PHARM 451

MEDICINAL CHEMISTRY II
DRUGS ACTING ON INFECTIOUS DISEASES

Addotey, J. N. A. (Dr. rer. nat.)

Dept. of Pharm. Chemistry
FPPS, CHS - KNUST
 (1)
Disinfectants and Antiseptics
PHARM 451
J. N. A. ADDOTEY (Dr. rer. nat.)

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History
• Joseph Lister 19th century introduced antiseptic principles using
carbolic acid during surgery.
• This lead to drastic decrease in postsurgical infections.
• Paul Ehrlich sought to develop agents which will be selective for
microorganisms and spare the human host (magic bullets). He
discovered that certain dyes could selectively stain target cells
• This formed the basis for antimicrobial chemotherapy.
• Local Anti-infective agents are referred to as GERMICIDES. There
are 2 main types of germicides.
• Antiseptics and Disinfectants
Ideal properties of Antiseptics Desirable properties of
Disinfectants Classification
Rapid and sustained lethal Rapid lethal action
activity
May be based on
Active in the presence of body Good penetration into organic • Chemistry of the agents
fluids matter
• Biological property
Low surface tension to enable Compatible with organic • Therapeutic indication
it spread into the wound compounds

Low toxicity, to allow for Non-corrosive

application on skin and wounds
Non-irritating Aesthetic attributes
Phenols
• Sir Joseph Lister introduced phenol as a surgical antiseptic in 1867
• still used occasionally as an antipruritic in phenolated calamine lotion
(0.1%–1% concentrations).
• A 4% solution of phenol in glycerin has been used to cauterize small
wounds.
• Phenol is almost obsolete as an antiseptic and disinfectant.
SAR
• Substitution with alkyl, aryl and halogen (especially para)
groups, enhances bactericidal activity.
• Straight chains contribute more to activity than branched
groups.
 Cresol
• Cresol is actually a mixture of
three isomeric methylphenols:
• Phenol coefficient 2.5
• Creosote odour (drawback)
Resorcinol
• It is a white, water-soluble
solid
• Susceptible to photolysis and
oxidation
• Phenol coefficient 0.4
• Keratolytic agent
Alcohols
• The activity of the primary alcohols (against S. aureus)
increase with molecular weight up to octanol.
• In general, one oxygen atom is capable of solubilizing seven or
eight carbon atoms in water.
• As the primary alcohol chain length increases, van der Waals
interactions increase, and the ability to penetrate microbial
membranes increases
• As water solubility decreases, the apparent antimicrobial
potency diminishes with molecular weight.
Alcohols
• Branching of the alcohol chain decreases antibacterial
potency; weaker van der Waals forces brought about by
branching do not penetrate bacterial cell membranes as
efficiently.
• The isomeric alcohols’ potencies decrease in the order
primary > secondary > tertiary.

• Isopropyl alcohol is more popular, why?

Metabolism
HALOGEN CONTAINING COMPOUNDS
• Iodophors
• nonionic and cationic surfactants can solubilize iodine
• complexes formed reduce its volatility and removing its
irritant properties
• the germicidal properties of the iodine is retained
• In some of the more active, nonionic surfactant complexes, it
is estimated that approximately 80 % of the dissolved iodine
remains available in bacteriologically active form.
• Povidone–Iodine
• is a charge-transfer complex of iodine with the nonionic surfactant
PVP.
• The complex is extremely water soluble and releases iodine very
slowly. Hence, the preparation provides a nontoxic, nonvolatile, and
nonstaining form of iodine that is not irritating to the skin or to
wounds.
• Chlorine-containing compounds

• These compounds release hypochlorous acid when dissolved in

water, especially in the presence of acid.
• Organic compounds that form stable N-chloro derivatives
include amides, imides, and amidines.
• N-Chloro compounds slowly release HOCl in water. The
antiseptic effect of these agents is optimal at around pH 7.
• Halazone
• photosensitive compound with a faint chlorine odor.
• Halazone is only slightly soluble in water at pH 7 but becomes very
soluble in alkaline solutions. The sodium salt of halazone is used to
disinfect drinking water.
CATIONIC SURFACTANTS

• They possess a polar head group and nonpolar hydrocarbon

chain and form micelles by concentrating at the interface of
immiscible solvents.
• The surface activity of these compounds results from two
structural moieties:
• (a) a cationic head group, which has a high affinity for water
and
• (b) a long hydrocarbon tail, which has an affinity for lipids
and nonpolar solvents.
• They are highly water soluble, relatively nontoxic, stable in
solution, non-staining, and noncorrosive.
• The surface activity causes a keratolytic action in the stratum
corneum.
• However, they are rendered inactive by soaps and other
anionic detergents.

Cetylpyridinium chloride
Dyes
• Gentian violet
• Basic Fuchsin
• Methylene Blue
Basic Fuchsin

Acids and derivatives

These include acetic acid, boric acid, salicylic acid and parabens eg.?

Oxides and Peroxides

Liberate oxygen eg. Hydrogen peroxide, ozone, KMnO4
Miscellaneous

• Aldehydes
• Chlorhexidine
• Ethylene oxide
• Nitrofurans
 (2)
Quinolones
PHARM 451
J. N. A. ADDOTEY (Dr. rer. nat.)

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Quinolones
• synthetic antibacterial agents patterned after nalidixic acid
• Isosteric heterocyclic groupings in this class include the
• quinolones (e.g., norfloxacin, ciprofloxacin, lomefloxacin)
• the naphthyridines (e.g., nalidixic acid, enoxacin)
• the cinnolines (e.g., cinoxacin)

• Clinically used for the treatment of urinary tract infections due to:
• good oral absorption,
• activity against common Gram-negative urinary pathogens, and
• comparatively higher urinary (compared with plasma and tissue)
concentrations
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21
• Newer members are
useful for the
treatment of various
serious systemic
infections.

• These more potent

analogs are
sometimes classified
separately (from the
urinary tract-specific
agents) as the
fluoroquinolones,
because all members
of the group have a 6-
fluoro substituent in
common.

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• Nalidixic acid and the earliest members (e.g., oxolinic acid, cinoxacin)
are largely effective against Gram-negative bacteria,

• Newer members with 6-fluoro and 7-piperazinyl substituents show

an extended spectrum of activity that includes effectiveness against
additional Gram-negative pathogens (e.g., P. aeruginosa, H.
influenzae, N. gonorrhoeae), Gram-positive cocci (e.g., S. aureus), and
some streptococci.

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SAR

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 Isosteric replacements of N for C atoms at positions;
• 2 (cinnolines e.g., cinoxacin),
• 5 (1,5-napthyridines),
• 6 (1,6-naphthyridines), and
• 8(1,8-naphthyridines) retains activity.

 positions 5, 6, 7 (especially), and 8 of the annulated ring may be substituted

with good effects but not 2.

 Fluorine atom substitution at position 6 is also associated with significantly

enhanced antibacterial activity. .

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26
SAR
Alkyl substitution at position 1 is
essential for activity, with lower
alkyl (methyl, ethyl, cyclopropyl)
compounds generally having
progressively greater potency.

Aryl substitution at position 1 is

also consistent with antibacterial
activity, with a 2,4-difluorophenyl
group providing optimal potency.

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https://youtu.be/IkKZ_gxAOXI 28
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Toxicity
• CNS effects (Less than 1%)
• attributed to antagonism of -aminobutyric acid (GABA)
receptors in the brain by the quinolones.
• low incidence of CNS effects largely due to inability to
penetrate the blood-brain barrier.
• Quinolones possessing a halogen atom at the 8-position
(e.g., lomefloxacin) have the highest incidence of
phototoxicity,
• those having an amino (e.g., sparfloxacin) or methoxy
group at either the 5- or 8-position have the lowest
incidence.

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Ionization equilibria
• 2 classes
a. Single ionizable group (nalidixic acid, oxolinic acid)
• pKa= 5.6 to 6.4 (benzoic acid = 4.2)

b. fluoroquinolones
• pKa values for the more basic N atom of the piperazino group fall in
the range of 8.1 to 9.3
• At physiological pH, exist predominantly as zwitterions

• Water solubilty of FQs depends largely on pH

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https://www.mdpi.com/1420-3049/18/9/11153/htm

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Interactions
• Based on chelating properties towards divalent and trivalent ions.
• Ca+2, Mg+2, Zn+2, Fe+2, Fe+3, and Bi+3
chelates are often insoluble in water,
Therefore???

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Ofloxacin and Levofloxacin
• Students to read on
• Activity
• ADME

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 Ciprofloxacin
• monohydrate phase of its hydrochloride salt
formulated for oral/ophthalmic administration.

• lactate salt for use in IV administration

• Injectable forms of ciprofloxacin are

incompatible with drug solutions that are
alkaline

• Interactions with food and antacids

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 Metabolism
• Ciprofloxacin is eliminated by
renal and non-renal mechanisms.
• The drug is partially metabolized
in the liver by modification of the
piperazinyl group to at least four
metabolites.
• Ciprofloxacin and its metabolites
are excreted in urine by both
glomerular filtration and by
tubular secretion.

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Examples

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 (3)
ANTIFUNGALS
PHARM 451
J. N. A. Addotey (Dr. rer. nat.)

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 Introduction Superficial Systemic
common Less common
• Fungal infections fall into two well-
defined groups: the superficial and Homogenous (mainly Heterogenous
dermatophytes) aetilogy
the deep seated mycoses
Mild superficial and Severe, deep
restricted lesions
• Opportunistic infections – form of
systemic mycoses
• Due to overuse/misuse of antibiotics,
steroids, immunosuppressants
• Eg. Systemic candidiasis, aspergillosis

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Classification

https://www.future-science.com/doi/10.4155/fmc-2018-0479

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General Mechanism action of Antifungal agents

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POLYENES
• isolated from soil bacteria of the genus Streptomyces
• Two groupings based on size of the macrolide ring.
• 26-membered–ring polyenes
• 38-membered macrocycles

• The use for the treatment of systemic infections is limited by

• toxicities of the drugs
• their low water solubilities, and
• poor chemical stabilities.

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 Polyenes
• Amphotericin B
• was purified from soil culture of
Streptomyces nodosus

• interacts with membrane sterols (ergosterol in fungi) to

produce an aggregate that forms a transmembrane
channel.
• Intermolecular hydrogen bonding interactions among OH,
COOH, and NH2 groups stabilize the channel in its open
form, destroying symport activity and allowing the
cytoplasmic contents to leak out.
• The effect is similar with cholesterol. This explains the
toxicity in human patients.
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Cholesterol embedded in lipid bilayer ergosterol

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 Nystatin

• First isolated in 1951 from a strain of

Streptomyces noursei.
• Very slightly water soluble
• unstable to moisture, heat, and light.
• The entire compound is constructed by linking
the aglycone to mycosamine.
• Not absorbed when taken orally

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 Azoles
• The first members of the class were highly substituted
imidazoles, such as clotrimazole and miconazole.Later the
triazoles were developed

• The fungicidal effect (high conc) - damage to the cell membrane,

with the loss of essential cellular components such as K+ ions
and amino acids.
• The fungistatic effect (low conc) - inhibition of membrane-bound
enzymes

• Generally, higher concentrations are required to inhibit the

mammalian enzyme -selectivity

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SAR

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SAR
• The basic structural requirement for members of the azole class is a weakly basic imidazole or
1,2,4-triazole ring (pKa of 6.5–6.8) bonded by a nitrogen–carbon linkage to the rest of the
structure.

• At the molecular level, the amidine nitrogen atom (N-3 in the imidazoles, N-4 in the triazoles) is
believed to bind to the heme iron of enzyme-bound cytochrome P450 to inhibit activation of
molecular oxygen and prevent oxidation of steroidal substrates by the enzyme.

• The most potent antifungal azoles possess two or three aromatic rings, at least one of which is
halogen substituted (e.g., 2,4- dichlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl), and other
nonpolar functional groups.

• Only 2, and/or 2,4 substitution yields effective azole compounds.

• The halogen atom that yields the most potent compounds is fluorine
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• MOA
• large nonpolar portion of these molecules
mimics the nonpolar steroidal part of the
substrate for lanosterol 14-demethylase,
lanosterol, in shape and size.

• The nonpolar functionality confers high

lipophilicity to the antifungal azoles.

• Fluconazole, which possesses two polar triazole

moieties, is an exception, in that it is sufficiently
water soluble to be injected intravenously as a
solution of the free base.
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51
 Clotrimazole
• Broad spectrum
topical agent
• Reasonable well
absorbed but
extensively
protein bound
• Not suitable for
systemic
infections

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 Ketoconazole
• The oral bioavailability of ketoconazole depends
on an acidic pH for dissolution and absorption
• Ketoconazole is a racemic compound, consisting
of the cis-2S,4R and cis-2R,4S isomers.

• four possible diastereomers of ketoconazole

• 2S,4R isomer was 2.5 times more active than its
2R,4S enantiomer against rat lanosterol 14-
demethylase

• The trans-isomers, 2S,4S and 2R,4R, are much

less active.

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Ketoconazole
• Interactions

• Antacids and drugs such as H2-histamine antagonists and anticholinergics that inhibit gastric
secretion interfere with its oral absorption.

• ketoconazole causes clinically significant increases in plasma concentrations of cyclosporine,

phenytoin, and terfenadine.

• Toxicity
• Ketoconazole is known to inhibit cholesterol biosynthesis, suggesting that lanosterol 14-
demethylase is inhibited in mammals as well as in fungi.

• High doses have also been reported to lower testosterone and corticosterone levels, reflecting
the inhibition of cytochrome P450-requiring enzymes involved in human steroid hormone
biosynthesis.

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Fluconazole
• broad-spectrum
• suitable for both oral and IV administration as the free base.
• Excellent oral bioavailability, why?
• Not affected by gastric acidity
• Fluconazole has a relatively long elimination half-life.
• It penetrates well into all body cavities, including the CSF.
• Plasma protein binding of fluconazole is less than 10%

• Inhibition of cytochrome P450

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Voriconazole & Posaconazole

• voriconazole has potent activity against a broad variety of fungi,

including the clinically important pathogens.
• The in vitro activity of posaconazole appears to be similar to that of
voriconazole.
• Posaconazole is now in phase III clinical trials, and evidence of the
efficacy of posaconazole against various fungal models, especially the
rarer ones, continues to accumulate.

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 Allylamines
• interfere with an early step in
ergosterol biosynthesis,
namely, the epoxidation of
squalene catalyzed by
squalene epoxidase.

• Can be fungistatic or -cidal

depending on the organism

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• Naftifine is the original member of the class and is efficacious when
administered topically against superficial dermatomycoses.41
• Terbinafine can be utilized both topically and orally to treat fungal
infections of skin, nails, and hair and is the drug of choice
for dermatophyte onchomycosis

Naftifine Terbinafine

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Griseofulvin
• Griseofulvin is a fungistatic agent
• Griseofulvin is a mitotic spindle poison

• After systemic absorption, griseofulvin is carried to the

skin, nails, and hair follicles, where it concentrates in
keratin precursor cells, which are gradually exfoliated
and replaced by healthy tissue.

• oral bioavailability of griseofulvin is very poor

• Micronization has been the most successful attempt
• Advised to be taken with a fatty meal

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Synthesis
• Students to find out!

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Nucleoside antifungals
• Flucytosine/fluorocytosine

• Orally active, synthetic antimycotic compound

• narrow spectrum (Candida and Cryptococcus spp.)
• no intrinsic antifungal capacity,
• converted into 5-fluorouracil (5-FU), which is further
converted to metabolites that inhibit fungal RNA and
DNA synthesis.
• Resistance very common due to impermeability of transport
system to the drug
• to prolong the effect of 5-FC, administer it with the polyene
antibiotic amphotericin B.

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Mechanism of action of 5-FC.

2/24/2021 62
Topical Agents
• ACIDS
• Fatty acids
• Similar to sebum (natural antifungal), found in and on the skin of
Adults
• Fatty acids and salts have feeble antifungal activity

• Eg
• Propionic acid (Zn), Caprylic acid (Na, Zn)
• Triacetin (Structure & MOA)?

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 Other acids
• Salicylic acid
• used externally in ointments and solutions
• for its antifungal and keratolytic properties.
• By itself, salicylic acid is a poor antifungal agent.

• Benzoic acid
• appreciable antifungal effects, but it
• cannot penetrate the outer layer of the skin in infected
areas.

• Whitfield’s Ointment
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Phenols and derivatives

• All of these agents appear to

interfere with cell membrane
integrity and function in
susceptible fungi. Clioquinol

• ciclopirox olamine, is not a

phenol but has similar
properties to phenols haloprogin

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 (4)
ANTIBACTERIAL
SULFONAMIDES/SULFONES
PHARM 451
J. N. A. Addotey (Dr. rer. nat.)

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ANTIBACTERIAL SULFONAMIDES
• first effective chemotherapeutic agents that could be used
systemically for the cure of bacterial infections in humans.
• Have become less useful due to resistance and emergence of other
antiinfective agents eg. Penicillins
• Lead compound was red dye Prontosil
• Prontosil showed in-vivo antibacterial activity while it was in-vitro
inactive

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Sulphanilamide – active form

these findings ushered in the modern era of chemotherapy and the concept of the prodrug.

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• Today, there are a few sulfonamides and especially sulfonamide-
trimethoprim combinations that are used extensively for
opportunistic infections in patients with AIDS.
• The sulfonamide-trimethoprim combination can be used for
treatment and prophylaxis of PCP .
• Additionally, cerebral toxoplasmosis can be treated in active infection
or prophylactically.

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Classification
• can be grouped into three classes on the basis of their use:
• oral absorbable agents
• oral nonabsorbable eg. Sulphasalazine
• topical agents eg. sodium sulfacetamide ophthalmic drops.

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Nomenclature of the Sulfonamides
• Sulfonamide is a generic term that denotes
three different cases:

• 1. Antibacterials that are aniline-substituted

sulfonamides (the “sulfanilamides”).

• 2. Prodrugs that react to generate active

sulfanilamides (i.e., sulfasalazine).

• 3. Nonaniline sulfonamides (i.e., mafenide

acetate).
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MOA

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 MOA
• Sulfonamides mimic P-aminobenzoic acid (PABA) which is the normal
substrate for dihydropteroate synthetase. This means that
sulfonamide will bind in the same manner as PABA:

The competitive nature of the sulfonamides’ action means that the drugs do no
permanent damage to a microorganism; hence, they are bacteriostatic.
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Crystalluria and the pKa
• Sulfonamides are mostly excreted in urine as acetylated metabolite.
• They are relatively water insoluble mainly due to the formation of the
acetylated metabolites.

• The acetylated metabolite is non-ionizable under the pH conditions

of the urine (≈ 7) that increase the possibility of precipitation and the
formation of crystals in the urine (crystalluria)
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• How to minimize the possibility of crystalluria formation with
sulfonamides:

• Increase the urine flow.

• Increase the pH of the urine (this can be done by taking sodium

bicarbonate or potassium citrate.

• Lowering the pKa of the sulfonamide group which will help to

increase the ionization under the acidic conditions. This can be
done by adding electron withdrawing group on the sulfonamide
side chain

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Sulfonamides with reduced crystalluria formation

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 Sulfonamide derivatives

• Differ mainly in the substitution at the sulfonamide side chain…

derivatives with heterocyclic or aromatic ring. This was done to:
• Reduce the pKa of the sulfonamide... Reduce crystalluria.
• Increase protein binding by adding lipophilic heterocycles…. Long lasting
derivatives.
• Few derivatives have the amino group at the P position being
derivatized except in sulfonamide prodrugs

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Sulfonamide prodrugs
• Succinyl sulfathiazole:
• Mainly used for intestinal infections.
• It has a carboxylic acid at the amine side chain… ionized in intestine… will not
be absorbed…. So it has only local effect.

• The gradual hydrolysis of the amide will liberate the active form; sulfathiazole.
Students to read on sulfasalazine
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SULFONES
• They are less effective than the sulfonamides.

• PABA partially antagonizes many of the sulfones, implying similar

MOA

• Sulfones were used to treat leprosy after it was found that sodium
glucosulfone was experimental effective.

• The parent sulfone is, dapsone (4,4’-sulfonyldianiline),

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• Four variations on this structure have given active compounds:
1. Substitution on both the 4- and 4’-amino functions
2. Monosubstitution on only one of the amino functions
3. Nuclear substitution on one of the benzenoid rings
4. Replacement of one of the phenyl rings with a heterocyclic ring

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 (5)
Antitubercular and Antilepral
agents
PHARM 451
J. N. A. Addotey (Dr. rer. nat.)

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Antitubercular Agents
• The discovery of the antitubercular activity of the aminoglycoside
antibiotic streptomycin by Waksman et al. in 1944 ushered in the
modern era of tuberculosis treatment.
• This development was quickly followed by discoveries of the
antitubercular properties of p-aminosalicylic acid (PAS) first and then,
in 1952, of isoniazid.
• Later, the usefulness of the synthetic drug ethambutol and,
eventually, of the semisynthetic antibiotic rifampin was discovered.

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Anti-tuberculous drugs

First-line Second-line
• Isoniazid • Clarithromycin
• Rifampicin • Ciprofloxacin
• Ethambutol • Capreomycin
• Pyrazinamide • Cycloserine
• Kanamycin
• Amikasin
• streptomycin
 Isoniazid
• It is prepared by reacting the methyl ester of isonicotinic acid
with hydrazine (hydrazinolysis of esters in alcoholic solutions)

• The activity of isoniazid is manifested on the growing tubercle

bacilli and not on resting forms.

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 MOA
• the principal effect of isoniazid is to inhibit the synthesis of mycolic
acids
• MAs are extremely long chained, β-unsaturated, branched fatty acids,
which contribute to the impermeability of the cell envelope.
• They are confined essentially to mycobacteria and are therefore
considered as selective targets for anti-TB drugs
• MA is essential for survival, virulence, and antibiotic resistance of
MTB

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MOA
• A mycobacterial catalase–peroxidase enzyme complex (KatG) is required for the
bioactivation of isoniazid
• Generation of reactive species which attacks a critical enzyme for the production
of mycolic acid.
• The target for the action of INH has recently been identified as an enzyme that
catalyzes the NADH-specific reduction of 2-trans-enoylacyl carrier protein, an
essential step in fatty acid elongation
• This enzyme is encoded by a specific gene, inhA, in M. tuberculosis

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MOA
• INH affects several pathways involved in
macromolecular synthesis, such as
• nucleic acid synthesis
• protein synthesis
• lipid synthesis
• carbohydrate synthesis

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Resistance
• very complex and involves mutations in a relatively large number of
genes.
• Among all the genes involved in INH resistance, mutation in katG
appears to be the major contributor
• Approximately 20% to 25% of INH-resistant clinical isolates display
mutations in the inhA gene, leading to altered proteins with
apparently reduced affinity for the active form of the drug.
• Interestingly, such INH-resistant strains also display resistance

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90
 Ethionamide
• This nicotinamide has weak bacteriostatic activity in vitro
but, because of its lipid solubility, is effective in vivo.
• In contrast to the isoniazid series, 2-substitution
enhances activity in the thioisonicotinamide series.
• It is used in the treatment of isoniazid resistant
tuberculosis or when the patient is intolerant to isoniazid
and other drugs.

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Pyrazinamide
• Its antitubercular properties were discovered as a
result of an investigation of heterocyclic analogs of
nicotinic acid, with which it is isosteric.
• Pyrazinamide has recently been elevated to first-line
status in short-term tuberculosis treatment regimens
because of its tuberculocidal activity and
comparatively low short-term toxicity
• Since pyrazinamide is not active against metabolically
inactive tubercle bacilli, it is not considered suitable
for long-term therapy.

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• Pyrazinamide is maximally effective in Metabolism

the low pH environment that exists in

Unchanged pyrazinamide, the corresponding carboxylic acid
macrophages (monocytes). (pyrazinoic acid), and the 5-hydroxy metabolite are excreted in
• Evidence suggests bioactivation of the urine.
Pyrazinamide and its metabolites are reported to interfere with
pyrazinamide to pyrazinoic acid by an uric acid excretion. Therefore, the drug should be used with
amidase present in mycobacteria. great caution in patients with hyperuricemia or gout.

• Despite its structural similarities to

isoniazid and ethionamide, pyrazinamide
apparently does not inhibit mycolic acid
biosynthesis in mycobacteria.
• The drug penetrates inflamed meninges
and, therefore, is recommended for the
treatment of tuberculous meningitis.
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Ethambutol
• active only against dividing mycobacteria. It has no effect on
encapsulated or other nonproliferating forms
• The in vitro effect may be bacteriostatic or bactericidal, depending on
the conditions.
• Its selective toxicity toward mycobacteria appears to be related to
the inhibition of the incorporation of mycolic acids into the cell walls
of these organisms.
• This compound is remarkably stereospecific.

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SAR
• The dextro isomer is 16
times as active as the meso
isomer.
• the length of the alkylene
chain,
• the nature of the branching
of the alkyl substituents on
the nitrogens, and
• the extent of N-alkylation all
have a pronounced effect on
the activity.
Metabolism
• Up to 80% is excreted unchanged,
with the balance being
metabolized and excreted as 2,2’-
(ethylenediimino)dibutyric acid
and the corresponding
dialdehyde.
• Structures?
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Aminosalicylic Acid
• PAS is administered orally in the form of the sodium salt, usually in
tablet or capsule form.
• Symptoms of gastrointestinal irritation are common with both the
acid and the sodium salt. Various enteric-coated dosage forms have
been used in an attempt to overcome this disadvantage.
• Other forms that are claimed to improve gastrointestinal tolerance
include the calcium salt, the phenyl ester, and a combination with an
anion exchange resin (Rezi-PAS).
• An antacid such as aluminum hydroxide is frequently prescribed.

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Metabolism
• The N-acetyl derivative is the principal
metabolite, with significant amounts of the
glycine conjugate also being formed.

• When administered with isoniazid (which

also undergoes N-acetylation), PAS increases
the level of free isoniazid.

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 RIFAMYCINS
• obtained by fermentation from cultures of
Streptomyces mediterranei.
• They belong to a class of antibiotics called
the ansamycins that contain a macrocyclic
ring bridged across two nonadjacent
positions of an aromatic nucleus.

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MOA
• Rifamycins bind to the beta subunit of bacterial DNA-dependent RNA
polymerases to prevent chain initiation.
• Bacterial resistance to rifampin due to mutations leading to amino acid
substitution in the beta subunit.
• Cross resistance is common
• Rifampin is a powerful inducer of hepatic cyt P450 oxygenases. It can
markedly potentiate the actions of drugs that are inactivated by these
enzymes. Eg?
• should be combined with dapsone or some other leprostatic agent to
minimize the emergence of resistant strains of M. leprae.

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 Cycloserine
• It is stable in alkaline, but unstable in
acidic, solutions. The compound slowly
dimerizes to 2,5-bis(aminoxymethyl)-
3,6-diketopiperazine in solution or
standing.
• Cycloserine is stereochemically related
to D-serine. However, the L-form has
similar antibiotic activity.

100
 MOA
• Cycloserine is presumed to exert its antibacterial action
by preventing the synthesis of cross-linking peptide of
bacterial cell walls.

• Has been also suggested that it is an antimetabolite for

alanine, which acts as a suicide substrate for the
pyridoxal phosphate-requiring enzyme alanine racemase.

• Irreversible inactivation of the enzyme thereby deprives

the cell of the D-alanine required for the synthesis of the
cross-linking peptide.

• It is only recommended for patients who fail to respond

to other tuberculostatic drugs due to toxicity
101
Others
• Rifabutin
• Sterile Capreomycin Sulfate
• Clofazimine

102
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