Organic Medicinal Chemistry

Memorize chemical classes!!!

Common Heterocycles within Drug Molecules

IMIDAZOLE IMIDAZOLINE

PYRROLE PYRROLIDINE

TRIAZOLE TETRAZOLE

INDOLE INDOLINE

BENZIMIDAZOLE

PYRIDINE PIPERIDINE

PYRAZINE PIPERAZINE

QUINOLINE ISOQUINOLINE

PYRIMIDINE PURINE

QUINAZOLINE

THIAZOLE ISOXAZOLE

FURAN PYRAN Metabolic Changes to Drugs

Metabolism
 Aka “Biotransformation”
 Effect is to deactivate the drug resulting to
detoxification (main goal)
 Drugs will become more polar (ionized) so…
 reabsorption  water solubility
BENZOXAZOLE

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 
Organic Medicinal Chemistry
Metabolism exception: Prodrugs (drugs that are monoamines with phenolic
metabolically activated) ring
Phase I. FUNCTIONALIZATION ii) MAO-B: for nonphenolic
b) Dehydrogenase
Phase I. FUNCTIONALIZATION  Found in the cytoplasm
 + functional groups (HOR)  solubility  E.g. Alcohol & Aldehyde
Dehydrogenase
1) Hydrolytic Reaction/Hydrolysis c) Purine oxidation
 + H2O to esters, amides, & isosteres (kamukha ng  E.g. Xanthine Oxidase
functional group)
***Example of isosteres:

Ester Thioester 3) Reduction Reactions

 E.g. esters, amides, thioesters, carbonates, a) Reduction of aldehydes & ketones
carbamates
 E.g.
o Aspirin (ASA)
o Procainamide
Ketone 2 Alcohol
o Procaine

2) Oxidation Reaction
 More common: hydroxylation
 E.g. hydroxylation of Hexobarbital to 3’-
Aldehyde 1 Alcohol
hydroxyhexobarbital
b) Reduction of –NO2 & azo compounds
 –NO2 is toxic
 E.g. Chlorampenicol

N O2 N H2
[ R ] N =O [ R ] NH −OH [R]
( Nitro) → (Nitroso ) → ( Hydroxylamine) → (1 ° Amine)

c) Reduction of azo
Hexobarbital  Methyl red, orange, yellow (hard
(2) Enzyme Systems indicator)
1) Hepatic Microsomal Flavin-containing
Monooxygenases N=N NH −NH N H2
 Oxidation of S & N functional groups [ R] [R]
( Azo) → ( Hydrazo) → (1 ° Amine)
 Reaction different from CYP450
 E.g. Cimetidine  E.g.
Prontosil
1,2,4−triaminobenzene+ Sulfa
(¿ dye ) →

Cimetidine
2) Nonmicrosomal
a) Monoamine oxidase (MAO)
 Found in the outer mitochondrial Prontosil
membrane
d) Reduction of sulfur group
 Isomers:
 Disulfide reduction
i) MAO-A: prefer
o PI in hair rebonding
catecholamine &
o Disulfide is found in the 3
structure of proteins

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 Organic Medicinal Chemistry 4) Acetyl Conjugation
2 SH  Metabolism for drugs containing 1 amine group
S−S [ R ] SH −SH [ R ] (alipathic or aromatic), AA, sulfonamides,
→ → (thiol)
hydrazines, hydrazides
 Function: to detox the drug except for NAPA (N-
acetylprocainamide)
 E.g.  Enzyme: NAT (N-acetyltransferase)
Disul firam ( 2 ) N , N−diethylthiocarbamic acid
→
5) Methyl Conjugation
 Minor conjugation pathway
 Important for biosynthesis of Epi & Melatonin
 Enzyme: Methyltransferases
o COMT: Catechol-O-methyltransferase
o PENMT: Phenylethanolamine N-
methyltransferase
Disulfiram  Source: SAM (S-adenosylmethionine)

Phase II. CONJUGATION

Prodrugs
1) Glucuronidation
 Most common conjugation pathway Advantages:
 Glucuronides are highly hydrophilic & water- 1) absorption
soluble 2) Alleviation of pain at injection site
 UDP-glucuronosyltransferase 3) Elimination of unpleasant taste (palatability)
o Enzyme for transfer  E.g. Chloramphenicol
o Underdeveloped in neonates so 4) toxicity
administration of Chloramphenicol 5) metabolism inactivation
would lead to “Gray Baby Syndrome” 6) chemical stability
7) Prolonged/shortened DOA
2) Sulfate Conjugation  E.g. Pivalic ester of Epi resulting to IO
 Phenolic group requirement: SO42- binds to O of – concentration of Epi
OH of phenol (Epi for glaucoma)
 Sulfate conjugates can be hydrolyzed back to the
parent compound by various sulfatases so sulfate


conjugation is an incomplete reaction (reversible)
Phenolic O-glucuronidation competes favorably
Antihistamines
with sulfate conjugation due to limited sulfate ***Antihistamines – 2 receptors
availability
o Amount: Glucuronides > Sulfates
A. H1 Antagonists
 E.g. MATA-POBRE (Methyldopa, Albuterol,
Terbutaline, APAP, Phenacetin)
General structure of H1 Antagonists:

3) Amino Acid Conjugation

 Hippuric acid
o 1st mammalian metabolite isolated
o Product of glycine conjugation of
benzoic acid
 Glycine Conjugation
o Most common AA conjugation
 Glutathione Conjugation
o In all mammalian tissue General Structure of H1 Antagonist
o Glutathione – tripeptide consisting Glu-
Cys-Gly Structural Features of H1 Antagonists:
 Thiol of Cys is the antioxidant 1) Protonable amine
(free radical scavenging  2 amine – most basic amine coz they can
activity) accept proton due to lone pair
2) Connecting carbon chain usually ethyl
3) Connecting O, N, C

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
SAR of H1 Antagonists
Organic Medicinal Chemistry
1) Aromatic groups 2ND GENERATION MISCELLANEOUS
 Function: provide bulk (aromatic/alkyl) Piperidine  Cetirizine
producing antagonistic activity  Astemizole  Acrivastine
 (2) aromatic rings either phenyl, benzyl, or  Terfenadine
pyridyl potency  Loratadine
 Para-substitution with small, lipophilic
group, metabolism coz OH is usually on
para that’s why 1st gen is more potent
 Ortho- & Meta-substitution activity
 NOT rec. no activity (2nd gen)

2) Separator carbon chain

 Function: separate rings from nitrogen
 May be saturated, unsaturated or part of ring
Pyrilamine Acrivastine
 potency DOA if chain length
 Ethyl is the optimum chain length
B. H2 Antagonists
3) Basic amino group
H2 receptors
 Function: must accept a proton at physiologic
pH  Imidazole binds to it
 Potency: R1 & R2 = 3 > 2 > 1
Guanylhistamine
 Quarternization does not antihistaminic
 Lead compound
activity but does anticoholinergic activity
 Diacetyl is the optimum configuration
 Larger substituents antihistaminic activity
due to steric hindrance but incorporation
into heterocycle retains activity

4) X is the basis of classification

Guanylhistamine
X=O Aminoalkyl ethers Cimetidine
 Ethanolamines  Prototype
 Propanolamines  S/E: antiandrogenic (gynecomastia)
 CYP inhibitor

X=C Alkylamines
 Propylamines

X=N Ethylenediamine
Piperazine
Tricyclics
Cimetidine

SAR of Cimetidine:
1ST GENERATION 1) 5-methyl group
Ethanolamines Piperazine  Function: e- donating
 Carbinoxamine  Hydroxyzine ***
 Diphenhydramine  Meclizine e- donating : e- density TO the ring
 Dimenhydrinate  Cyclizine e- withdrawing : e- density AWAY FROM
 Doxylamine the ring

Ethylenediamines Alkylamines 2) Terminal N (N of C≡N)

 Pyrilamines  Brompheniramine  Should be polar but not basic for maximum
 Tripelennamine  Chlorpheniramine potency
 With delocalizing electrons due to
Phenothiazine conjugation
 Prometazine

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 Organic Medicinal Chemistry
||
NC≡N

3) Separator carbon chain

 Separation of the ring from the N group
should be 4C apart Acetyl p-
Other H2 blockers: aminophenol
1) Ranitidine (APAP)
 Furan derivative
 50% BA 2) Acetyl p-aminophenol (APAP) / Acetaminophen /
Paracetamol
 4-10x more potent
 Safest anti-inflammatory (???)
2) Famotidine
 Thiazole derivative  But peripheral anti-inflammatory coz its action
is central
 40-60x more potent
***Best peripheral: Ibuprofen or Mefenamic acid
3) Nizatidine
 Thiazole derivative
 5-18x more potent
NSAIDS
Biosynthesis:
Proton Pump Inhibitor (PPI) Phospholipids
PPI
 Substituted benzimidazole
 All are drugs which are converted to sulfanilamide on
acid media (
Arachidonic acid
(1 hour before meals)
 Activated PPI forms disulfide link with the enzyme
(H+/K+ ATPase) leading to inactivation
Leukotrienes Prostaglandins

Thromboxanes
p-Aminophenol

Eicosanoids

COX
 COX-1 – “constitutive” (always expressed)
p-Aminophenol  COX-2 – “inducible” (triggered by inflammation)
o COX-2 inhibitors: Celecoxib (prototype)
Structural Features of p-Aminophenol:
1) Have aromatic ring but do NOT have acidic group Prostaglandin (PG)
ionizable at physiologic pH so activity  1 ________
 Prostanoic acid – basic nucleus of PG
1) Acetanilide
 Prototype

Acetanilide Phenacetin Prostanoic acid

Structural Features of Prostaglandins:

1) All have a cyclopentane ring
2) A letter code is used to denote ring modification

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 Organic Medicinal Chemistry  Isostere of salicylic acid (-OH is replaced by –NH 2
to produce a nonacidic ____)

PGE PGF PGI

(Keto) (Hydroxyl) (Cyclic ether)
Salicylamide
*E, F, I – common
3) Subscript refers to the # of double bonds in the (2) 2) Diflunisal
side chains
E.g.

Diflunisal
PGE2
PG Analogs B. Fenamates
PGE1 Alprostadil (Caverject), Misoprostol
PGE2 Dinoprostone Fenamates
PGI Epoprostenol
 Derivative of anthranilic acid
PGF2 Latanoprost, Carboprost
 Most potent analogs are disubstituted at 2’- & 3’-
SAR of NSAIDS (positive)
1) Ionizable acid groups and aromatic rings
2) 2nd non-coplanar ring (potency) 1) Mefenamic acid
3) Limiting the number of possible conformers
4) (2) atom separation between the charge and aromatic
ring is the optimum
5) S-isomers are more potent isomers
6) size of alkyl potency but incorporation of the alkyl
into the heterocycle retains potency

 Important size
 Not all needs to be fulfilled, just 1
Mefenamic acid

A. Salicylates C. Pyrazoles
1) Antipyrine
Salicylate
 Prototype
 From salicylic acid
 More potent &
longer DOA but
causes
agranulocytosis

Antipyrine
Salicylic acid Salicylate
SAR of Salicylates: D. Pyrrazolidinediones
1) The –COOH is necessary and –OH must be ortho- to
it 1) Phenylbutazone
2) Introduction of electronegative & lipophilic groups  Equipotent to Antipyrine and more potent than
potency ASA
2) Oxyphenbutazone
1) Salicylamide  Derived metabolite of Phenylbutazone

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 Organic Medicinal Chemistry

Ibuprofen

Phenylbutazone Oxyphenbutazone 2) Naproxen

 Does NOT possess a 2nd non-coplanar ring but the
E. Aryl Acetic Acid naphthyl rings are fused and flat
 Only drug marketed in optically pure form
Aryl acetic acid G. Miscellaneous NSAIDS
 “-ac”
1) Nabumetone
Structural Features of Aryl acetic acid:  Ketone and thus, nonacidic
1) Ionizable acid group  Classified as alkanone
2) Non-coplanar ring  Activated by -activation to 6-methoxy-2-
3) Indole ring naphthylacetic acid or “Naproxen”
4) (2) atom separation between the aromatic group
***
1) Indomethacin All NSAIDs are weakly acidic.
 FALSE! (Nabumetone)

All active NSAIDs are weakly acidic.

 TRUE! (Activated Nabumetone)

Hypoglycemic Agents

Indomethacin

2) Sulindac
 Prodrug which is metabolized to sulfide with long
t1/2 allowing BID administration

Sulindac

F. Aryl Propanoic Acid

Aryl propanoic acid
 “-profen”

1) Ibuprofen
 Prototype

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 Organic Medicinal Chemistry

Sulfonylurea

 SAR of Sulfonylurea:
o R1
 Must be lipophilic
 With aromatic ring next to the sulfoxide
group
1) Insulin  All marketed drugs have a phenyl ring
 Protein  Larger, more complex, para-substituted
 Polypeptide hormone with (2) peptide ( & ) comprises the 2nd generation (more potent)
linked together by disulfide bonds (folded)  Possible substitution: methyl, amino, acetyl,
 Storage: Islets of Langerhans methylthio, Br, Cl, trifluoromethyl
o R2
2) Lispro (Humalog)  Must be lipophilic
 N-propyl, N-hexyl, N-cyclohexyl are more
 1st monomeric insulin analog in the market
potent
 rDNA technology: Lysine & Proline exchanged at
positions B28 & B29
 E.g. Glyburide
 Stabilized into hexamers by a cresol preservation

3) Aspart (Novolog)
 Formed by replacing Proline at B28 with aspartic
acid

4) Glulisine (Apidra)
 Glutamic acid replaces Lysine at B29 & Glyburide
Lysine replaces Asparagine at B3
 MOA of Sulfonylurea: _____________________
5) Regular Insulin
***Usual question: What is the MOA/class/common
 Soluble crystalline Zn Insulin made by rDNA SE of the structure presented or shown below?
technology
 Only type administered IV  Least potent: Tolbutamide
 Most potent: Glimepiride
6) NPH / Isophane
 Suspension of insulin complexed w/ Zn + 2) Thiazolidinediones (TZDs)
Protamine in Phosphate
 General structure:
 SC

7) Insulin Zn Suspension
 Mixture of crystalline & amorphous forms of
insulin w/c minimizes the solubility of insulin R
8) Glargine (Lantus)
Thiazolidinediones
 Asparagine at 2 is replaced by glycine
 Suffix: -“glitazone”
o Pioglitazone (Actos)
9) Detemir (Levemir)
o Rosiglitazone (Avandia)
 Fatty acid chain (myristic acid) is attacked by
Lysine residue at B28 o Troglitazone
 Lipophilic  longer DOA o Ciglitazone

Other Hypoglycemic Agents:

OHAs: 1) Biguanides
1) Sulfonylurea

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 
Organic Medicinal Chemistry
Contains a biguanide in the structure where (2)
molecules of guanidine linked together

Biguanides

2) Guanidine

Guanidine
 E.g. Metformin (SE: Lactic acidosis)
3) Meglitinides
 Repaglinide
 Nateglinide – D-phenylalanine derivative

4) Alpha-Glucosidase Inhibitors
 Miglitol, Acarbose, Voglibose

Adrenergic Agents
Catecholamines
 Dopamine, Epi, NorEpi
 Usually with catechol/resorcinol
Adrenergic Agents

A. Adrenergic Agonists
Biosynthesis of Catecholamines:

Catechol Resorcinol
(1, 2) (1, 3)

SAR of Adrenergic Agonists:

Adrenergic Agonist

Note:
 Replacement of catechol nucleus w/ resorcinol 
selectivity

B. Adrenergic Antagonists
Adrenergic Antagonists
“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
  -blockers (-olol)
Organic Medicinal Chemistry
SAR of Aryloxypropanolamine
 E.g. Propanolol

Acetylcholine

1) Acetoxy, ethylene bridge, and 4 amine are ALL essential

 You can’t change, but can add nang kaunti.

4 ° 3 ° (↓ effect)
→

Propranolol Ethylene 3 C( ↓effect )

→

SAR of -blockers (2 classes)

1) Quinazolines
Acetoxy Ether (↓ effect)
→
 (4) amino group in the quinoline ring is
essential for 1 antagonistic activity 2) Overall size of the molecule cannot be altered.
 At the 2nd position of the quinolone ring, any 3) -CH3 of the acetoxy cannot be extended but piliting palitan
heterocyclic moiety (either piperazine or
piperidine) retains activity Conformation of Acetylcholine:
 E.g. (-zosin) Prazosin, Doxa, Tera

***Several freely rotatable single bonds

Gauche, staggered, ____

Instabilities of rotation:
1) Acid sensitivity
Prazosin  Neighboring group participation

2) Non-quinazolines
 Only non-quinazolines -blockers: Tamsulocin
(very big)

Cholinergic Agents
2) Susceptibility to esterases
Solutions to Instabilities to Rotation:
1) Address acid sensitivity
Cholinergic Agents  + e- withdrawing group to partial (-) charge
at carbonyl O

A. Direct-Acting Cholinergic Agonists

Direct-Acting Cholinergic Agonists
 Bind to nicotinic & muscarinic receptors to where ACh H2N
binds
2) Address susceptibility to esterases
Requirements for Cholinergic Drugs:  “Umbrella Effect”
1) Stabilized to stomach acid & esterases  Block the access of acetoxy group to the active
2) Selectivity to cholinergic receptors site of the enzyme
3) Knowledge to binding site

SAR of Acetylcholine:

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 Organic Medicinal Chemistry  Antidotes for organophosphate poisoning:
a) Hydroxylamine
 1st organophosphate antidote
 Serine ???
 Very toxic
Methacholine b) Pralidoxime
 IM
3) Combination of EN group and bulky group  More potent than Hydroxylamine
 Note: can be used if there’s no aging

C. Cholinergic Antagonists
General Structure of Cholinergic Antagonists:
Betanechol  Same to H1 antihistamines

B. Indirect-Acting Cholinergic Agonists

Structural Features of Cholinergic Antagonists:
Indirect-Acting Cholinergic Agonists 1) 3 or 4 amine (ionized)
 Inhibits Acetylcholinesterase 2) Acetoxy
3) Ethylene
1) Physostigmine 4) N-alkyl group can be larger than methyl
 From Calabar beans (Physostigma venenosum) 5) R’ = aromatic/heteroaromatic

Cell Wall Synthesis Inhibitors

Cell Wall Synthesis Inhibitors

A. Penicillins
Physostigmine Penicillins
 Alexander Fleming
 Derived from cysteine & valine
 SAR of Physostigmine:  Overall shape of the molecule is “half-open book”
a) With carbamate – essential and is equivalent
to the ester group of ACh
b) Pyrrolidine N – essential and is equivalent to
(40) amino group of Ach


Physostigmine analogues:
a) Miotine
b) Neostigmine
2) Organophosphates
 MOA: irreversibly inhibit the AChE by forming Penicillin
covalent bond w/ -OH of serine residues of SAR of Penicillins:
enzyme
 E.g.
a) Nerve gases: Tabun, Sarin, Soman
b) Medicinal organophosphates: Ecothiophate
(Tx for glaucoma but no longer used)
c) Organophosphate insecticides:
Malathion , metabolism Malaoxon,
Parathion → Paraoxon

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 Organic Medicinal Chemistry  + isoxazolyl group

Penicillin
R1HN
Instabilities of Penicillins:
1) Acid sensitivity (like Acetylcholine) Isoxazolyl Penicillin
 Neighboring group participation
 Examples of Isoxazolyl Penicillin

Oxacillin Cloxacillin
2) Susceptibility to -lactamase
 -lactamase – produced by bacteria to
hydrolyze -lactam ring

Solutions to Instabilities of Penicillins:

1) Vary the R group to make it e- withdrawing to
nucleophilicity of carbonyl oxygen Dicloxacillin Fluoxacillin

***Extended-spectrum

B. Cephalosporins
General Structure of Cephalosporins:

Phenoxymethylpenicillin or Pen V

2) “Umbrella Effect”
 Block the access of Penicillin to the active site
of the enzyme by introducing bulky groups

Cephalosporins
Short-acting
Structural Features of Cephalosporins:
1) -lactam ring
2) –COOH
3) Acyl amino
Methicillin 4) cis stereochemistry
3) Combination of EN & umbrella effect New:

“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD
 
Organic Medicinal Chemistry
Cephalosporins have different SARs because there are
(5) generations of cephalosporins so they have Tetracylines
different spectrums also.  Derivatives of octahydronaphthalene  hydrocarbon
consisting of (4) annulated (6)-membered ring

Sulfonamides General Structure of Tetracyclines:

General Structure of Sulfonamides:

NHR2

Sulfonamides Tetracycline
SAR of Sulfonamides:
1) Para-amino group should be substituted only w/ H  Classified according to DOA:
1 amine except R1 = acyl (amide).
Chlortetracyline
Short
Oxytetracyline
 Amide is inactive but metabolized in the body to
liberate the active drug   Sulfanilamide is a
Demeclocyline
prodrug (active: ionized) Intermediate
Methacyline
2) Aromatic ring & sulfonamide are both essential.
3) The sulfonamide group should be directly attached to
Doxycycline
the aromatic ring (no carbon spacers). Long
Minocycline
4) Aromatic ring should be para-substituted only. No
ortho- & meta-.
5) Sulfonamide N should be either 1 or 2. Very long Tigecycline
6) R2 is the only possible site for variation.

Sulfonamide
Summary of Bacterial Sources of
Based on absorption site Antibacterials
Cycloserin Streptomyces orchidaceus
Vancomycin Streptomyces orientalis
SULFONAMIDE Daptomycin Streptomyces roseosporus
Steptomycin Streptomyces griseus
Macrolides (Erythromycin) Streptomyces erythreus
Chloramphenicol Streptomyces venezuelae
Lincosamide Streptomyces lincolnensis
Oral, Oral, Rifamycin Streptomyces mediterranae
Topical Amphotericin B Streptomyces nodosus
absorbable non-absorbable
Ivermectin Streptomyces avermitilis
Capreomycin Streptomyces capreolus
Tetracyclines Streptomyces aureofaciens
Bacitracin Bacillus subtilis
Polymyxin B Bacillus polymyxa
Intermediate-
Long-acting
Teicoplanin Actinoplanes teicomyceticus
acting Mupirocin Pseudomonas fluorescens
Aztreonam Chromobacterium violaceum
Gentamicin Micromonospora purpurea

Tetracyclines
“Give it all you’ve got. And trust that it will give back.” 
MANOR Lecture transcribed by ValdezCLD