUBSTITUENTS
The C-12a hydroxyl group is needed for antibacterial activity although this moiety can be
esterified to provide tetracycline with increased lipophilicity. Antibacterial properties are
retained if the alkyl ester is small and readily undergoing hydrolysis to liberate free tetracycline.
Mechanism of action
Tetracycline are specific inhibitors of bacterial protein synthesis. They bind to the 30S ribosomal
subunit and thereby prevent the binding of aminoacyl t-RNA to the m-RNA-ribosomes complex.
Both the binding of aminoacyl t-RNA and the binding of tetracycline at the ribosomal binding
site require magnesium ions. Tetracyclines also bind to mammalian ribosomes but with lower
affinities and they apparently don’t achieve sufficient intracellular concentration to interfere
with protein synthesis. The selective toxicity of the tetracyclines towards bacteria depend
strongly on the self-destructive capacity of bacterial cells to concentrate these agents in the
cell.
Tetracyclines enter bacterial cell by two processes
 Passive diffusion
 Active transports
Active uptake of tetracyclines by bacterial cell is an energy dependent process that requires ATP
and Mg++ ion.
Resistance
Three biochemically distinct mechanism of resistance to tetracyclines have been describes in
bacteria
a- Efflux is mediated by transmembrane spanning active transport proteins that decrease
intracellular tetracyclines concentration.
b- Ribosomal protection: in which the bacterial protein synthesis apparatus is rendered
resistance to the action of tetracyclines by an inducible cytoplasmic protein.
c- Enzymatic oxidation: efflux mediated by plasmid or chromosomal protein determinant
tet-A,-E, -G, -H, -K, and -L, and ribosomal protection mediated by the ribosomal protein
determinant tet-M, -O, and -S are more prominent resistant mechanism for
tetracyclines.
Adverse effects
1- Allergy: urticaria, dermatitis, fever, burning of eyes
2- GIT: nausea, vomiting, diarrhea, abdominal discomfort, epigastric burning
3- Phototoxicity
4- Hepatic toxicity
5- Fanconi’s syndrome: ingestion of outdated and degraded tetracyclines leads to
Fanconi’s syndrome characterized by nausea, vomiting, diarrhea, polyuria, acidosis and
sensitivity to sunlight (due to anhydro derivative)
6- Vestibular toxicity: characterized by dizziness, nausea, vomiting etc. increased
intracranial pressure, thrombophlebitis, deafness
7- Toxicity to calcified tissues: tetracyclines may deposit in bones making them weak and
deposit in teeth causing discoloration to brown color.
8- Superinfection
Therapeutic uses
 Rickettsial infection gram positive infection
 Chlamydial infection gram negative infection
 Mycoplasmal infection urinary infection
 Bacillary infection syphilis
 Spirochetes infection leptospirosis
Chlortetracycline
Introduction
OH 0 0
Chlorteteracycline
It was isolated by Duggar in 1948 from S. aureofaciens. This compound, which was produced in
an extensive search for new antibiotics, was the first of the group of highly successful
tetracyclines. It soon become established as a valuable antibiotic with broad spectrum
activities. It is used in medicine chiefly as the acid salt (crystalline powder with bright yellow
color). It is stable in air but slightly photosensitive and should be protected from light.
Oral and parental form of chlortetracycline are not now a day, because of poor bioavailability. It
is mainly used in the form of ointment for topical application and ophthalmic solution.
Synthesis
CH3
0
condensation
NH 2 NH2
0 0 0 0 0 OH OH OH OH 0
polyketide
11
Cl
CH3
chlorination
NH2
NH2
OH OH
Cl
l' hydroxylation
NH2
NH 2 OH 0 0
OH OH Chlorteteracycline
Tetracycline
Chemical studies on chlortetracycline revealed that controlled catalytic hydrogenolysis
selectively removed the 7-chloro atom and so produced tetracycline. This process was patented
by Conover in 1955. Later tetracycline was obtained from fermentation of Streptomyces spp.
But the commercial supply still chiefly depends on hydrogenolysis of chlortetracycline’s.
OH 0 0
tetracycline
Tetracycline is a bright yellow, crystalline salt that is stable in air but darken on exposure to
strong sunlight. Tetracycline is stable in acid solution with a PH above 2. It is somewhat more
stable in alkaline solutions than chlortetracycline, but like those of other tetracyclines, such
solution rapidly loss potency. The HCl salt is used most commonly in medicine, though the free
base is absorbed from the GIT about equally well. Tetracycline HCl is also available in ointments
for topical and ophthalmic administration. A topical solution is used for the management of the
acne vulgaris.
Synthesis
hydrogenolysis
►
Zn/HCI
OH 0 0 OH 0 0
Chlorteteracycline tetracycline
Oxytetracycline
Early in 1950, Finlay et, al. reported the isolation of oxytetracycline from S. rimosus. This
compound was soon identified as a chemical analogue of chlortetracycline that showed similar
antibiotic properties.
OH 0 0
oxytetracycline
Oxytetracycline, pale yellow, amphoteric base is only slightly soluble in water and slightly
soluble in alcohol. It is odorless and stable in air but darken on exposure to strong sunlight. The
HCl salt is stable yellow powder that is more bitter than the free base.
Synthesis
nitration
OH 0 0 OH 0 0
tetracycline
c3 ci1
-
I
N
C:
a.
C:
g
0
:]
hydroxylation
◄
NaNO3+ HCI
OH 0 0
oxytetracycline
Doxycycline
CH 3
I
OH N-CH3
OH
OH 0 0
doxycycline
Doxycycline was first reported by Stephens et al in 1958. It was first obtained in small yield by a
chemical transformation of or, but it is now produced by catalytic hydrogenation of
methacycline.
Absence of the 6-hydroxyl group produces a compound that is very stable in acids and bases
and that has a long biological half-life. In addition, it is absorbed very well from GIT, thus
allowing a smaller dose to be administered.
High tissue level is obtained with it and unlike other tetracycline, doxycycline, apparently does
not accumulate in patients with impaired renal function. Therefore, it is preferred for uremic
patients with infection outside the urinary tract. Its low clearance may limit its effectiveness,
however, in urinary tract infections (UTI).
It is available as hydrate salt, a HCl-salt solvated as the hemi-ethanolate, hemihydrate and or
monohydrate the hydrate form is sparingly soluble in water and is used in a capsule.
Synthesis
CH3 CH3
I I
CH2 OH N-CH3 OH N-CH3
OH Raney nickel OH
OH 0 0 OH 0 0
Methacycline doxycycline
Degradation
OH 0 0
Chlortetracycline Chlorteteracycline
Chlortetracycline undergoes two chemical degradation

1- Epimerization
It involves the dimethylamine group (-N(CH3)2) at C-4 -N(CH3)2 group moves from back of
plane to front of plane and 5-10% biological activity is lost.
2- Degradation
Chlortetracycline undergoes three types of degradation
a- Reductive degradation
When Chlortetracycline is treated with zinc and acetic acid under mild condition, the
dimethylamine group is eliminated to form des-dimethyl-amino-Chlortetracycline, which is
converted to naphthacene by zinc dust distillation.
Mild
Chlortetracycline desdimethylamin oxytetracycline

N
::::,
Dl
::::,
a.
0
:r:
(")
0
0
:r:
ccco
naphthacene
,0
Zn dust
heat
OH O OH 0
deoxydesdimethylamine oxytetracycline
b- Alkaline degradation (Enaization)
After alkaline treatment third ring is broken down to form enol form. The product is called iso
Chlortetracycline. This iso-derivative undergoes epimerization at C-4 at PH 2-6 to form 4-epi-
isooxytetracycline.
strong alkali
chlortetracyclin
4-epi-isochlortetracycline
c- Acid degradation
At vigorous and exposure dehydration of Chlortetracycline occurs through a reaction involving
the 6-OH group and the 5ahydrogen. The double bond thus formed between positions 5a and 6
induce a shift in position of double bond between C-11 and C-11a to form inactive 6-anhydro
Chlortetracycline derivative which cause Fanconi’s syndrome.
Thus 6-anhydroderivative undergo epimerization at C-4 to form 4-epi,6-anhydro
Chlortetracycline derivatives which are four-time toxic than 6-anhydro derivatives.
Tetracycline
Tetracycline like chlortetracycline, contains -OH group at C-6 and shows degradation similar to
that of chlortetracycline.
Oxytetracycline
CH 3
I
N-CH3
OH
OH 0 0
oxytetracycline
Degradation pathways of oxytetracycline are like that of chlortetracycline.

Epimerization in oxytetracycline and doxytetracycline, epimerization at position-4 is less than
5% due to the presence of -OH group at C-5a compared to chlortetracycline and tetracycline
which lack -OH group at C-5.
Doxycycline
OH 0
doxycycline
Due to absence of 6-OH group, it is much resistant to acids and bases, so there is no formation
of iso and anhydro derivatives 4 and 6-epimerization is less common.
Methacycline
OH 0
methacycline
Due to absence of -OH group at C-6 methacycline is much more resistant to both acids and
bases, preventing the formation of iso-derivatives by bases but anhydro derivatives are still
possible by acids.
4-epimerization is less common due to the presence of -OH group at C-5.
Minocycline
OH 0
minocycline
The absence of -OH group at C-6 makes the minocycline resistant to acids and bases and so
anhydro or enolized forms are much less common.
4-epimerization is possible.
SULPHONAMIDE
INTRODUCTION:
The compound p-aminobenzene sulphonamide now known as
sulphonilamide, was first synthesized by Gelmo in1908 as an intermediate in the study of azo
dyes Gerhard Domayk in 1935 screened a no of these azo dyes for their antibacterial effect and
observed that they were active against streptococci in 1935, a German firm prepared a red dye
4-sulphonamide-2’,4’-diamin-benzene or p’-sulphonyl Chrysoidine and after three years
Domayk suggested significant curative properties of this compound and named it prontosil.
Trefoil et at Pasteur institute discovered that prontosil breaks down in the tissues to p-
aminobenzene sulphonamide, now known as sulphonilamide and suggested that the
antibacterial characteristics of drugs resided in this part of the molecule.
Mechanism of action of sulphonamide
Folic acid is an essential growth factor for humans. It has to be supplied from outside
intracellularly, it is reduced to dihydrofolic acid and then to tetrahydrofolic acid by the enzyme
folic acid reductase tetrahydrofolic acid undergoes further complex structural changes to form
the co factor for one carbon transfer enzymes requires for the synthesis of purine nucleotide in
both humans and microbes. Since folic acid is an essential metabolite for humans, it has be
supplied from outside. However, microbes synthesize their own requirement of dihydrofolic
acid. This is then converted to tetrahydrofolic acid which is then converted to various cofactors
of one-carbon transferases.
Microbes are not able to utilize the preformed folic acid of the host because it requires
as enzyme for its transport across the bacterial cell wall which it lacks. The microbes utilize
hydroxymethyldihydropterin for the synthesis of dihydrofolic acid.
Dihydroxymethyldihydropterin is converted to its pyrophosphate which reaction with p-
aminobenzoic acid (PABA) is converted to dihydropteroate. This iin presence of dihydrofolate
synthetase reacts with glutamic acid to give dihydrofolate. The dihydrofolate is then converted
to tetrahydrofolate acid by dihydrofolate reductase and the tetrahydrofolic acid to various
cofactors.
Sulphonamide inhibits the dihydropteroate synthetase while trimethoprim inhibits the
dihydrofolate reductase so a combination of these two drugs (e. g co-trimoxazole in septran)
block these two successive steps of DNA synthesis.
Folic acid (folic acid reductases) dihydrofolic acid (FA reductases) tetra hydrofolic acid
FOLIC ACID REDUCTIONAL PROCESS:
Hydroxymethyldihydropterin (dihydropeterin + pyrophospokinase) pyrophosphate
[ dihydropeteroate
J
Glutamic acid
Dihydrofolate synthase
Dihydrofolic acid
Trimethoprim block DHFR Dihydrofolate reductases
( NADPH --+ NADP)
[_!_]
Tetrahydro folate
-
Various co-factors of one
carbon transferase
Protein synthesis
D DNA
synthesis
sulphonilamide ( NaNo2/ HCL + 1OC ) diazotized sulphonilamide + P-benzylenediamine = prontosil
(reduction) sulphonilamide
Interestingly it has been observed that prontosil is absolutely inactive in vitro but possess superb and
excellent antimicrobial activity in vivo.
 Fuller (1937) further substantiated and confirmed by isolating free sulphonamide from blood
and urine of subjects been treated with prontosil.
 In 1937, two British researchers prepared sulphapyridine that was indeed the first and foremost
structural analogue of sulphanilamide. This particular compound proved to be a grand and
tremendous in curing pneumonia. This magnificent discovery, infarct, paved the flood gates for
the synthesis and screening of hundred of derivatives of sulphanilamide, but only a few have
retain the glory of being potent medicinal compounds.
CLASSIFICATION of sulfonamide
PHARMACOLOGICAL CLASSIFICATION CHEMICAL CLASSIFICATION
 For systemic use  N1-substituted sulphonamides.
Short acting: sulfadiazine Sulfa pyridine, sulfathiazole, sulfadiazine
Intermediate: sulfisoxazole
Long acting: sulfamethoxazole
 For GIT use  N4-substituted sulphonamides
Sulfasalazine Prodrugs which require change to N4-
unsubstituted form to show activity.
Sulfasalazine
 For topical use
Sulfacetamide
MECHANISM OF ACTION:
 Bacteria cannot absorb folic acid from medium which is required for growth and reproduction.
In contrast, human cells obtained from diet as vitamins.
 So bacteria has to synthesize folic acid inside the cell using para amino benzoic acid PABA with
the help of certain enzymes.
 Sulphonamide being structural analogue of PABA inhibits the pathway of folic acid synthesis and
growth of bacteria becomes arrested
PABA dihydropteroate synthetase dihydro folic acid DHF reductase
Tetrahydro folate purine DNA

 Sulphonamides inhibits the dihydropteroate synthetase whike trimethoptim inhibit the
dihydrofolate reductases. So the combination of these two drugs (septrun) blocks the two
successive steps of DNA synthesis and results into bacterial action.
CLINICAL USES:
ORAL: acute complicated urinary tracts infections, respiratory tract infections.
TOPICAL: burn, sepsis, wounds, conjunctivitis, colitis, enteritis, intestinal infection.
I/V: patients unable to take orally especially with meningitis.
ADVERSE EFFECTS:
 Allergic reactions: rashes, fever, purpura, agranulocytosis, aplastic anemia, serum sickness
 Crystalluria
 G-6-PD deficiency
 Git upset, stomatitis , headache
Structure activity relationship

The molecular modification of sulphonamides have resulted into about 10000 compound of
only less than three dozen have attained therapeutic significance.
The nitrogen of sulphonamide group is designated as N1 of that of aniline as N4
Isomeric form of sulphonamide
The ortho or meta isomers i.e orthonilamide or metanilamide as well as corresponding isomer
of N- hetrocyclic derivative are antibacterially inactive both in vivo or invitro.
Some metanilamide have been proved effective as antimalarial e.g 3-metanilamide-5-
chloropyramide is 16 times more active against plasmodium gallinaecum than quinine or
sulfadiazine
Substitution on benzene ring
In general any Substitution of the nucleus of sulphonamide leads to complete loss of activity or
diminished. This effect is related to mechanism of action which require a basic amine group
that should be free to conjugate sulfan group e.g 3-carboxyhydrazide is active only
aganist staphylococcus or pneumococcus in vitro.
Replacement of SO2 group

The antibacterial activity lies in SO2 group or any addition or removal at SO2 group or even SO3
will result in total loss of antibacterial activity
Replacement of 4 amino group
If an alkyl an alkoxy or other functional group is placed in the para-position no activity is
observed. So any permanent Substitution at N4 results in loss of antimicrobial activity. So 14
amino group at position 4 is responsible for the antimicrobial activity of sulphonamide
Prodrugs can be formed by attacking at functional group at N4 which can be hydrolyzed in body
to resume free NH2 state again necessary for antibacterial activity
N4 acetylation with dicarboxylic acid such as succinic acid or phthalic acid yield sulfonamide
which are not absorbed in small intestine to yield free active form of drug allowed to act locally.
Other example N4 succinyl sulfathiazole, sulfasalazine, N4 pthnyl sulfathiazide.
Sulfonamides are weak Acids they will form Salt with base.
N1 Substitution derivatives .
The substitution of N1 amide nitrogen with various groups results in a wide fluctuation in activity and is
the most important type of modification that has been used in the design of antibacterial sulfonamides.
Sulfonamides which have non substituted or mono-substituted N1-amides nitrogen are acidic and will
readily form salts. The maximum activity usually shown by those compounds having a pk2 of about 6.7
Activity diminishes if the compound are either more are less acidic. N1 Acetylation of N1 heterocyclic
substituted sulfonamides gives a less soluble compounds. The acetyl group is removed in the intestinal
tract to yield the free and active drug. This type of modification has been drug used to decrease the
bitter taste when the drug is used in suspension for pedriatic administration.
Following are different N1 substitution

Sulfonamides which are more active clinically when compared to sulfanilamides. For example
 Sulfonamides SNM:
 Very soluble in water 1:125
 Should be given with NaHCO3.
 More effective against skin infection.
 Sulfadiazine: SDZ
 When one of H-atom of N1 is substituted by pyrimidine resultant is sulfadiazine which is 10

times more potent than SNN.
 It is less soluble in water than SNM but can crystallize in kidney due to high acidic level.
So should be given with N2HCO3.
 Sulfamerazine SMZ.
 The addition of –CH3 group in pyrimides of SDZ result in SMZ which is 5 times more active than
SNM.
 Sulfamethazine:
 It is dimethylated subsititution of SDZ. Its activity is compareable to SNM.
 Very soluble in water.
 Sulfapyridine:
 It is water soluble and it is 1:3500 > SMZ
 It is copareable to SDZ in efficancy but is more toxic than SDZ in term of crystallurea
 Sulfamethiazole 1:2000
 Its oral absorption is adequate and more potent than SNM.
 Sulfisoxazole:
 Also effective against G-ve bacteria
 Sulfmethoxazole:
 Its oral absorption is less than sulfisoxazole but efficacy is similar to it but larger half life.
 Sulfacetamide:
 It is very much soluble in water. It is used in opthalmic

infection.
 Sulfaguanidine:
 It is not well absorbed orally and used for GIT infection.
 Sulfathiazole:
 It shows moderate solubility in water and relatively low toxicity.

Two stages
Anti viral drugs 1, Lytic cycle (Master slave relationship)
2. Lysogenic cycle (Host guest relationship)
Introduction:
Viruses are obligate parasites having the operational characteristic of an exogenous submicroscopic unit
capable of multiplication only inside specific cell.
In general viruses are essentially made up of a nucleic acid core having either deoxyribonucleic acid DNA
or RNA that provides the genetic material and also forms the basis for classification of viruses.
The viruses may be conceived as particle attaching themselves to particular receptors of the susceptible
cells. These receptors may be chemical configuration that combine e- either virus or allied substances of
similar composition. After due attachment the viruses gain entry into the cell and subsequently multiply.
Thus the newly constituted viruses are eventually released from the cell to parasitize other cells of the
host. In such transformation on the metabolic activity of the host cell is modified in the same manner.
Classification of Transformation
Viruses in general, utilize only the enzyme-system of the host-cell for two purposes namely: first, to
synthesize DNA and secondly, to replicate virus, thereby enabling it to perform their usual metabolic
activities. They may carry out either the transformation or the replication processes of the cell at the same
time.
By virtue of the fact that viruses are obligate intracellular parasites, therefore, their replication
phenomenon solely depends on the host’s cellular processes.
Classification
Antiviral drugs are broadly classified on the basis of their specific mode of action as stated before.
1. Agents that inhibit the early stages of the viral replication ( inhibit viral DNA chain growth) (e.g.
amantadine, interferon)
2. Agents that interfere with the viral nucleic acid replication (e.g. acyclovir, idoxuridine,
ribavirin)
3. Agents that effect translation on cell ribosome (e.g. methisazone, Arildone) so no capsid
formation
Replication
A good no. of antiviral drugs exerts their effect against DNA viruses either by interfering with their
replication due to its similarity of structure to the nucleotide structure in natural DNA viruses or by
interfering with nucleic acid replication of virus, significantly inhibiting the early steps in DNA synthesis.
DNA Nucleotides
The building blocks of nucleic acids are nucleotides. Nucleotides that compose DNA are called
deoxyribonucleotides. The three components of a deoxyribonucleotide are a five-carbon sugar called
deoxyribose, a phosphate group, and a nitrogenous base, a nitrogen-containing ring structure that is
responsible for complementary base pairing between nucleic acid strands. The carbon atoms of the five-
carbon deoxyribose are numbered 1ʹ, 2ʹ, 3ʹ, 4ʹ, and 5ʹ (1ʹ is read as “one prime”). A nucleoside
comprises the five-carbon sugar and nitrogenous base.
H2N
HO-P-0
0
I
11
o-
< N
0
OH H
phosphate deoxyribose base OH H
sugar
deoxyribose
(a) (b)
The deoxyribonucleotide is named according to the nitrogenous bases (Figure 2). The nitrogenous
bases adenine (A) and guanine (G) are the purines; they have a double-ring structure with a six-
carbon ring fused to a five-carbon ring. The pyrimidines, cytosine (C) and thymine (T), are smaller
nitrogenous bases that have only a six-carbon ring structure.
pyrimidines purines
0
II
_......C......_ /CH3
HN C
I II
~C......_ _......CH
0,:9" N
H
cytosine thymine (in DNA) adenine guanine

C T A G
Individual nucleoside triphosphates combine with each other by covalent bonds known as 5ʹ-3ʹ
phosphodiester bonds, or linkages whereby the phosphate group attached to the 5ʹ carbon of the sugar
of one nucleotide bonds to the hydroxyl group of the 3ʹ carbon of the sugar of the next nucleotide.
Phosphodiester bonding between nucleotides forms the sugar-phosphate backbone, the alternating sugar-
phosphate structure composing the framework of a nucleic acid strand.
During the polymerization

0
process, deoxynucleotide II
triphosphates (dNTP) are used.
HN
.,,..c,C / CH3
To construct the sugar- I T II
phosphate backbone, the two ~c, .,,..cH
o::7 N
terminal phosphates are H
released from the dNTP as a o- NH3
pyrophosphate. The resulting 1 0 II
-o- P-o-cV 0
C
strand of nucleic acid has a free II
0
N~ 'CH
phosphate group at the 5ʹ I c II
~c, .,,..cH
carbon end and a free hydroxyl o::7 N
group at the 3ʹ carbon end. The ester bond -
H
two unused phosphate groups 0

I 5'
from the nucleotide -o - P-0-C 0
phosphodiester 0
triphosphate are released as bond 4'
pyrophosphate during
phosphodiester bond ester bond
formation. Pyrophosphate is OH 1
subsequently hydrolyzed, I
-o- P-o
II
- - -c 5
releasing the energy used to 0
drive nucleotide
polymerization.
OH
NORMAL BASE PAIRING MONO AND BICYCLIC RINGS
(b)
Cytosine Guanine Thy mine Adenine
1) ACYCLOVIR 9-[(2-hydroxy ethoxy methyl guanine)]
MODIFIED GUANINE
SYNTHESIS:
Dioxolane + acetic chloride or 2acetic acid molecules → Dioxolane acetylated
Guanine + acetic chloride → acetylated guanine
Dioxolane acetylated + acetylated guanine → (condensation with NaOH) removal of 1 acetic acid mol.
+ Acetylated Acyclovir → hydrolysis and Acyclovir
It is the most effective of series of tricyclic nucleoside that possess antiviral activity. The clinically useful
antiviral spectrum of acyclovir is limited to herpes viruses. It is the most effective (in vitro) against HSV-
Type1 about 2 times, less against HSV-ii and 10 times less potent against varicella zoster virus. An
advantage is that uninfected human cells are unaffected by the drug.
Mode of Action: we modified the sugar molecule

➢ Acyclovir is easily converted to active acyclovir monophosphate within cells by viral
thymidine kinase. This phosphorylation reaction occurs faster by cells infected by herpes virus
than the normal cells because acyclovir is a poor substrate for normal cell thymidine kinase.
Acyclovir is _further converted to di and triphosphate by a normal cellular enzyme called
guanosine monophosphate kinase.
➢ Viral DNA polymerase is competitively inhibited by acyclovir triphosphate at lower
concentrationthan in cellular DNA polymerase. Acyclovir triphosphate is incorporated into viral
DNA chain during DNA synthesis. Because acyclovir triphosphate lacks 3'-hydroxyl group,
no 3',5'- phosphodiester bond can form. It terminates further elongation of DNA chain.
➢ Preferential uptake of acyclovir herpes infected cell as compared to uninfected cell result in
higher concentration of acyclovir triphosphate, which leads to a useful drug to toxicity ratio of
herpes infected cells to normal cells.
2) Ribavirin:
Ribavirin is a purine nucleoside analogue with a modified base a D-ribose sugar moiety. It has
broadspectrum antiviral activity against both DNA and RNA viruses.
Mode of Action: we modified the nucleotide molecule and inhibit base

pairing with the double chain of DNA
It is phosphorylated by adenosine kinase to ribavirin triphosphate resulting in the inhibition of viral
specific RNApolymerase, m-RNA of nucleic acid synthesis.
USES:
It is highly active against influenza A and B and the parainfluenza group of viruses, genital herpes zoster
measles and acute hepatitis A, B and C. It also inhibits HIV-1 which is involve in AIDS.
SYNTHESIS
Pentagonal molecule (triazole carboxylate) + ribose sugar R=COCH3(acetylated sugar)→ Condensed
structure of these 2 molecules → amination, react with ammonia (ammonium hydroxide) → carboxamide
group obtained→ hydrolysis→ Ribavirin
0
3) Tromantadine HCL:
BICYCLIC STRUCTURE, 6 AND 8 MEMBER RINGS
A ~r'"·
4j
HN~ O
ca,
It is used to treat herpes simplex virus. It is available in a topical

gel. Its performance is similarto acyclovir.
TWO MECHANISM:
1. It inhibits the early and late events in the virus replication cycle. It changes the
glycoprotein ofthe host cells, therefore impaired the absorption of virus. It inhibits
penetration of the virus. It also prevents uncoating of the virus. NO BINDINDING NO
PENETRATION
2. ALSO INHIBIT THE EARLY AND LATE STAGES OF VIRAL REPKICATION

Β-Lactam Antibiotics (Penicillin).
Even though penicillin had been discovered in 1928, and is a member of B-lactam antibiotic, the
term B-lactam antibiotic has to wait till 1942 to get registered in the dictionary of medicinal
chemists. Thanks to prof. Howard W. Florey and Dr. Ernst B. chain, working at that time at the
William Dunn school of pathology, Oxford with their sincere efforts, isolated and characterized
the basic structure of penicillins. This work was supplimented by the efforts of chemists Dr.
Abraham and Dr. Heatley. The clinical effectiveness of penicillin was first tested on 12
February, 1941 in the form of a sodium salt.
Aeyl Side Bct:c1•L:1ct:m1 I hlazolldJne

Chain
Ri:t1:;:, Ring
,. H
~ c N c , COOH
O Gencr:tl Stl'ucture of Penicillins
• Thus long after the antibiotic projected its appearance on the screen of research, the
structure of penicillin was determined.
• Thus penicillin can be considered as the amino derivatives of the 6-aminopenicillenic
acid.
• In the basic skeleton, a thiazolidine ring (A) is fused with a Beta-lactam ring (B) which is
a 4-membered cyclic amide.
• The penicillins differ from each other in antibacterial and pharmacological characteristics
due to variation in the structure of acid moiety of the amide side chain at C-6. After about
45 years of clinical use, remain an extremely effective and the only natural penicillin
used clinically.
• Acylation of 6-APA with appropriate carboxylic acids resulted in new penicillins, some
of which are broad-spectrum antibiotics.
Stereochemistry:
1. Penicillin molecule contains 3 assymetric carbon atoms such as C-3, C-5, C-6.
2. All naturally occuring and active synthetic and semisynthetic penicillins have the same
absolute configuration at three asymmetric centers.
3. The carbon atoms bearing the acylamino group C-6 has the L-configuration, whereas the
carbon to which COOH group attached has the D-configuration. Thus the acylamino and
carboxyl group are trans to each other.
4. The atom comprising the 6-aminopenicillenic acid portion structure is derived
biosynthetically.
5. The absolute stereochemistry of penicillin is designated as 3S:5R:6R.
Chemistry:
1. The penicillin can be considered as derivatives of the 6-aminopenicillenic acid.
2. The basic skeleton of penicillins consist of the thiazolidine ring which is fused with the
B-lactam ring.
3. The early commercial penicillin was a yellow-brown or red amorphous powder that was
so unstable that refrigeration was required to maintain potency, even for short period of
time.
4. For stability purpose, penicillin is converted into salt form, which is crystalline white in
nature and we can store such penicillin for years without refrigeration, only required
thing is that it should be protected from moisture.
5. The sodium and potassium salts of most of the penicillins are water soluble and readily
absorbed when given by injection or orally, but the less stable, free acid is not suitable for
incorporation into the dosage form.
6. Treatment of penicillins with strong mineral acid or mercuric chloride causes breakdown
of the molecule to penicillamine and a penaldic acid, which are unstable.
7. Alkalies and the specific enzyme penicillinase are more selective in their action,
attacking only the B-lactam ring to yield penicilloic acid causing inactivation.
8. Similar reaction is also shown by alcohols and amines.
9. The strong gastric acid leads to hydrolysis of the amide side chain and opening of the B-
lactam ring, with resultant loss of activity.
DEGRADATION PRODUCTS OF PENICILLINS
Natural penicillins are acid and base unstable. Instability in acid media logically
precludes their oral administration due to the highly acidic pH in stomach. At acidic pH,
a sort of molecular arrangement results. The structure is known as a penillic acid and
loses its activity. Similarly, at basic pH, penicillin molecule gets converted to penicilloic
acid which is again an inactive form. The mechanism of degradation is described below
Degradation of penicillin:
The first step involve the protonation of the B-lactam nitrogen, followed by the
nucleophilic attack of the acyl oxygen atom on the B-lactam carbonyl carbon that results
in opening of both the rings, which leads to the formation of penicillenic acid.
Penicillenic acid is unstable and experiences the two major degradation pathways.
Path-I: Here the oxazolone ring of penicillenic acid undergoes to the hydrolysis to form
unstable penamaldic acid. Penamaldic acid further yields penicillamine and penaldic acid
on hydrolysis. Next step involves the formation of penicilloaldehyde bydecarboxylation
of penaldic acid.
Path-II: The second pathway involves a complex rearrangement of penicillenic acid to a
penicillic acid through a series of intramolecular processes. Penicillic acid upon
decarboxylation and hydrolytic cleavage under acid condition gives rise to penilloic acid.
Path-III: Under weakly acidic or alkaline as well as enzymatic hydrolysis condition,
penilloic acid is formed, which is not observed as intermediate under strongly acidic
condition. However, it is known to exist in equilibrium with penamaldic acid and
undergoes decarboxylation in acid to form penilloic acid.
Certain strains of microorganisms can destroy beta-lactam antibiotics enzymatically. The

enzymes more popularly known as penicillinases or beta-lactamases can open the B- lactam
bond. The difference in the susceptibility to the B-lactamase enzymes depend upon the nature of
the amide side chain at C-6. It also depends upon the bacterial strain involved.
Allergy to Penicillin (Allerginicity)

Approximately 6-8% of the US population is allergic to B-Lactam antibiotics. Most commonly
this is expressed as a mild drug rash or itching and is of delayed onset. Occasionally, the reaction
is immediate and profound (anaphylactic shock). It may include cardiovascular collapse and
shock and can result in death. Sometimes, penicillin allergy can be anticipated by taking a
medication history, and after the patient who are likely to be allergic are those who have history
of hypersensitivity to a wide variety of allergens (e.g foods and pollens). When an allergic
reaction develops the drug must be discontinued, and because cross sensitivity is common, other
B- lactam drugs(cephalosporin) should generally be avoided. Considering all therapeutic
categories, penicillin, especially the ones most commonly employed (benzylpenicillin and
ampicillin/amoxicillin) are probably the drugs most associated with allergy. Erythromycin and
clindamycin are ester alternate choices for therapy in many cases of penicillin allergy.
In some cases, the patient may have become sensitized without knowing it because of previous
passive exposure through contaminated food stuff or cross-contaminated medications. Penicillin
are manufactured in facilities separate from those used to prepare other drugs to prevent cross-
contamination and possible sensitization. Animals treated with penicillin are required to be drug-
free for a significant time before products prepared from them can be consumed.
Chemical Mechanism of allergy
The chemical mechanism by which penicillin preparation become antigens have been studied
extensively, evidence suggest that
a. Penicillin or their rearrangement products are formed in vivo ( e.g penicillenic acids)
react to lysine amino groups of protein to form penicilloyl proteins, which are major
antigen determinants. Early clinical observations with the biosynthetic Penicillin-G and V
indicated a higher incidence of allergic reactions with unpurified,amorphous preparation
than with highly purified, crystalline forms, suggesting that small amounts of highly
antigenic penicilloyl present in unpurified samples were a cause.
b. Polymeric impurities in ampicillin dosage form have been implicated as possible

antigenic determinants and a possible explanation for the high frequency of allergic
reaction with this particular semisynthetic penicillin. Ampicillin is known to undergo
pH- dependent polymerization reactions (especially in conc. Solutions) that involve
nucleophilic attack of the side chain amino groups of one molecule on B-Lactam
Carbonyl C-atom of a second molecule and so on. The high frequency of antigenicity
sown by ampicillin polymers, together e- their isolation and characterization in some
ampicillin preparations, support the theory that they can contribute to ampicillin-induced
allergy.
Mechanism of Action of Penicillins
Penicillin have a potent and rapid bactericidal action against growing

bacteria. The cell wall of most of gram positive organisms is a complex structure made-up
of variety of polymeric material including lipoproteins ,lipopolysaccharides, techoic acid
and mucopeptide.The mucopeptide is highly cross-linked giant molecule that provide
rigidity to the cell wall. This cross-linked structure is called Murein sacculus.The
carboxyl of NAMA (n acetyle murenic acid) is attached to polypeptide chain which varies
with bacterial species. In case of S.aureaous this chain consists of L-alanine(L-ala),D-
glutamic acid(D-Glu) and D-alanine(D-ala). The glutamic acid linked through r-carboxyl to
the L-amino of L-lys. The murien strands are cross-linked by bridges of 5-glycine units to
form murien sacculus these bridge link to L- amino of L-lys with carboxyl terminal of D-
ala. This cross-linking is carried out by transpeptidase. Before the cross-linking by
pentaglycil units take place the peptide strands from lactate carboxyl of muramic acid unit
terminals in D- ala-D-ala. The terminal D-Ala unit of this strand is cleaved by
transmidase,which is one of the Penicillin-binding Protien(PBP). This enzyme normally
residue in the bacterial inner membrane and perform construction, repair and housekeeping
maintaining cell wall integrity and playing a vital role in cell growth and division.
In order to cleave the terminal D-Ala residue from pentapeptide attatched

to muramic acid,the transmidase(PBP) uses its serine-OH group. After the terminal D-ala
unit is cleaved ,it diffuses away.Next,the tetrapeptide is attatched by the free amino end of
pentaglycl unit in the presence of transpeptidase to crosslink the different strands.The
Penicillins and other B-lactam antibiotics act by acylating. The serum-OH of the
transamidases (irreversible process). The penicillins of the other B-lactam antibiotics have a
structure that closely resembles that of acylated D-Ala-D- Ala enzyme mistakenly accepts the
penicillin as Were its normal substrate. The highly strained B-lactam ring is much more
reactive than a normal amide moiety, particularly when fused into the appropriate bicyclic
system. The intermediate aryl-enzyme complex however, is rather different structurally from
the normal intermediate in that the hydrolysis does not break penicillin into two pieces, as it
does with its normal substrate. In the penicillins, a heterocyclic residue is still covalently
bonded and cannot diffuse away as the natural terminal D-ala unit does. This represents a
steric barrier to approach by the nearly pentaglycyl unit and therefore keeps the enzyme’s
active site from being regenerated and the cell wall precursors from being cross-linked. The
resulting cell wall is structurally weak and is subjected osmotic stress. Cell lysis can result and
the cell rapidly dies, assisted by another class bacterial enzyme, the autolysis
Muramic acid
Penicilin From Code 432

Beta-lactam
antibiotics
Antibiotics that possess the beta-lactam (a four-membered cyclic amide) ring structure are the
dominant class of agent currently used for the chemotherapy of bacterial infection.
While lactams are the internal cyclic amides which are formed by L-cysteine and L-valine.
Lactams are of two types
1- Beta-lactam: 4-membered lactam is called beta-lactam.

2- Alpha-lactam: 3-membered lactam is called alpha-lactam.
Usually beta-lactam antibiotics are derived from two types of amino acids.
efo
0
HH N
H
beta-lactam alpha-lactam
Amino acids with lesser member of primary amine and -COOH groups, give rise to 3-membered
ring called alpha-lactam.
Amino acid with higher number of primary amine and -COOH group give rise to 4-membered
beta-lactam ring.
Beta-lactam is the carbonyl derivative of azetidine which are cyclic amide.
0
HH +
6 0
H~
penam
beta-lactam
Saturated thiophene
0
HH +
6 0
µ -=u s
Unsaturated thiophene
beta-lactam unsaturated thiophene penem
Penicillinsn (beta
lactams)
Penicillin was the first antibiotic to be used therapeutically obtained from the fungus penicillium
notatum. Over 30-penicillins have been isolated from fermentation mixtures some of these occur
naturally; others have been biosynthesized by altering the culture medium to provide certain
precursors that may be incorporated as acyl groups. Commercial production of biosynthetic
penicillin today depends chiefly on various strains of penicillin notatum and P. chrysogenum.
In recent years many more Penicillins have been prepared semi synthetically.
General properties
The early commercial penicillin was a yellow to brown amorphous powder. Its stability was
maintained in a refrigerator. Now white crystalline powder material is produced by improved
procedure. Purified Penicillins are odorless, white or cream colored crystalline powder and
strongly dextro-rotatory.
TAUTOMERSIMS
0
Beta lactam (4 member cyclic amid ring)
11
Beta lactim (4 members cyclic amidic ring)
L N IH
Alpha lactam (3 member cyclic amid ring) C/_ -- l actam 13-lac t a m
Alpha lactim (3 member cyclic amidic ring)
Structure (MONO BASIC ACID)

The Penicillins are commonly named as penams (without double bond), a designation in which
the S-atom is given the top priority.
PENAM
The basic structure of all penicillin is substituted 6-carboxyamide penicillenic acid. This
penicillin nucleus consists of a fused thiazolidine ring A and β-lactam ring B (both form penam)
with a 6- carboxamide derivative chain C. Penicillin differ chemically in the acid moiety of the
amide chain. Variation in this moiety results in different physical, chemical and antibiotics
activities. All Penicillins are monobasic acids that readily form salts and esters.
R -C- HN CH
II )-rS--r( 3
0 f-N~ CH3
0 COOH
PENCILLANIC ACID
6-CARBOXYAMIDE
Stereochemistry of penicillin (8 STERIO STRUCTURES)

The penicillin molecule contains three chiral C-atom (C-2, C-5 and C-6). All naturally occurring
and microbiologically active synthetic and semisynthetic Penicillins have the same absolute
configuration about these three centers. The carbon atom bearing the acyl-amino group (C-6) has
the L-configuration, whereas the carbon (C-2) to which the carboxylic group is attached has the
D- configuration. Thus, the acyl-amino and carboxyl groups are trans to each other with the
former in the alpha and later the β-orientation relative to the penam ring system.
CLASSIFICATION
Natural penicillin Semisynthatic Semisynthatic Semisynthatic Semisynthatic

penicillinase penicillinase penicillinase penicillinase
resistant resistant (oral) Sensitive sensitive (Oral)
(Parenteral) (Parenteral)
penicillin G nafcillin cloxacillin carbenicillin amoxicillin
Penicillin V methicillin Oxacillin ticarcillin ampicillin
dicloxacillin
SAR of penicillin
PENICILLIN
Any change in the arrangement by rupturing β-lactam ring / thiazolidine ring R-HN results in
complete loss of antimicrobial activity.
1. 6-amino west end substitution
• The design and development of the west end substituents has been aimed at strengthening
various weakness which have traditionally hampered Penicillins in terms of activity,
stability, resistance and absorption/ distribution.
• The C-6 amino moiety itself is necessary for appreciable antibacterial activity, but
substitution of the amine via monoacylation can offer much more potent congeners.
• The addition of an electron attracting group into amide linkage increases the stability of
penicillin in gastric acid.
• The addition of oxygen in the side-chain of benzyl penicillin (Penicillin-G) results in

Penicillin-V which has different pharmacokinetics and toxic properties from Penicillin-G.
Penicillin-V is well absorbed from GIT but more toxic to liver as compare to Penicillin-G.
0- 0 -H C-
2
C -HN
0II ~~CH33
CH 0- H C-
2
C-HN
II
0 ~~CH33
N
CH
N 0 COOH
0 COOH
penicillin-v penicillin-G
• The addition of -NH2 group in penicillin-G at -CH2 group of amide chain results into
ampicillin, which has broad spectrum antibacterial than parent compound and is better
absorbed from GIT than penicillin-G and V.
0-
-
HC ~ C -H N
I
NH2 0
11 y----i-- S--(:.CH 3
}---N----\ CH3
0 COOH
AMPICILLIN
• Addition of -OH group at para-position in ampicillin results in amoxycillin which is more
better absorb from GIT due to increase water solubility and has antimicrobial spectrum
like that of Ampicillin.
0 - Q - ~ H9 ~ CH3
~ - HNr r S--r(CH3
H - NH2 0 _f-N~ COOH
0
AMOXICILIN
• The spectrum of activity was further expanded with introducing strong acidic groups at the
alpha- carbonyl center of the side chain, e. g removal of NH2 group and addition of -COOH
group in amoxicillin gives carbenicillin which is acid labile and can’t be given as such
orally. It has broad antimicrobial spectrum than any other penicillin, attributed to its unique
-COOH group.
~ H 9~ CH3
~ - HNr rS--r(CH3
~ =9 O _f-N~ COOH
OH 0
CARBENCllllN
• Agents that were stable to penicillinase enzymes were created by introducing a more
crowded environment group beta lactam moiety e.g replacement of benzyl group in
penicillin-G with dimethoxy benzene results into the formation of Methicillin which is
penicillinase resistant. It retains the good activity but show less GIT absorption
1- If one -OCH3 group is removed, its 50% biological activity is lost.

2- Addition of ethoxy group instead of methoxy ones, creates no change in
antimicrobial activity but toxicity increases.
OCH3 CH
Q- OC~3
3
~ - HNr rS--r(CH3
Of -N~COOH
METHICILLIN
2. Substituents at Sulphur
Sulphur is the only atom at position-1 of the penicillin in order to retain appreciable antibacterial
activity.
C-2 substituents
The germinal dimethyl group at C-2 is characteristics of penicillin.

C-3 substituents
Esterification of -COOH at C-3 results in total loss of activity in type of penicillin.
Variation at N-4
The N-atom at the ring junction is vital for antibacterial activity. The N-atom contribute to the
reactivity of the beta-lactam ring. If the beta-lactam is disrupted by beta-lactamase, penicilloic acid
is produced which is pharmacologically inert and have no antimicrobial activity.
Chemical degradation
Hydrolysis: first stable degradable part Penicillenic acid

The main cause of deterioration of penicillin is the reactivity of the lactam ring, particularly to
hydrolysis. The cause of the hydrolysis and nature of the degradation product are influenced by
the PH of the solution. Thus, the beta-lactam carbonyl group of penicillin readily undergo
nucleophilic attack by water (or especially) hydroxide ions (-OH) to form the inactive penicilloic
acid, which is reasonably stable in neutral to alkaline solutions but readily undergoes
decarboxylation and further hydrolytic reactions in acidic solution. Other nucleophiles, such as
hydroxylamine, alkyl-amines and alcohol, open the beta-lactam ring to form the corresponding
hydroxamic acids, amides and esters.
It has been speculated that one of the causes of penicillin allergy may be the formation of antigenic
penicillolyl proteins in vivo by the reaction of nucleophilic groups (e. g amino)
Acidic degradation
In strongly acidic solutions (PH less than 3), penicillin undergoes a complex series of reactions
leading to a variety of inactive degradation products. The first steps appear to involve rearrangement
to the penicillenic acid. This process is initiated by protonation of the beta-lactam nitrogen,
followed by nucleophilic attack of the acyl oxygen atom on the beta-lactam carbonyl carbon. The
subsequent opening of the beta-lactam ring destabilize the thiazoline ring, which than also suffers
acid-catalyzed ring opening to form the penicillenic acid. The latter is very unstable and experience
two major degradation pathways. The most easily understood path involves hydrolysis of the
oxazolone ring to form the unstable penamaldic acid. Because it is an enamine penamaldic acid
easily hydrolyzes to penicillamine ( a major degradation product) and penaldic acid. The second
path involves a complex arrangement of penicillenic acid to a penillic acid through a series of
intramolecular processes that remains to be elucidated completely.
Penillic acid (an imidazoline-2-carboxylic acid) readily decarboxylated and suffers hydrolytic ring
opening under acidic condition to form a second major end product of acid catalyzed penicillin
degradation, penilloic acid.
R
C HN ~CH3
O y-i--- CH3
0 j -N- COOH
penicillin
~ 8
HN
penicillic acid R
C
11 ')-----i--::;S --r<.CH3
CH 3 H2N) = r - ~ CH3
CH3
O ,,9 N~COOH
O OH
N COOH
CH - N H- CH-
I COOH
0 .d
HN-{' HS y - CH3 ~ penicilloic acid 6-amrn
. o-pencillinic ac,
R ---(o
_~ 0 CH3
peocillao;c acid \
H- C= C H- NH- CH-COOH
I
R- C-
II N CI OOH HS C-CH3
I
0 CH 3
HOOCL_ -S CH3
dd
7
/ l ::; --r(.CH3
N'y N- - - \COOH
R .d
penicillic acr
0
11
R- C-NH- C,H -C
OHH
0II CQ
penaldic acid
penacillamine
lo
R- C- NH- CH2 CH
II
0
II
penalloic acid
. ·11oaldehyde
penrcr
Alkaline degradation
Penicilloic acid, the major product formed under weakly acidic to alkaline (as well as enzymatic)
hydrolytic conditions, can’t be detected as an intermediate under strongly acidic conditions. It
exists in equilibrium with penamaldic acid, however, and undergoes decarboxylation in acid to
form penilloic acid. The third major product of the degradation is penicilloaldehyde formed by
decarboxylation of penaldic acid (alpha derivative of malonaldehyde).
By controlling the PH of aqueous solutions within a range of 6.0 to 8.0 and refrigerating the
solutions, aqueous preparations of the soluble Penicillins may be stored for up to several weeks.
Temperature affects the rate of deterioration although the dry salts are stable at room temperature
and don’t require refrigeration, prolonged heating inactivates the penicillin.
Acid catalyzed degradation in the stomach contributes strongly to the poor oral absorption of
penicillin substitution of an electron withdrawing group in the alpha-position of benzylpenicillin
markedly stabilizes the penicillin to acid catalyzed hydrolysis. Thus, phenoxymethylpenicillin,
alpha-aminobenzylpenicillin and alpha-halobenzylpenicillin are significantly more stable than
benzylpenicillin in the acid solutions. The increased stability imparted by such electron-
withdraw groups have been attributed to decreased reactivity (nucleophilicity) of the side chain
amide carbonyl oxygen atom towards participation in beta-lactam ring opening to form
penicillenic acid.
Bacterial
resistance
Some bacteria in particular most species of gram-negative bacilli, are naturally resistant to the
action of penicillin. Other normally sensitive species can develop penicillin resistance. The best
understands and probably the most important biochemical mechanism of penicillin resistance is
the bacterial elaboration of enzyme that inactivates penicillin. Such enzymes are given the name
penicillinases, are of two general types i. e beta- lactamases and acylases.
i. Beta-lactamases catalyze the hydrolytic opening of the beta-lactam ring of penicillin to

produce inactive penicilloic acids (staphylococcus aureus).
ii. Specific acylases, enzymes that can hydrolyze the acyl-amino side chain of penicillins,
have been obtained from several species of gram-negative bacteria, but their possible role
in bacterial resistance has not been well defined.
iii. Another important resistance mechanism especially in gram-negative bacteria, is

decreased permeability to penicillin. The cell envelop in most gram-negative bacteria is
more complex than in gram-positive bacteria. It contains an outer membrane which
creates a physical barrier to the penetration of antibiotics, especially those that are
hydrophobic. (porins)
Certain strain of bacteria is resistant to the hydrolytic properties of penicillin but remain
susceptible to their growth inhibiting effects. Thus, the action of the antibiotic has been converted
from bacteriocidal to bacteriostatic. This mechanism of resistance is termed tolerance.
Allergy to penicillin
Allergic reaction to various Penicillins, ranging in severity from a variety of skin and mucous
membrane rashes to drug fever and anaphylaxis, constitute the major problem associated with
the use of this class of antibiotics.
The chemical mechanisms by which penicillin preparations become antigenic have been studied
extensively. Evidences suggest that Penicillins or their rearrangement product formed in vivo
(e. g penicillenic acids) react with the lysine amino group of proteins to form penicilloyl proteins,
which are major antigenic determinants.
Mechanism of action
Beta-lactam are bactericidal antibiotics that act by inhibiting the bacterial cell wall synthesis. Beta
lactam attach to specific penicillin-binding sites(PBP) of bacteria and block the trans-peptidation
of peptidoglycans of the bacterial cell wall then autolytic enzymes of cell wall become activated
and cell wall is lysed.
Therapeutic uses
Penicillin are used to eradicate pneumococcal infections, streptococcal infection,
meningococcal infection, syphilis, actinomycosis, diphtheria, clostridial infection, rat bite fever.
Adverse reaction
Hypersensitivity reaction, diarrhea, nephritis, neurotoxicity, platelet dysfunction, superinfection.
Generic name Chemical name R-group

Penicillin-G Benzyl penicillin
O-cH 2
Penicillin-V Phenoxy methyl penicillin

~ Fo-cH 2-
Methicillin 2,6-dimethoxyphenyl OCH 3

penicillin
Q- OCH3
-
Naficillin 2-ethoxy-1-naphthyl
penicillin
Oxacillin 5-methyl-3-phenyl-4-
~
isoxazolyl penicillin
~ ~l'Q>-CH3
Cloxacillin 5-methyl-3-(2-chlorophenyl)-
4-isoxazolyl penicillin Cl
F\_,,....,
~ ~',o'J- CH 3
Dicloxacillin 5-methyl-3-(2,6-
dichlorophenyl)-4-isoxazolyl
penicillin
Cl
~
y c1 N',o'>- CH,
Ampicillin D-alpha-amino-benzyl
penicillin
Amoxacillin D-alpha amino-p-

hydroxybenzyl penicillin
HO 0- CH-
NH2
carbenicillin Alpha-carboxybenzyl-
penicillin
0- CH-
C- OH
II
0
Cephalosporins
Discovery
The cephalosporins are beta lactam antibiotics isolated from cephalosporium spp. Or prepared
semi synthetically.
Giuseppe Brotzu’s epock making discovery in 1945, in the species cephalosporium fungi
obtained from Cephalosporium acremonium showed a remarkable inhibition in the growth of a
rather wide spectrum of both gram positive and gram-negative organisms. Abraham and
Newton (1961) at oxford for the first time not only isolated successfully but also
characterized cephalosporin C. However, the confirmation of this structure was ascertained by
X-ray crystallography.
Inspite of the glaring evidence that cephalosporins C was resistant to S. aureus beta
lactamase besides its prevailing antibacterial activity was inferior in comparison to penicillin-N
and other penicillin structure analogues.
Structure derivative of cephem

Cephalosporins have basic ring cephem, Cephem is active form and beta lactam ring fused with
thiophene ring
0
~)
cepham cephem
Typically, naturally acting Cephalosporins are Cephalosporins-N (Penicillin-N) and

Cephalosporins-C.
Cephalosporins-N has the 6-amino penicillanic acid ring with alpha-amino-adipoyl side chain at
C-6.
n
C= alpha-amino adipoyl side chain
A= beta lactam ring
~ # B= thiazolidine ring 5 membered

~OC-HC-H C-H C-H C-C-HN
1
NH2
2 2 2 II
0
tr-~N
~-
CH 3
3
0 COOH
penicillin-NI cephalosporin-N
Cephalosporins-C has 7-aminoCephalosporanic acid (7-ACA ) ring and alpha-amino adipoyl side
chain at C-7.
n
C= aminoadipoyl side chain
A= beta lactam ring B= dihydro meta-thiazine ring (thiopyrone)
~OC-HC-H C-H C-H C-C-HN

I
NH
2 2 2 II
O
n -. ,
)=£ S /
H
I 2
O
II
2
0 Nyc . . c'o . . c'CH3
COOH
CEPHALOSPORIN C
7-amino cephalosporinic acid cephalosporic acid
cephalosporin
C-7 has L-configuration while C-4 has D-configuration so the amino side chain and -COOH group
are trans to each other with former in alpha and latter in beta-position relative to cephem ring.
Classification
Based on
discovery, spectrum and
resistance to beta lactamase
enzyme
cephalosporin
First generation cephalosporins:
These drugs have the highest activity against gram-positive bacteria and the lowest activity against
gram negative bacteria
Generic name R R1
Cephalexin
Cefadroxil -CH3
H0-0---{-
NH2
Cephradine -CH3
~~H2
Cephalothin
G-- ✓
0
II
S C -CH2·0-C-CH3
H2
Cephacetrile N=C-CH2- 0
II
-CH2·0-C-CH3
cefazolin N-7'-N-CH
, 2- N-N
k==N
-H 2C-S
A S)>--cH3
Second generation cephalosporins:
These drugs are more active against gram-negative bacteria and less active against gram-positive
bacteria than first-generation members.
Generic name R R1
Cefaclor
O-t, -Cl
Cefamandole
O--t -H2C-S
N-N
-1( ,,
N,N
I
CH3
cefuroxime
w O N-O-CH3
0
II
-CH2·0-C-NH2
Third generation cephalosporins:
These drugs are less active than first-generation drugs against gram-positive organisms, but have
a much-expanded spectrum of activity against gram-negative organisms.
Generic name R R1
Cefotaxime
N
-!O-CH3
R
0
II
-CH2·0-C-NH2
H2N--<(5
Ceftizoxime
N
-!O-CH3
R
-H
H2N--<(5
Ceftriaxone H3C ... ,NXOH
/O-CH3 N "
N R
-H2C-S
AN 0
H2N-<(
s
Ceftazidime CH 3
-H2C-N£>
N-O~COOH
N
~ CH,
Cefoperazone
HO
d
H2N,J(_S
O
I I0~
NH_.C ... N O
l_,N-cH2·CH2-
N-N
-H 2c-s---lCN~N
I
CH 3
Spectrum of activity:
The Cephalosporins are considered broad-spectrum antibiotics with patterns of antibacterial
effectiveness comparable to ampicillin. Several significant differences exist, however,
Cephalosporins are much more resistant to inactivation by beta-lactamases, particularly those
produced by gram-negative bacteria, than in ampicillin. Ampicillin, however, is generally more
active against non-beta lactamases producing strains of gram positive and gram-negative bacteria
sensitive to both it and the Cephalosporins among beta-lactam antibiotics, exhibit uniquely
potent activity against most species of Klebsiella.
Structure of activity (SAR of cephalosporin)

All Cephalosporins are acidic compound as they contain carboxylic acid group.
C=AMINOACYL SIDE CHAIN
Cephem ring substitution
1- Any change in the cephem ring results into complete loss of biological activity.
2- Chelation occurs due to the presence of -COOH group.
3- If carboxylic acid group at P-4, substituted with any other group, the biological activity of
entire cephalosporin family is lost e. g if -COOH group is replaced with
carboxamide (CONH2) than about 50% biological activity is lost.
4- Oxidation of ring Sulphur to sulphoxide or sulphone greatly diminish or destroy the
5- Replacement of SULPHUR with OXYGEN leads to oxacepam (latamoxef) with increased
antibacterial activity because of its enhanced acylating power. Similarly, replacement of
Sulphur with methylene group (loracarbef) has greater chemical stability and a longer half-
life.
6- The carboxyl group of P-4, has been converted into ester prodrug to increase bioavailability
of cephalosporin and these can be given orally as well, e. g cefuroxime axetil, cefdoxime
proretil.
7- Olefinic linkage at C-3-4 is essential for antibacterial activity. Isomerization of the double
bond to 2-3 position leads to greater losses in antibacterial activity.
7-Acylamino substituents
1- Acylation of amino group generally increases the potency against gram positive bacteria,
but it is accompanied by a decrease gram-negative potency.
2- High antibacterial activity is observed only when new acyl groups are derived from
carboxylic acid for gram positive bacteria.
3- Substituents on the aromatic ring phenyl that increases lipophilicity provide higher gram-
positive activity and generally lower gram-negative activity e. g cefadroxil, cefoperazone.
4- The phenyl ring in the side chain can be replaced with other heterocycles with improved
spectrum of activity and pharmacokinetic properties, these include thiophene, tetrazole,
furan, pyridine and aminothiazole (e. g cephalothin, cephaloridine).
C-3 substituents
The nature of C-3 substituents influence pharmacokinetic and pharmacological properties as well
as antibacterial activity. Modification at C-3 position has been made to reduce the degradation
(lactone of desacetyl cephalosporins) of cephalosporins.
1- The benzoyl ester displaces improved gram-positive but lower gram-negative activity.
2- Pyridine imidazole replaced acetoxy groups show e.g cephaloridine improved activity
against P. aeruginosa.
3- Displacement with aromatic thiols of 3-acetoxy group result in enhancement of
activity against gram-negative bacteria with improved pharmacokinetic properties.
4- Replacement of acetoxy group at C-3 position with -CH3, Cl has resulted in orally active
compound.
Synthesis of cephalothin and cephaloridine
reflux H2Nr-7s~
nitrocyl chlon'de J--N '('cH2 OCOCHa acetoxy/

O COOH methyl group
CEPHALOSPORIN C
7-AMINO- PORINIC ANID
CEPHALOS
0-
S
C-CI
H2C--II
0
0N
0- H2C -C-HN
II ls
0- H2C--II
c-HN ls -
S O p:: .o CH 2 OCOCH3
s O p::-" CH,-ND
O COOH
O COOH
CEPHALOTHIN
CEPHALORIDINE
Cephalosporin C is isolated on an industrial scale by fermentation using cephalosporium

acremonium.
Cephalosporin-C
A= B lactam ring
B= Dihydro meta Thaizine ring
C= aminoadipoyl side chain
Synthesis of cephalexin
H2O2 oxidation acid
acetate
hydrolysis
catalyst
penicillin v
cephalexin
Chemical degradation
Degradation by beta-lactamases
R-C-HN
0 rrJ S
~,H
OJ---N~C-R
beta-lactamase
--0--®-----1►-
R-C-HN
o r-(~
.?o~ HN,
s
'° c-R
COOH OH/ H30 cooi!il2 ""'- degradation
cephalosporin beta-1. cephalosporic acid ~
actarr,
ase
0 -"" fermentation
Ol-/1 ,_, ® 9001 / ' and
•iJo no activity
R-C-HN-HC----(0 rearrangement
0 N
~ CH 2
products
COOH
nhydro-des-acetyl-cephalosporic acid
anhydro-des-acetyl-cephalosporic
Degradation by acylase
desacelylation actonization
R-C-HN s acylase H2 N r - ( s l 'd' d't'
8 o)=ryl~~R _w_a_t-er----►► 0)----N~~~R ac, ,coo,::., ,on H,Ngsl ~H
COOH COOH O ~f
o:::.C-O
cephalosporin
7-amino cephalosporinic acid des-acetyl- 7-amino-
cephalosporanic acid lactone
By strong acidic condition
R-C-HN
0 rrJ s
~,H
OJ---N~C-R
acidic condition
solvolysis
R-C-HN
►
O rr~~,Hs
OJ---N, .0 C-OH
H
® R-C-HN
► 0
o
g~, ~c
S
~,H
cephalosporin
COOH COOH
desacetyl cephalosporin
O=C-d
desacetyl cephalosporin
lactone
Cephalosporins experience a variety of hydrolytic degradation reactions whose specific nature

depends on the individual structure. Among 7-acylaminocephosporanic acid derivatives, the
3-acetoxylmethyl group is the most reactive site.
➢ In addition to its activity to nucleophilic displacement reaction, the acetoxyl function of

this group readily undergoes solvolysis in strongly acidic solutions to form the
desacetylcephalosporin derivatives. The latter lactonize to form the des
acetylcephalosrporin lactones, which are virtually inactive.
➢ The 7-acylamino group of same cephalosporins can also be hydrolyzed under enzymatic
(acylase) and possibly non-enzymatic condition to give 7-ACA (or 7-ADCA) derivatives.
Following hydrolysis or further solvolysis of the 3-acetoxymethyl group, 7-ACA also
lactonizes under acidic conditions.
➢ The reactive functionality common to all cephalosporins is the beta-lactam. Hydrolysis of
the beta-lactam of cephalosporin is believed to give initially cephalosporic acid (in which
the R’-group is stable, e.g R’=H or S. heterocycle) or possibly
anhydrodesacetylcephalosporic acid (for the 7-acylaminocephalosporanic acid). It has not
been possible to isolate either of this initial hydrolysis protuct in aqueous systems.
Apparently, both type of cephalosporic acid undergo fragmentation reactions that have
not been characterized fully.
Beta-lactamase resistance
The susceptibility of cephalosporins to various lactamases varies considerably with the source and
properties of these enzymes. Cephalosporins are significantly less sensitive than all but the beta-
lactamase resistant penicillin to hydrolysis by the enzymes from S. aureus and bacillus subtilis.
The penicillase resistance of cephalosporins appear to be a property of the bicyclic cephem ring
system rather than of the acyl group. Despite natural resistance to staphylococcal beta-lactamase,
the different cephalosporins exhibit considerable variation in rates of hydrolysis by the enzyme. e.
g cephalothin and cefoxitin are most resistant and cephaloridine and cefazolin are two least
resistant.
Some inducible beta-lactamases belonging to group-C, however, are cephalosporinases which

hydrolyze cephalosporin more rapidly inactivation by by beta-lactamases is an important factor in
determining resistance to cephalosporins in many strains of gram-negative bacilli.
➢ The introduction of polar substituents in the amino acyl moiety of cephalosporin appears
to confer stability to some beta-lactamases. E. g cefamandole and cefonicid contain an
alpha-hydroxyphenylacetyl (or mandoyl group) and ceforanide has an o-aminophenyl
acetyl groups are resistant to a few beta-lactamases.
➢ Steric factor also may be important because cefoperazone, an acylureidocephalosporin
that contain the same 4-ethyl-2, 3-dioxy-1-piperazinyl-carbonyl group present in
piperacillin, is resistant to many beta-lactamases.
Two structural features confer broadly based resistant to beta-lactamase among the cephalosporin.
❖ An alkoximine function in the aminoacyl group

❖ A methoxyl substituent at the 7-position of the cephem nucleus having alpha-
stereo-chemistry PRODUCTS
1- Cephalexin, USP
Cephalexin, 7-alpha (D-amino-alpha-phenyl acetamide)-3-methyl cephem carboxylic acid) was
designed purposely as orally active, semisynthetic cephalosporin. The oral inactivation of
cephalosporin has been attributed to two causes, instability of beta-lactam ring to acid hydrolysis
and solvolysis and microbial transformation of 3-methylacetoxy group. The alpha-amine group of
cephalexin renders it acid stable and reduction of the 3-acetoxy methyl is a methyl group
circumvents reaction at that site.
Cephalexin is freely soluble in water, resistant to acid and absorbed will orally.
2- Cephradine, USP
It is the only cephalosporin derivative available in both oral and parental dosage forms. It is also
stable to acid and absorbed almost completely after oral administration.
3- Cefadroxil, USP
It is an orally active semisynthetic derivative of 7-ADCA, in which 7-acyl group is the D-
hydroxylphenlglycyl moiety. This group is absorbed well after oral administration. It has
advantage of somewhat prolonged duration of action, which permits, once-a-day dosing. The
antimicrobial spectrum of action and therapeutic indications of cefadroxil are very like those
of cephalexial and cephradine.
4- Cefaclor, USP (Ceclor)

It is an orally active semisynthetic cephalosporin that was introduced in the American market in
1979. It differes from cephalexin in that the 3-metyl group has been replaced by a chlorine atom.
It is synthesized from the corresponding 3-methylenecepham sulfoxide ester by ozonolysis,
followed by halogenation of the beta-ketoester.
It is moderately stable in acid the antibacterial spectrum of activity is similar to that of cephalexin
but it is claimed to be ignore potent against some species sensitive to both agent.
5- Cephalothin sodium,USP
It is freely soluble in water and insoluble in most organic solvents. Its spectrum of activity is
broader than that of penicillin-G and more similar to that of ampicillin. Unlike ampicillins, it
is resistant to penicillinase produced by S. aureus.
It is poorly absorbed from GIT and must be administered parenterally for systemic infections.
6- Cefazolin sodium, sterile, USP

It is active by parenteral administration.
7- Cefamandole nafate, USP

It is the formate ester of cefamandole, a semisynthetic cephalosporin that incorporates D-mandelic
acids as the acyl portion of a third containing heterocyclic in place of the acetoxyl function or the
C-3 methylene carbon atom. Esterification of the alpha-hydroxyl group of the D-mandeloyl
function overcomes the instability of the cefamandole in solid state dosage form and provide
satisfactory concentration of parent antibiotic in vivo through spontaneous hydrolysis of the ester
at neutral to alkaline salt, this D-mandeloyl moiety appears to confer resistance to a few beta-
lactamases.
8- Cefoxitin sodium, sterile, USP

It is a potent competitive inhibitor of many beta-lactamases.
ANTIMALARIALS
Malaria remains the world’s devastating human infection with 300-500 million clinical cases and
nearly 3 million deaths each year. It is caused by several species of the protozoan plasmodium, of
which p.vivax, p.falciparum are the most common . They all have complex life cycle involving
both the Anopheles mosquitos and erythrocyte of the human host. In vivax, a persisting tissue
phase continues to infect the blood at interval for many years. thus, an ideal antimalarial should
not only eradicate the microzoam from the blood but also from the tissue to effect radical cure.
The several antimalarial differ in their point of interruption of the cycle of the parasite and in the
type of malaria affected. Following human infection caused by the bite of an infected anopheles
Plasmodium parasites accumulate in the hepatocytes and then invade the erythrocyte for the next
stage of their maturation. after a few days, the infected RBC’s burst, open and the merozoites are
released causing periodic fever of malaria. these merozoites infect new erythrocytes and the intra-
erythrocytic cycle start again within the erythrocytes of the host the parasite degrades. Hb and
digest 30% or more of protein moiety using it as a source of amino acid for the synthesis of its
own protein. the resulting free potentially toxic haeme (ferriprotoporphyrin ix ) left after digestion
is polymerized to a microcrystalline , redox inactive iron ( 3 ) haeme pigment called hemozoin (
non-toxic).
CLASSIFICATION OF ANTIMALARIALS:
PHYSIOLOGICAL CLASSIFICATION:
1. Sporontocides:
Drugs that are capable of killing the sporozoits as soon as they are introduced into the blood
stream by bite of mosquito.
2. Exo-erythrocytic schiznoniocides/ tissue schizontocide :
These drugs kill the parasite as it exists in the schizoint stage in either primary or secondary
erythrocytic form. These drugs eradicate the organism before it enter the RBCs.
3. Erythrocytic schizontocides:
These drugs kill the parasite when it is multiplying in RBCS.
4. Gametocytocides:
These drugs act on the sexual form of parasite.
5. Sporontocide:
These drugs act on the sporogenic forms in the mosquito.
CHEMICAL CLASSIFICATION:
• Cinchona alkaloids: Quinine, cinchonine
• 4-amino-quinolines: Chloroquine, amodiaquine, sontoquine
• 8-amino-quinolines: Pamaquine, primaquine
• 9-amino acridines: Mepacrine
• Biguanides: Proguanil
• Pyrimidines: Pyrimethamine
• Sulfones: Dapsone
Cinchona Alkaloids:
Cinchona alkaloids are obtained from cinchona bark. The crude drug contains of some 20-alkaloids of
which only 4-atom most important clinically.
-Quinine -Quinidine
-Cinchonidine -Cinchonine
Quinine was the first cinchona alkaloids to be extracted. However, cinchonine was the first to be
employed clinically but second to be extracted.
3
9cH,
/b.·
s y
/; /, r
...
N
1'
2·
R o bane
N
Quinoline nucleus quinuclidine nucleus RUBANE
Chemistry:
These alkaloids are said to be RUBAN derivatives, which contains quinoline nucleus & quinuclidine
nucleus which are condensed together.
➢ 3-vinyl-6’-methoxy-9-rubanol a quinine and quinidine is its diastereoisomer
➢ 3-vinyl-9-rubanol is cinchonidine & its diastereoisomer is cinchonine.
Cinchonidine Quinidine
Quinine
H O , ,,
cinchonine
Structure Activity Relationship (SAR of Cinchona Alkaloids)
These are five major functional groups changes on which can cause variations in the activity of
derivatives.
a) Quinoline Nucleus:
➢ Any changes brought to the positions 2’, 3’, 5’, 7’ & 8’ of the quinoline nucleus will not cause the
complete loss of activity but there will be a drastic(sudden) loss in the therapeutic activity.
➢ Substitution on position 6’ is important
e.g., quinidine and quinine have a –OCH3 group at position 6’ of quinoline nucleus which makes
the compounds more potent therapeutically than the ones which lack 6’ –OCH3 group.
b) 6’-methoxy Group
➢ If the –CH3 moiety is the methoxy group at position 6’ is replaced by
-C2H5, THERE WILL BE NO DIFFERENCE IN ACTIVITY, however the compound will
become more toxic.
_ replacement of 6’ – methoxy group with alkyl ethers forms the comp which are often more
active than parent comp.
c) 9-hydroxyl group and diastereoisomers:
1. –oh group at c-9 is considered to be important for antimalarial activity

2. If the –oh group is replaced by -H Almost 90% activity is lost.
3. Replacement of C-9, –oh group with halogens also cause loss in the activity.
4. C-8 and C-9 unsaturation resulting from loss of –oh group causes loss of activity.
5. C-9 ketone and acetoxy derivatives are almost 50 % less active than parent compound e.g:
cinchoninone which is more safer than quinidine but higher doses are required to achieve
therapeutic level which render it more toxic and clinically unsuitable cinchoninone.
6. Replacement of –oh group with –CN causes no loss in activity but daughter comp become
extremely toxic.
stereochemical changes at C-9 & C-8 result into diastereoisomers which differ in activity
• Quinine & quinidine are diastereoisomers & quinidine is about 1/2 half active as quinine against
P.relictum but twice as active against P.gallinaceum. It is somewhat more active than quinine
against both P.vivax and p.falciparum
• Cinchonine and cinchonidine are diastereoisomers differing at position 9 and 8
• Interferences at C-9 only resulting epiquinine and epiquinidine leads to a loss of antimalarial
activity
11,co
Epiquinine structure Epiquinidine struture

d) Quinuclide Nucleus
If any change is brought about in the quinuclidine nucleus there is loss of activity e.g. quinotoxins and
dihydroquinicinols are inactive due to breakdown of bond between N and C8. So N1 and C8 bond is must
for antimalarial activity.
quinotoxins structure
dihydroquinicinols structure
(e) 3-Vinyl Group
• Reduction of C-3 vinyl group does not have a profound effect on antimalarial activity of quinine
and related alkaloids
• Oxidation of C-3 vinyl group to -CooH forming Quinetenine destroys all activity but
esterification of -CooH restore the activity. But the corresponding amides are in active
• Ozonolysis of quinine give3-aldehyde i.e. quinimal which is still active as an antimalarial
Mechanism of action
Quinine is known to depress many enzyme systems
Quinine attack to plasmodial DNA this interfering with nucleic acid synthesis by preventing replication
and transcription
Pharmacological action
1- Antimalarial action: quinine primarily act as blood schizotocide against four malarial parasites. It
has no effect on sporozoal or liver stages of parasites. The drug is gametocidal for P.vivax and
P.ovale but not for P.falciparum
Semi-synthetic Drugs:
4- Amino quinolines:
• Chloroquine
• Santoquine
• 4-amino quinoline
• Hydroxy chloroquine
• Amodiaquine
SAR of 4 aminoquinolines:
• 7- halo substituted compounds particularly 7-chloro derivatives are the most active
• Chloro- substitution other than 7-position or sifting of chlorine from 7- position to others
reduces or abolishes the activity
• If CL is replaced by descending halogen activity is lost down the group gradually
• If aliphatic chain at position-4 is replaced by other groups activity is lost
• Substitution of –ch3 group on c-8 causes a complete loss of activity
• Substitution of –ch3 group on c-3 reduces the activity e.g chloroquine becomes
santoquines which is less effective
• If one of C2H5 group in chloroquine is converted to alcohol , the compound becomes
hydroxychloroquine with better solubility and absorption , reduces toxicity but activity is
almost same .
• If both C2H5 group are converted to alcohol , 50% activity is lost
Mechanism of Action;
• Chloroquine bocks the enzymatic synthesis of DNA and RNA in both mammalian and
protozoal cells
• It forms complex with DNA that blocks replication or transcription to RNA
• Being a weak base, it concentrates to high level in acidic food vacuole and raise PH of
these organelles of sensitive material parasite. Acidic PH is necessary for parasitic
inversion. Selective toxicity of chloroquine against malarial parasite depends upon drug
concentrating process in paracitized RBC’s.The concentration of chloroquine in
paractized RBC’s is 25 times more than that of in normal RBC’s
TOXICITY AND ADVERSE EFFECT :
• Gastrointestinal upset, anorexia
• Headache, malaise, vertigo, convulsion
• Urticaria, pruritis, loss of hair pigment
• Ototoxicity
• Retinopathy- blurred vision
• Blood dyscrasian, hypotension
8-Aminoquinolines
Pamaquine (synthetic antimalarial)
Primaquine (more active)
SAR of 8 aminoquinolines
• If methoxy group (-OCH3) at Position 6 is replaced by basic alkyl group (CH3 or C4H5)
activity is lost completely.
• If methoxy group at Position 6 is replaced by "H", 20% activity is lost completely.
• If methoxy group is replaced by phenyl group comp becomes toxic.
• If methoxy group is shifted from Position 6 to Position 2, 3, 50% therapeutic activity is
lost.
• If halogenation is done at P-6 comp becomes toxic to live but activity remains same.
• If OH group is added to one of the ethyl group of side chain, activity is lost.
• If both ethyl groups of side chain are replaced with hydrogen.
• Primaquine is formed which is more clinically active but more toxic to spleen.
• If both terminal ethyl groups are replaced with methyl group, Pentaquin is formed which
is less active than Primaquine.
• If aliphatic chain is shifted to P-4, activity is lost.
• Therapeutic activity of comp is maximum when aliphatic chain has 4-6 carbons. No
activity is seen if carbon number is less than 4 and less activity is seen if carbon number
is more than 6.
• If pyridine nucleus is replaced by pyridine or pyrazine, this comp losses activity.
Clinical Uses
Adverse Effects
9-Aminocridines
Mepacrine (quinacrine) Acridine nucleus (little antiseptic and anti bacterial activity)
6-aminoacridines contain acridine nucleus which is pyridine with two aromatic rings
SAR of 9-Aminocridines
9-aminoacrdine → 2,9-diamino-acrdine →cloro-2,9-diamino acridine → mepacrine(maximum
antimalarial activity)
Cl
MEACRINE Azacrine
• Acridine nucleus itself has little antiseptic and antibacterial activity but no anti-malarial
activity.
• Di-amino acridine has high anti-septic properties but no anti-malarial activity.
• 6 chloro-substitution of diamino acridine gives little malarial activity.
• By adding -OCH3 group at position-2 maximum antimalarial activity is obtained in
aminochloroacridine nucleus e.g mepacrine.
• By increasing the length of terminal alkyl amino-groups, toxicity can be reduced.
• If -Cl is changed with -Br, both activity as well as toxicity decrease.
• If amino group is acetylated, activity is lost.
• When aliphatic chain is lost activity is lost.
Clinical uses And Anti-Malarial Activity

• Mepacrine is used to treat black water fever where quinine is contraindicated. But
mepacrine is being disfavored due to yellow coloration of skin and eyes caused by it.
Chloroquine has replaced it.
• It is inactive against sporozoites of pro-erythrocytic form of all malarias.
• It is highly effective against the asexual blood forms of all specie of Plasmodia and
produce clinical care.
• It is excellent suppressive agent against all species of Plasmodia but it is incapable of
achieving a radical cure in vivax malaria.
Adverse Effects
• Gastrointestinal distress in the form of abdominal cramps, nausea, vomiting and diarrhea.
These symptoms disappear with continued use of drug.
• Mental disturbance such as extreme depression to extreme.
• Yellow skin and eye coloration.
Biguanides
Proguanil or chiloguanil
SAR of biguanides
• If cl atom is replaced by Br, no change in the activity but toxicity is increased.
• The addition of another cl atom e.g (Bromoglionide chloroprogunide) in the benzene
ring, cause the increase in the therapeutic activity and little increase in the toxicity but
this addition is not considered because it is quickly eliminated.
• If cl is replaced by methyl, ethyl or methoxy group, therapeutic activity decrease
• If one of the terminal CH3 is substituted by C2H5, compound will be very toxic to the
liver cell.
• If the amine (NH-) groups are replaced by other functional groups (like-R), there is
decrease in toxicity of therapeutic activity lies on 2nd guinidine group.
• If guinidine groups are replaced by basic alkyl radical, 50% loss of activity occurs. But if
simultaneous loss of group occurs, complete loss of activity take place.
• Guinidine group is replaced by urea or thiourea group, no activity is seen.
Clinical uses
Substituted compound
Toxicity x y
Proguanil -cl -H
Chlorophroguanil -cl -cl
Bromoguanide -Br -H
Sulfones
Sulfones or diaryl sulfones represent a major cell of drugs used to treat leprosy, also called
Hensen’s disease and is among the oldest which cause suffering to men. The initial discovery of
sulfonamides resulting from studies about SAR of sulfones. It has antibacterial activity but less
then sulfonamides. It is used in Rickteside and malarial injection.
Its mechanism of action is similar to sulfonamide because PABA partiality antagonizes the
action os sulfones.
Several sulfones have proved useful in the treatment of leprosy but depsone is more useful.
Others are Rifampin, Clofazimine, Thalidomide
Depsone
Parenteraal molecule DDS or Depsone
/4,4’-diamin, diphenyl sulfene
SAR of sulfones
Therapeutic activity lies in amino group both ring
1. If –SO2 group is removed, activity is
2. If –SO2 group is acetylated, activity becomes less toxic
3. If one/both –NH2 groups are changed –NO2 activity remains same but compound
becomes hemolytic.
4. If –SO2 group is substituted by any group antimalarial and antibacterial activity is lost
but antileptic activity remains same
5. If 1st structure of despone is changed into thiazole sulfone, it is active but less then
despone
6. If sod. Acetyl nitrile sulfinate is added on P-6,it becomes aceto sulfones which has less
activity and GIT disturbance occur
7. If sod. Methane sulfinate is attached to 4,and 4’ it becomes sulfoxone sodium and it
becomes water substituted form of depsone.
Example Sulfoxone sodium

Contents
PRACTICAL NOTEBOOK........................................................................................... 0
IMPORTANT DEFINITIONS ........................................................................................ 1
Experiment No. 1............................................................................................................. 5
Determine the percentage purity of known concentration of Acetyl salicylic acid ..... 5
Experiment number: 2 ..................................................................................................... 8
Determine the percentage purity of unknown concentration of Acetyl salicylic acid . 8
Experiment number: 3 ................................................................................................... 11
Determine the percentage purity of known concentration of Mefanemic acid.......... 11
Determine the percentage purity of unknown concentration of Mefanemic acid....... 14
Determine the percentage purity of known concentration of Sulfadimidine
(Sulphonamides)......................................................................................................... 17
Determine the percentage purity of unknown concentration of Sulfadimidine
(Sulphonamides)......................................................................................................... 20
Determine the percentage purity of known concentration of Benzyl Penicillin
Theory: ....................................................................................................................... 23
Determine the percentage purity of unknown concentration of Benzyl Penicillin
Theory: ....................................................................................................................... 26
Synthesis of Methyl Salicylate (Methyl 2-hydroxybenzoate) ................................... 29
Experiment number: 10 ................................................................................................. 31
Synthesis of 3-Nitro phthalic acid .............................................................................. 31
Experiment No. 11: ....................................................................................................... 33
Synthesis of sodium salicylat ..................................................................................... 33
Experiment No. 12: ....................................................................................................... 35
Synthesis of Paracetamol ........................................................................................... 35
Pictures of All Apparatus: ............................................................................................. 37
1
IMPORTANT DEFINITIONS
1. Volume Analysis. It is the branch of quantitative analysis in which volume of a solution which
completely reacts with a definite volume of the other solution is practically determined in the
presence of an indicator.
2. Titration. It is the process of determining practically the volume of a solution which completely
reacts with a definite volume of the other solution in the presence of an indicator.
3. Titrant. The solution which is take in the burette.
4. Titrand or Titrate. The solution which is taken in the conical flash.
5. Indicator. It is a chemical substance which tells us about the completion of a chemical reaction
in a volumetric analysis by a sharp color change e. g Phenolphthalein, Methyl orange etc.
6. End Point. It is the point at which reaction is complete. It is indicated by the change of color of
the indicator used.
7. Standard Solution. A solution of known molarity is called standard solution e. g 0.1M NaOH
solution.0.05M H2SO4 etc.
8. Primary Standard. It is a standard solution of a stable substance. Its molarity is taken as
standard as it is weighed accurately and does not absorb moisture e. g oxalic acid, succinic acid
etc.
9. Secondary Solution. The solution of which exact molarity is determined by comparing with the
primary standard. These substances cannot be weighed accurately as they absorb moisture e. g
NaOH, KOH etc.
10. Molarity. It is the number of moles of solute dissolved per dm3 of solution.
Molarity= No. of moles of solutes / Vol of solution in dm3
11. Strength. It is the amount of solute contained in one dm3 of the solution. Its unit is gram/dm3
Strength/dm3=Molarity × Molecular mass
12. Concordant Reading. The burette reading which is exactly alike.
13. To standardize a solution. It means to find out its strength by titrating the it against some
standard solution.
14. Normality. It is the no. of gram equivalent weight of solute per liter of solution normality is
analogue to molarity.
Normality=No. of equivalent of solute/ No. of liters of solution
15. GENERAL FORMULAS USED IN VOLUMETRIC ANALYSIS
(i) M1V1/n1 = M2V2/n2

Where, M1= Molarity of solution No.1 V1= Volume of solution No.1
n1= No. of moles of solution No.1
M2= Molarity of solution NO.2 V2= Volume of solution No.2
N2= No. of moles of solution No.2
(ii) For dilution only M1V1 = M2V2
(iii) Strength/dm3 = Molarity × Molar mass
2
(iv) %age purity= [Calculated amount (in gm/dm3) / dissolved amount (in gm/dm3)] ×100
16. ACID BASE TITRATION

It is the branch of volumetric analysis in which an acid is titrated against the base.
17. Basicity of Acid. It is the number ionizable H+ ions from one molecule of an acid in aqueous
solution e. g basicity of H2SO4 is 2
18. Acidity of Base. It is the number of ionizable OH- ions of a base in aqueous solution e. g Acidity
of NaOH is 1.
Common indicators in Acid-Base Titrations

Indicator Base (in the Color (in the Acid (in the End Point
titration flask) base solution) burette)
Phenolphthalein NaOH solution Pink HCL, H2SO4, Light pink
or KOH solution CH3COOH,
Oxalic acid e t c
Methyl orange Na2O3 solution, Yellow HCL, H2SO4, red
NaHCO3 CH3COOH,
solution or oxalic acid,
K2CO3 solution succinic acid
solution
Molecular Masses of Acids and Bases

(i) M. mass of Hydrochloric acid HCL= 36.5
(ii) M. mass of Acetic acid, CH3COOH= 60.0
(iii) M. mass of Sulphuric acid, H2SO4= 98.0
(iv) M. mass of oxalic acid dihydrate= 126.0
(v) M. mass of Succinic acid= 118.0
(vi) M. mass of sodium hydroxide, NaOH= 40.0
(vii) M. mass of soda ash, Na2CO3 10H20=106.0
(viii) M. mass of washing soda, Na2CO3=286.0
(ix) M. mass of baking soda, NaHCO3=84.0
(x) M. mass of potassium hydroxide, KOH=56.0
(xi) M MASS of potassium carbonate K2CO3 138
19. Uses of Salicylic Acid:
Salicylic acid is used as a medicine to help remove the outer layer of the skin. As such it is used to
treat warts, calluses, psoriasis, dandruff, acne, ringworm, and ichthyosis.
20. Burette:
A burette is a graduated glass tube with a tap at one end, for delivering known volumes of a liquid,
especially in titrations. It is a long, graduated glass tube, with a stopcock at its lower end and a
tapered capillary tube at the stopcock's outlet.
21. Purity:
The term pure in chemistry means a substance that contains only one element or compound.
Brand Name of Salicylic Acid:` Aspirin
22. Blank Titration:
A blank titration is carried out by titrating a fixed and known concentration of titrant into a solvent
3
with zero analyte. ... This allows the amount of reactive substance within the plain solvent to be
determined and hence allows a determination of the error in future titration experiments using this
solvent.
23. Standard Solution:
A standard solution is a a solution of accurately known concentration prepared from a
primary standard (a compound which is stable, of high purity, highly soluble in water and of a high
molar mass to allow for accurate weighing) that is weighed accurately and made up to a fixed
volume.
24. Pipette:
A small piece of apparatus which typically consists of a narrow tube into which fluid is drawn by
suction (as for dispensing or measurement) and retained by closing the upper end.
25. Measuring Cylinder:
A Measuring Cylinders / graduated cylinder / cylinder measuring / mixing cylinder is a piece of
laboratory apparatus used to measure the volume of a liquids, chemicals or solutions during the lab
daily work.
Available Measuring Cylinder:
10ml Glass Graduated Cylinder
25ml Glass Graduated Cylinder.
1000ml Glass Grad. Cylinder
26. Watch Glass

A watch glass is a round, concave glass dish used for evaporation in chemistry. It can also be
employed for weighing solids and as a lid for flasks and beakers.
27. Indicator:
A substance that changes color in response to a chemical change. An acid–base indicator (e.g.,
phenolphthalein) changes color depending on the pH
28. Titration:
Titration, process of chemical analysis in which the quantity of some constituent of a
sample is determined by adding to the measured sample an exactly known quantity of another
substance with which the desired constituent reacts in a definite, known proportion.
29. Types of Titration:
• Acid-base Titrations.
• Redox Titrations.
• Precipitation Titrations.
• Complexometric Titrations
30. Büchner funnel:
A Büchner funnel is a piece of laboratory equipment used in filtration. It is traditionally made
of porcelain, but glass and plastic
4
31. Reflux condenser:

Filters. (chemistry) A water-cooled, double walled piece of laboratory glassware that is fitted on top
of a vessel of boiling liquid such that vapour condenses and flows back into the vessel, preventing
the contents from boiling dry.
32. Filter Paper:
Filter paper is a semi-permeable paper barrier placed perpendicular to a liquid or air flow. It is used
to separate fine solid particles from liquids or gases.
33. Recrystallization:
Recrystallization, also known as fractional crystallization, is a procedure for purifying an impure
compound in a solvent.
34. Conc. H2SO4:
Concentrated sulfuric acid is 98% (18.7M) and is an oily liquid with a density of 1.83 g/cm3. It
decomposes at its B.P (330°C) and forms white fumes. H2SO4 (l) H2O (g) + SO3
35. Phthalic Acid:
Phthalic acid is an aromatic dicarboxylic acid, with formula C6H4(CO2H)2. It is an isomer of
isophthalic acid and terephthalic acid
5
Experiment No. 1
Determine the percentage purity of known concentration of Acetyl
salicylic acid
Apparatus:
Burette with stand
Pipette
Beakers
Funnel
Measuring cylinder and flask
Conical flask
Cotton
Stirrer
Spatula
Watch glass
Burner
Glass rod
Chemicals:
Sample
Distilled water
Sodium hydroxide
HCl
Phenol red
Raw material of acetyl salicylic acid (sample)
Standard Solutions:
0.5N Sodium hydroxide solution (20.00 g/1000.00 ml)
0.5N HCl solution (42.50 ml/1000.00 ml)
Principle:
Acid base titration
Indicator:
Phenol red (Freshly prepared)
End point:
Pale yellow
Chemical equation:
6
+2 NaOH _ _ _ _...,._ ONa
acetyl salicylic acid sodium salt o r sa licylic acid
ONa
OH + 2NaOH
I Iydrolysis
NaOH
NaOH + HCI NaCl + H20
Procedure:
Preparation of 0.5 N NaOH solution:
Take 20.0 g of NaOH in a beaker and dissolve it with few ml of distilled water.
When it’s dissolved completely, add further distilled water to make final volume 1
litre.
Preparation of 0.5 N HCl solution:
Take 42.50 ml concentrated HCl in a beaker and dissolve it with few ml of distilled
water.
When, it’s dissolved completely, add further distilled water to make final volume 1
litre.
Prearation of Phenol red indicator:’
Dissolve 0.1 g of phenol red in 1.42 ml of 0.2M NaOH solution.
Add 5.0 ml of 90 % alcohol and warm simply.
Lastly add 20 % alcohol to make final volume up to 250.0 ml
Sample titration:
Take I g of raw material of acetyl salicylic acid and dissolve in 50.0 ml of 0.5N NaOH
solution in a titration flask (solution should be clear).
7
Boil the solution for 1 min. and then cool to room temperature.
Add 2-3 drops of freshly prepared phenol red as an indicator.
Titrate the excess of alkali against 0.5N HCl solution, taken in a burette till the end
point is appeared.
Note the volume of HCl used and take three concordant readings.
Blank titration:
Take 50.0 ml of 0.5 N NaOH solution in a titration flask.
Boil the solution for 1 min. and cool to room temperature.
Titrate the solution against 0.5 N HCl solution taken in the burette, using 2-drops of
phenol red as an indicator till the end point is appeared.
Determine the % age of purity of sample by applying following formula:
Observations and calculation:
Sample titration:
Initial Volume (ml) Final Volume (ml) Volume used (ml)
Mean=
Blank titration:
Mean=
𝐃𝐢𝐟𝐟𝐞𝐫𝐞𝐧𝐜𝐞 𝐢𝐧 𝐯𝐨𝐥𝐮𝐦𝐞 𝐱 𝐟𝐚𝐜𝐭𝐨𝐫 𝐱 𝟏𝟎𝟎

% 𝐚𝐠𝐞 𝐩𝐮𝐫𝐢𝐭𝐲 =
𝐖𝐞𝐢𝐠𝐡𝐭 𝐨𝐟 𝐬𝐚𝐦𝐩𝐥𝐞
Factor: Each ml of 0.5 N HCl = 0.04504 g of acetyl salicylic acid

8
Experiment number: 2
Determine the percentage purity of unknown concentration of Acetyl
salicylic acid
Apparatus:
Burette with stand
Pipette
Beakers
Funnel
Conical flask
Cotton
Stirrer
Spatula
Watch glass
Burner
Glass rod
Chemicals:
Sample
Distilled water
Sodium hydroxide
HCl
Phenol red
Raw material of acetyl salicylic acid (sample)
Standard Solutions:
0.5N HCl solution (42.50 ml/1000.00 ml)
Principle:
Acid base titration
Indicator:
End point:
Pale yellow
Chemical equation:
9
+ 2 NaOH - - - - - - . . ONa
acetyl alicyl ic acid sodium salt o f salicyl ic acid
ONa
OH + 2NaOH
Hydrolysis
NaOH
NaOH + HCI
Procedure:
Preparation of 0.5 N NaOH solution:
When it’s dissolved completely, add further distilled water to make final volume 1litre.
Preparation of 0.5 N HCl solution:
Take 42.50 ml concentrated HCl in a beaker and dissolve it with few ml of distilledwater.
When, it’s dissolved completely, add further distilled water to make final volume 1litre.
Preparation of Phenol red indicator:’
Sample titration:
Take I g of raw material of acetyl salicylic acid and dissolve in 50.0 ml of 0.5NNaOH solution in a
titration flask (solution should be clear).
Boil the solution for 1 min. and then cool to room temperature.
Titrate the excess of alkali against 0.5N HCl solution, taken in a burette till the endpoint is appeared.
10
Blank titration:
Take 50.0 ml of 0.5 N NaOH solution in a titration flask.
Boil the solution for 1 min. and cool to room temperature.
Titrate the solution against 0.5 N HCl solution taken in the burette, using 2-drops ofphenol red as an
indicator till the end point is appeared.

Sample titration:
Mean=
Blank titration:
Mean=

Factor: Each ml of 0.5 N HCl = 0.04504 g of acetyl salicylic acid
11
Determine the percentage purity of known concentration of
Mefanemic acid
Apparatus:
Burette with stand
Pipette
Beakers
Funnel
Conical flask
Cotton
Stirrer
Spatula
Watch glass
Burner
Glass rod
Chemicals:
Sample
Distilled water
Sodium hydroxide
Phenol red
Raw material of Mefanemic acid (sample)
Standard Solutions:
Principle:
Acid base titration
Indicator:
End point:
Sharp pink cooler
Chemical equation:
12
0 0
NH + NaOH NH +
mefanemic acid sodium salt of mefanemic acid
Procedure:
Preparation of 0.1N NaOH solution:
Preparation of Phenol red indicator:
Sample titration:
Take 0.5 g of raw material of Mefanemic acid and dissolve with 50.0 ml of ethanol in a titration
flask (solution should be clear).
Warm the solution on water bath to dissolve the sample completely.
The solution is cooled before titration.
Sample is titrated against 0.1 N NaOH solution, taken in a burette till the end point is appeared.
Note the volume of NaOH used and take three concordant readings.

Mean =
13

Factor: Each ml of 0.1 N NaOH = 0.02413 g of Mefanemic acid

14
Determine the percentage purity of unknown concentration of
Mefanemic acid
Apparatus:
Burette with stand
Pipette
Beakers
Funnel
Conical flask
Cotton
Stirrer
Spatula
Watch glass
Burner
Glass rod
Chemicals:
Sample
Distilled water
Sodium hydroxide
Phenol red
Raw material of Mefanemic acid (sample)
Standard Solutions:
Principle:
Acid base titration
Indicator:
End point:
Sharp pink colour
Chemical equation:
15
0 0
NH + NaOH NH +
mefanemic acid sodium salt of mefanemic acid
Procedure:
Preparation of 0.1N NaOH solution:
Preparation of Phenol red indicator:’
Sample titration:
Take 0.5 g of raw material of Mefanemic acid and dissolve with 50.0 ml of ethanol ina titration flask
(solution should be clear).
Warm the solution on water bath to dissolve the sample completely.
The solution is cooled before titration.
Sample is titrated against 0.1 N NaOH solution, taken in a burette till the end point is appeared.
Note the volume of NaOH used and take three concordant readings.
Mean =
16

Factor: Each ml of 0.1 N NaOH = 0.02413 g of Mefanemic acid

17
Determine the percentage purity of known concentration of
Sulfadimidine (Sulphonamides)
Apparatus:
Burette with stand
Pipette
Beakers
Funnel
Conical flask
Cotton
Stirrer
Spatula
Watch glass
Glass rod
Marble sheet
Chemicals:
Sample
Distilled water
Sodium hydroxide
Phenol red
Raw material of Sulfadimidine (sample)
Standard Solutions:
N/10 (0.1 N) Sodium nitrite solution
Principle:
Diazotization reaction
Indicator:
Starch-iodide paste (External indicator)
End point:
Immediately sharp blue color
Chemical equation:
NaN02 + HCI NaCl + HN02

18
5 °C
D iazotization
Kl + HCI KCI + HI
2 HI + 2 HN02 _ _ _ _ ___.
12 + Starch - - - - - ~ ntue Colour
Procedure:
Preparation of 0.1 N Sodium nitrite solution:
Dissolve 6.90 g of NaNO2 in distilled water and make up the volume upto 1000.0 mlwith distilled
water.
Preparation of Starch paste:
Take 2.00 g of ZnCl2 and dissolve in small amount of distilled water.
Dissolve 0.75 g of KI in 5.00 ml of distilled water in a separate beak.
Mix two solutions and add 100.0 ml more distilled water.
Boil the mixture and then add a suspension of starch (5.00 g starch/30 ml water).
Now boil the mixture again for two minutes and cool.
Sample titration:
Take 0.5 g of raw material of sulphonamide drug in the titration flask.
Add 50.0 ml of distilled water and 10.0 ml of concentrated HCl.
Keep the flask in ice bath until the temperature reach below 10. C
Titrate it against N/10 sodium nitrite solution using starch iodide paste as an externalindicator.
The appearance of immediately blue color is the endpoint as the starch paste is smearedon marble
tile.

19
Mean =
𝐕𝐨𝐥𝐮𝐦𝐞 𝐨𝐟 𝐬𝐨𝐝𝐢𝐮𝐦 𝐧𝐢𝐭𝐫𝐢𝐭𝐞 𝐱 𝐟𝐚𝐜𝐭𝐨𝐫 𝐱 𝟏𝟎𝟎

Factor:
20
Determine the percentage purity of unknown concentration of
Sulfadimidine (Sulphonamides)
Apparatus:
Burette with stand
Pipette
Beakers
Funnel
Conical flask
Cotton
Stirrer
Spatula
Watch glass
Glass rod
Marble sheet
Chemicals:
Sample
Distilled water
Sodium hydroxide
Phenol red
Raw material of Sulfadimidine (sample)
Standard Solutions:
Principle:
Indicator:
Endpoint:
Immediately sharp blue colour
Chemical equation:
NaN02 + HCI NaCl + HN02

21
- +
Cl N==N
5 °C
D iazotization
Kl + HCI KCI + HI
2H I + 2 HN02 _ _ _ _ __.
12 + Starch - - - - - ~ Blue Colour
Procedure:
water.
Sample titration:
The appearance of immediately blue colour is the end point as starch paste issmearedon marble tile.
22
Mean =

Factor:
23
Determine the percentage purity of known concentration of Benzyl
Penicillin Theory:
Apparatus:
Burette with stand
Pipette
Beakers
Funnel
Conical flask
Cotton
Stirrer
Spatula
Watch glass
Glass rod
Chemicals:
Sample
Distilled water
Sodium hydroxide
Phenol red
Raw material of Benzyl penicillin (sample)
Standard Solutions:
Principle:
Indicator:
Endpoint:
Chemical equation:
24
0 0
II
H2C-C--NH
II
H2C-C-NH
s s
HO
N HN
OH OH
0 O OH
0 0
benzyl pen icillin pcnicilloic acid
/
" )- O
H
H,C--S::,,,, C-NH-C)-----◊H +
OH
0
0
pcnald ic ac id
penicillamine
Procedure:
water.
Sample titration:
25

Mean =

Factor:
26
Determine the percentage purity of unknown concentration of Benzyl
Penicillin Theory:
Apparatus:
Burette with stand
Pipette
Beakers
Funnel
Conical flask
Cotton
Stirrer
Spatula
Watch glass
Glass rod
Chemicals:
Sample
Distilled water
Sodium hydroxide
Phenol red
Raw material of Benzyl Penicillin (sample)
Standard Solutions:
Principle:
Indicator:
End point:
Chemical equation:
27
0 0
II
H2C-C--NH
II
H2C-C-NH
s s
HO
N HN
OH OH
0 O OH
0 0
benzyl pen icillin pcnicilloic acid
/
" )- O
H
H,C--S::,,,, C-NH-C)-----◊H +
OH
0
0
pcnald ic ac id
penicillamine
Procedure:
water.
Sample titration:
28

Mean=

Factor:
29
Synthesis of Methyl Salicylate (Methyl 2-hydroxybenzoate)
Apparatus:
Round bottom flask
Heating mantle
Reflux condenser
Beakers
Pipette
Buchner funnel
Filter paper etc.
Chemicals:
Salicylic acid… 05.00 g
Methanol… 11.50 g
Conc.H2SO4 02.00 ml
NaHCO3 ……………………………
Ethyl acetate ……………………….
Distilled water ………………
Chemical Equation:
0 0
OH
+ CH30H
(Salicylic Acid) (Methyl salicylate)
Procedure:
Take 5 g of salicylic acid and 11.5 g (14.5 ml) of absolute methanol in a 250 ml roundbottom flask.
To this, add continuously and slowly 2 ml of conc. H2SO4.
Adjust reflux condenser and reflux the reaction mixture on heating mantle for about 2hours.
After completion of the reaction, distil off the excess of methyl alcohol under reducedpressure.
30
Pour the residue into about 250 mL of water in a separatory funnel, and add 10%NaHCO3
solution until all the free acid is removed.
After that extract the methyl Salicylate with ethyl acetate (20×3mL) and combine allupper organic
layers.
Distill off the excess of solvent under reduced pressure to get methyl Salicylate (acolorless oil of
delightful fragrance, “oil of winter green’’).
𝐏𝐫𝐚𝐜𝐭𝐢𝐜𝐥𝐞 𝐲𝐞𝐢𝐥𝐝 × 𝟏𝟎𝟎

% 𝐚𝐠𝐞 𝐲𝐞𝐢𝐥𝐝 =
𝐓𝐡𝐞𝐨𝐫𝐚𝐭𝐢𝐜𝐚𝐥 𝐲𝐞𝐢𝐥𝐝
Observation and Calculation:

Theoretical Yield:
Molecular weight of Salicylic acid = 138 gm
Molecular weight of Na. Salicylate = 160 gm
138 gm of salicylic acid gives = 160 gm of Na. salicylate
3 gm of salicylic acid gives = 160

138×3
= 3.478 gm of sodium salicylate

Actual Yield:
Weight of beaker =
Weight of beaker + Precipitate =
Weight of precipitate = Weight of beaker + precipitate – (Weight of beaker)
=
Uses:
Topical analgesic
31
Synthesis of 3-Nitro phthalic acid
Apparatus:
Round bottom flask
Heating mantle/burner
Reflux condenser
Beakers
Measuring cylinder
Funnel
Filter paper etc.
Chemicals:
Phthalic acid 10.0 g
Nitric acid 15.0 g
Conc.H2SO4 15.0 g
Chemical Equation:
0
CJGo 0
HN0 3 -
H 2S O ,.
q . C0 2 H
I
N 02
C 0 2H
+
N 02
_ . O . . C 02H
C02H
3 - itrophthalic 4- itrophthalic
Phthalic Acid
Acid Acid
Procedure:
Take 10.0 g of phthalic acid in a beaker.
Add 15.0 g of nitric acid and 15.0 g of sulfuric acid gradually and slowly.
Heat the beaker over water bath for 2 hours at a temperature not exceeding than 70.C.
After two hours’ treatment, cool and add 30.0 ml of ice cold water, stir, and filter theprecipitates.
Recrystallization: Dissolve the ppts in 15.0 ml of ice cold water and refilter.
Dry the ppts., weight and calculate the %age yield by following formula:

32
Observation and Calculation:

Theoretical Yield:
Molecular weight of Phthalic acid = ?? gm
Molecular weight of Nitro phthalic acid = ?? gm
??? gm of Phthalic acid gives = ???? gm of Nitro phthalic acid
?? gm of Phthalic acid gives = ???×??

. ???
. = ??? gm of Nitro phthalic acid
Actual Yield:
Weight of beaker =
=
Uses:
As antiseptic
It is used as an intermediate for the synthesis of corrosive inhibitors, medicine andagro chemicals.
33
Experiment No. 11:

Synthesis of sodium salicylat
Apparatus:
Beaker
Stirrer
Burner
Wire gauze
Weighing balance
Chemicals:
Ethanol 10.00 ml ~ OIi ~ ON•
~~
Salicylic acid…………………0.3.00 g -►
Sodium bicarbonate…………. ~ •¥
Distilled water.
Sodium Aoctyl Salicyla1e
Chemical reactions:
At.11\ yJi..ifk'YHt a r.ld
Procedure:
Wash clean and dry the apparatus.
Accurately weigh 3.00 g of salicylic acid and transfer to a beaker which isalready weighed
Add 10 ml of ethanol and 20 ml of distilled water into a beaker.
Add small amount of sodium bicarbonate until effervescent stop.
Warm the solution slowly and then heat to evaporate the solvent on low flame.
Weigh the beaker again.
The weight of the product was calculated by subtracting weight of emptybeaker from the final
weight.
Calculate its %age yield by following formula as:
Observation and Calculation: Theoretical Yield:

34
3 gm of salicylic acid gives = 160×3

138

Actual Yield:
Weight of beaker =
=
Result
35
Experiment No. 12:

Synthesis of Paracetamol
Apparatus:
Beaker
Stirrer
Burner/oven
Wire gauze
Funnel
Conical flask
Chemicals:
Para-aminophenol… 06.00 g
Acetic anhydride 06.50 ml
Concentrated sulphuric acid… ..3-4 drops
Chemical reactions:
Procedure:
Weigh 6.0 g of p-aminophenol and transfer to a 100 ml clean and dry conicalflask.
Add to the flask 6.50 ml of acetic anhydride and 3-4 drops of concentratedsulphuric acid cautiously.
Mix the contents in flask thoroughly.
Warm the flask on a water bath, previously maintained at 60.C for about 20-25minutes with constant
stirring.
Allow the flask to cool at room temperature and pour the contents into abeaker having 100.0 ml of
cold water and stir it vigorously.
Crude/ppts are filtered by funnel and wash product with cold water.
Dry the product on oven at 100.C.
Calculate its %age yield by following formula as:
Observation and Calculation: Theoretical Yield:

36
3-----~-
gm of salicylic acid gives = 160■
×3
138
Actual Yield:
Weight of beaker =
=
Uses:
It is used as analgesic and antipyretic.
37
Pictures of All Apparatus:
Burette with Stand Pipette Beaker
Funnel Measuring Cylinder Conical Flask
Cotton Stirrer Spatula
Using O 8
, ....... {°""91' unsen Burner
~·
Watch Glass Burner Glass Rod
Buchner Funnel Round Bottom Flask Heating Mantle
Reflux Condenser Filter Paper

• End point of phenol red is yellow
• Example of brand of salicylic acid is aspirin
• We find percentage purity by titration
• Indicators include phenolphthalein, phenol, starch, etc
• Famous brand of mafenamic acid is ponston
• Famous brand of sulphonamide is trimethoprim
• Sulfamethoxazole+trimethoprim=ceftran
• Examples of sulphonamides include sulfanilamide, acetamide
• Concentration of sulphuric acid in concentrated sulphuric acid is 32 percent
• Famous brands containing methyl salicylate include; wintogeno, move,
iodex
• Nitrophthalic acid is used as disinfectant and ansaid, its famous brand is
dettol
Stock bottle of 37% HCL.

Determination of molarity of 37% HCL V/V
37 ml of solute/100 ml of solution.
HCL - 37% v/v. Specific gravity: 1.19 g/ml

37ml/100 ml or 370 ml/1000 ml x 1.19 g/ml = 440.3 g/L
HCL Molecular weight = 36.5

Molarity:
440.3 grams /36.5 grams = 12.06 M or ~12M
====================
Compounding 1 liter of 0.1N Solution
====================
M1V1 = M2V2
(0.1)(1000) = (12) (x)
x = (0.1) (1000) / 12
x = 8.3 ml
Therefore add 8.3 ml of 37% HCL to 1 liter of D5W or NS to create a 0.1N HCL
solution.
---OR ---(Alternative calculation)
12M (37% HCL) = 12 moles/L = 12 x 36.5 = 438 g/L = 438 mg/ml.

Need 0.1 N = 0.1 M
M x 36.5 = 3.65 g/L = 3650 mg.
3650 mg / 438 mg = 8.33 ml*

Medicinal Theory+Practicals

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Medicinal Theory+Practicals

Uploaded by

Copyright:

Available Formats

The number of hosts involved in the life cycle of Plasmodium are:

a. None of the options

6-Chloro-2-methoxy-9-(diethyl amino isopentyl)amino acridine is the chemical

In the structure of Quinine, group is attached at 6'-position in quinoline

Folic acid can help to synthesize

Cephalothin belongs to:

Beta lactamase resistant by cephalosporins depend upon:

Uptake of tetracycline by bacteria require:

Cephalosporins-N has following components:

Cefamendole belongs to:

Dioxolane is used in the synthesis of .............. antiviral drug.

Which one is used to synthesize

Sulfonamides can block:

Tromantadine HCL is used to treat:

Amodiaquine chemically belongs to:

The degradation by hydrolysis is influenced by:

2-Ethoxy-1-naphthyl penicillin is the chemical name of:

Sulfonamides being structural analogue of ............... inhibit the pathway of

The reduction of methacycline in the presence of rancy nickel produces:

The natural source of Penicillins is/are:

Identify the group at position-2 of tetracyclines and is crucial for

The addition of amino group in penicillin-G at CH2 (methylene) group of

Chemically tetracyclines are:

During folic acid synthesis in microbes, is converted into pyrophosphate.

3-Metanilamide-5-chloro pyrimide (sulfonamides derivative) is 16-times

Dimethylated substitution of sulfadiazine is known as:

Doxycycline is one of the efficient tetracyclines because it:

6-Methoxy-8-(dimethyl amino isopentyl)amino quinoline is the chemical name

During life cycle of Plasmodium, merozoites are released by/;

Chemically Proguanil belongs

Demethlation of Santaquine results in:

Pro-drugs of sulfonamides can be formed by reaction of sulfonamides with

Identify the organisms having obligate parasitic condition, operational

2,6-Dimethoxy phenyl penicillin is the chemical name of:

The number of naturally occurring cephalosporins are:

During folic acid synthesis in microbes, Dihydrofolic acid is synthesized by

The pro-drugs of cephalosporins to increase the bioavailabilty can be achieved

During cell wall synthesis in bacteria, cross-linking is controlled by.

Replacement of benzyl group in penicillin-G with dimethoxy benzene results

4,4-Diamino diphenyl sulfone is the chemical name of:

a.All of the options

Which one is used to synthesize Ribavirin drug?

29. Seldomycin Belongs to

31. Gray baby syndrome is the adverse effect of:

a. mask bitter taste

b. increase water solubility

c. increase shelf life

33. Chloramphenicol is not produced by:

36. The type of Gentamycin which is resistant to acetyltransferase is:

37. Number of basic groups present in Streptomycin are:

40. Chemically Netilmicin is:

41.Fanconi's syndrome is due to the degradation of:

44.During folic acid synthesis in microbes, …….. is converted into pyrophosphate.

Classification Based Upon Mode of Action

1. Based upon spectrum of action

 Broad-spectrum antibiotics Cephalosporin, rifamycin tetracycline

2. Based upon Source from which it is obtained

 Natural source: Totracyclin, polymixin streptomycin

3. Based upon mode of action

 Drugs that interfere in cell wall synthesis: Penicillin, cephalosporin cycloserine,

 B-lactam antibiotics Penicillin, cephlosporin

Depending Upon the Sources from which Antibiotics is Obtained

Beta-Lactam Antibiotics (Penicillins)