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Thus, non-critical part of a drug molecule is not involved in drug receptor interactions
but is involved in passive transport of the drug.
While any change or modification of critical part of the drug molecule will result in the
change of its biological activity, only those groups having similar steric, electronic and
solubility characteristics can be interchanged. The study of such groups (bio-isosters) and
their application in medicinal chemistry is known as Bio-isosterism.
More recently Burger classified and subdivided bio-isosters as:
(1) Classical bio-isosters:
(a) Monovalent atoms and groups, e.g. CH2, NH2, OH and SH.
(b) Divalent atoms and groups, e.g. R–O–R', R–NH–R', R–CH2–R' and R–Si–R'
(c) Trivalent atoms and groups, e.g. R – N = R', and R – CH = R'
r r
(d) Tetrasubstituted atom, e.g., = C =, = N =, and = P =
(e) Ring equivalents, e.g. – CH = CH –, – S –, – O – , – NH and – CH2 –
(2) Non-classical bio-isosters:
These non-classical bio-isosters do not rigidly fit the steric and electronic rules of the
classic bio-isosters. These are further subdivided into,
(a) Exchangeable groups
(b) Rings versus non-cyclic structures.
BIO-ISOSTERIC APPLICATIONS
(1) An important compound of catecholamine series is phenylephrine.
OH
CH — CH2 — NHCH3
HO
Phenylephrine
An alkylsulphonamido group may be substituted for the phenolic hydroxyl group. Some
of the resulting compounds have agonist activity whereas others are antagonist.
OH
CH — CH2 — NH2
RO2SNH
Alkylsulphonamidophenylethanolamine
While a classic example of rings versus non-cyclic structures is diethylstilbestrol and
estradiol.
OH
OH
HO HO
Diethyl stilbestrol Estradiol
Medicinal Chemistry-I 2.17 Physico-Chemical Parameters & Drug Action
Diethylstilbestrol has about the same potency as the naturally occurring estradiol. The
central double bond of diethyl stilbestrol is highly important for the correct orientation of
the phenolic and ethyl groups (trans) at the receptor site. Table 2.6 contains a variety of bio-
isosters including classical and non-classical examples, incorporating marketed drugs as well
as interesting experimental compounds.
Applications of bio-isosterism were also found in the designing of histamine -1- receptor
antagonists and anticholinergics (antispasmodics) by replacing benzene by thiophene,
The first application of classical isosterism may be found in ring equivalents. Examples
include pyridine and thiazole, benzene and thiophene.
The sulphur atom of the phenothiazine ring system of neuroleptic agents was replaced
by – CH = CH – or – CH2CH2 – leading to the azepine ring analogues that opened up the
field of tricyclic antidepressants. In imipramine by isosteric exchange of N – with C =,
amitriptyline was obtained.
The purpose of molecular modification is usually to seek subtle change in the compound
that should not alter some properties but change others in order to improve potency,
selectivity, duration of action and reduce toxicity. Bioisosterism makes it possible to limit
some of these changes. All aspects considered, retention of overall molecular shape is the
overriding condition for analogy of action.
In the design of bio-isosters an appreciation of the biochemical mode of action may play
an important role e.g., aspirin acetylates prostaglandin synthetase and thereby deactivates
this enzyme which ordinarily catalyses the biosynthesis of nociceptive prostaglandins.
Isosters of aspirin in which the phenolic oxygen atom (X) has been replaced by 'classical'
isosteric groups or atoms are inactive because they cannot release the acetyl group at all
(X = CH2) or at an adequate rate (when X = S, NH).
OH OH
O N
H RO2S H
Receptor Receptor
Medicinal Chemistry-I 3.2 Drug Metabolism
Some drugs are considered biochemically inert as they have been excreted unchanged
i.e. without any metabolic transformation e.g., barbitone, diethyl ether, only because they
cannot easily penetrate the lipoprotein membrane of tissues and were rapidly excreted by
active transport mechanisms of kidney.
Metabolic conversions
Storage
sites Oxidases
reductases Polar drug
hydroxylases metabolite
Lipophilic
drug
Free lipophilic
drug
Conjugation
Elimination
Kidney Liver Lungs
Fig. 3.2
Cl OH Cl
Cl — C — CHOH Cl — C — COOH
Cl Cl
Chlorol hydrate Trichloroacetic acid
(3)
(4)
Medicinal Chemistry-I 3.4 Drug Metabolism
(5)
(6)
(8)
(9)
Medicinal Chemistry-I 3.5 Drug Metabolism
(10) Sulphoxidation:
Other oxidative reactions: These include sulphur atom replacement reaction and ring
formation. Former is an important and significant metabolic reaction for thiobarbiturates
and for phosphorothionate insecticides. Parathion through the latter reaction, is transformed
to a very toxic compound, paraxon (an active cholinesterase inhibitor in mammals) by the
liver microsomes as shown in Fig. 3.3.
O O
C2H5 C2H5
HN HN CH3
CH(CH3)CH2CH2CH3 CH
(O) C 3H 7
S N O O N O
H H
Thiopental Pentobarbital
OC2H5 S OC2H5
O
O2N O—P=S O2N O—P O2N O—P=O
(O)
OC2H5 OC2H5 OC2H5 OC2H5
Parathion Paraxon
Low antichloine-estrase activity High anticholine-estrase activity
Fig. 3.3
Medicinal Chemistry-I 3.6 Drug Metabolism
[B] Reduction:
These processes play an important role in the metabolism of many compounds
containing carbonyl, nitro and azo groups. Bioreduction of carbonyl compounds generates
alcohol derivatives, while nitro and azo reduction leads to amino derivative. Since, the
hydroxyl and amino groups are much more susceptible to conjugation than the functional
groups of the parent compounds, reductive processes facilitate the drug elimination.
Examples:
(1)
OH
– H2O
Cl3C — C — OH Cl3C — CH2OH
H
Chloral hydrate Trichloroethanol
(2)
NO2 NH2
+H
Nitroreductase
HOCH O HOCH O
CH—NH—C—CHCl2 CH—NH—C—CHCl2
CH2OH CH2OH
Chloramphenicol Arylamine
(3)
NH2 NH2
NH2
+H
H2N N=N SO2NH2 +
Azoreductase
NH2
SO2NH2 NH2
Prontosil Sulphanilamide
(4)
N N
O
CH3 (1) Bis-N-de-methylation
CHCH2CH2N CHCH2C — H
CH3 (2) Oxidative deamination
Cl Cl
N
Chlorpheniramine
Reduction
CHCH2CH2OH
Cl
Medicinal Chemistry-I 3.7 Drug Metabolism
(5)
O
C OH
OH CH2 CH3 OH CH2 — CH — CH3
CHC6H5 CHC6H5
+ [H]
O O O O
R (+) Warfarin
(6)
CH2 — CH — CH3 CH2 — C — CH3 CH2 — CH — CH3
[+ H]
NH2 O OH
(7)
H H
N O N O
O2N N H2N N
Cl Cl
Clonazepam
The metabolism of ester and amide linkages in many drugs is catalysed by hydrolytic
enzymes present in liver, kidney, intestine, blood and other tissues. The metabolic products
formed, namely carboxylic acids, alcohols, phenols and amines generally are polar and
functionally more susceptible to conjugation and excretion than the parent ester and
amides.
Amide hydrolysis appears to be mediated by liver microsomal amidases, esterases and
deacylases.
COOH COOH
OCOCH3 OH O
(1) + HO — C — CH3
CH3 CH3
(2)
Cl O — C — COOC2H5 Cl O — C — COOH
CH3 CH3
Clofibrate P-chlorophenoxyisobutyric acid
(3)
N N
H
C=O
H2N Metabolite
Carbamazepine
COOH
(4)
CH3O CH2COOH CH3O CH2COOH
+
N CH3 N CH3
Cl
C=O H
Cl
Indomethacin
CH3 CH3
(5) O
C2H5 C2H5
NH — C — CH2N NH2 + HOOC — CH2N
C2H5 C2H5
CH3 CH3
Lidocaine
+ HO — CH2CH2N(C2H5)2
COOCH2CH2N(C2H5)2 COOH
Procaine Para-amino benzoic acid Diethylaminoethanol
Medicinal Chemistry-I 3.9 Drug Metabolism
(1) N-dealkylation:
CH3 H
N C C CH3 N C C CH3
4 3
CH3 CH3
2
C N C5 1 N
O N CH3 O N CH3
Aminopyrine Antipyrine
(2) O-dealkylation:
NHCOCH3 NHCOCH3
H5C2O HO
Acetophenetidine p-Hydroxyacetanilide
N — CH3 N — CH3
H3CO O OH HO O OH
Codeine Morphine
(3) Aromatization:
COOH COOH
OH CH — COOH CH — COOH
CH3O
OC6H5
Salicylic acid Naproxen Fenoprofen
Medicinal Chemistry-I 3.12 Drug Metabolism
Sulphate conjugates are formed by the reactions of phenolic and aliphatic hydroxyl
group and of certain amino groups with an activated form of sulphate through an ether
linkage. Hence, they are also termed as "etheral sulphates". Sulphate conjugation generally
results into highly polar compounds that are readily excreted in the urine. The soluble
fraction of liver contains the enzymes that catalyse the sulphur activation and transfer of
sulphate to the substrate.
The sulphate moiety is present in activated state in 3' - phosphoadenosine - 5' -
phosphosulphate (PAPS). The sulphotransferase enzyme then catalyses the transfer of
sulphate group to the phenolic acceptor. The sulphotransferase enzymes are structure
specific. Hence for different substrates, specific sulphotransferase enzymes catalyse the
reactions.
R
O O
Adenine
+ HO — S — O — P — O — CH2 R
O OH O
OH
O O
HO — P — OH O — S — OH
O O
Sulfate conjugate
Medicinal Chemistry-I 3.13 Drug Metabolism
O Cl O O O
C — NHNH2 C — OH C — NHCH2C — OH
Hydrolysis
N N N
Isoniazid Isonicotinic acid Glycine conjugate
O O O O
(2) C C C C
NH CH3 N CH3 NH CH3 NH CH3
GSH CH
d+ S — CH2 COOH
OH O OH
C=C C—C
H H H2
S — CH2 — CH — COOH
NHCOCH3
Diethylmaleate Mercapturic acid conjugate
HS
NH2
H 2C H
HC N H 2C CH — COOH
C H2C
O=C
O
N CH2 or HS — G
H
COOH
Glutathione
Medicinal Chemistry-I 3.15 Drug Metabolism
O = C — NH CH2 O = C — NH CH2
Procainamide
NH2 NHCOCH3
N-Acetyltransferase
Dapsone
(3) Sulphonamides:
NH2 NHCOCH3
N-Acetyltransferase
N N
O2SNH O2SNH
N-Acetyltransferase
Phenelzine
CONHNH2 CONHNHCOCH3
N-Acetyltransferase
N N
Isoniazid
HO HO
Phenyl ethanolamine
HO CH — CH2 — NH2 HO CH — CH2 — NHCH3
N-methyl transferase
OH OH
Norepinephrine Epinephrine
Medicinal Chemistry-I 3.17 Drug Metabolism
(1) O-methylation:
I I
Hydroxy indole-o-methyl
HO COOH CH3O COOH
transferase
I I
4-hydroxy-3,5-diiodo benzoic acid
HO CH3O
Catechol-o-methyl transferase
HO COOH HO COOH
3, 4-dihydroxy-benzoic acid
(2) N-methylation:
HO HO
Phenyl ethanolamine
HO CH — CH2 — NH2 HO CH — CH2 — NHCH3
N-methyl transferase
OH OH
Norepinephrine Epinephrine
Medicinal Chemistry-I 4.8 Drugs Acting on Autonomic Nervous System
Site 1: Acetylcholine synthesis can be blocked by styryl pyridine derivatives such as NVP.
Site 2: Acetylcholine transport into vesicles is blocked by vesamicol (AH 5183). (±) Vesamicol
is a potent inhibitor of vesicular ACh storage with L (-)-Vesamicol being more potent
than D(+) - Vesamicol.
Release is promoted by -bungarotoxin, black widow spider venom, and Ca . Release
++
Site 3:
++
is blocked by botulinum toxin, cytochalasin B, collagenase pre-treatment, and Mg .
Site 4: Postsynaptic receptors are activated by cholinomimetic drugs and anticholinesterases.
Nicotinic receptors, at least in the peripheral nervous system, are blocked by rabies
virus, curare hex amethonium, or dihydro-β-erythroidine; n-methylcarbamylcholine and
dimethylphenyl piperazinium are nicotinic agonists. Muscarinic receptors are blocked by
atropine, pirenzepine, and quinuclidinyl benzilate.
Medicinal Chemistry-I 4.9 Drugs Acting on Autonomic Nervous System
Site 5: Presynaptic muscarinic receptors may be blocked by AFDX - 116 (an M2 - antagonist),
atropine or quinuclidinyl benzilate. Muscarinic agonists (e.g. oxotremorine) will inhibit
the evoked release of acetylcholine by acting on these receptors.
Site 6: Acetylcholinesterase is inhibited reversibly by physostigmine (eserine) or irreversibly by
DFP.
Site 7: Choline uptake competitive blockers include hemicholinium 3, troxypyrrolium tosylate.
The biosynthesised acetylcholine is stored within the synaptic vesicles immediately inside
the membrane of the nerve terminal. Each vesicle is expected to contain about 5,000 -
10,000 molecules of acetylcholine. The number of such vesicles present in the nerve terminal
varies in different organs. For example, a motor nerve terminal may contain 300,000 or more
synaptic vesicles.
When an impulse reaches to nerve terminal depolarisation causes an activation of
calcium ionophore. It allows an influx of extracellular calcium ions which is an essential step
for the rupturing of storage vesicles of almost all neurotransmitters. The extracellular
calcium then leads to the release of acetylcholine from the vesicles. Four calcium ions are
taken up for each molecule of acetylcholine released. The ruptured synaptic vesicles again
re-shape to store fresh neurotransmitter.
The vesicular release of acetylcholine is reported to be inhibited by excess of magnesium
ions. The released acetylcholine along with extracellular calcium ions then mobilise intra-
cellular calcium ions from the sacs present on sarcoplasmic reticulum. The increase in the
concentration of free intracellular calcium ions then activates calmodulin dependent myosin
light chain kinase and phosphorylation of myosin, in turn, creates the conditions that initiate
muscle contraction. In general, minimum concentration of calcium ions needed to evoke
muscle contraction is estimated to be 10–6 mol/litre.
The free acetylcholine present in blood and other tissues, gets quickly hydrolysed by
either e-cholinesterase (present in erythrocytes) or s-cholinesterase (present in serum). Upon
hydrolysis, acetylcholine is converted into acetic acid and choline molecule.
The cholinesterase enzyme is present in high concentration in the synapses of both,
cholinergic and somatic nerves and striated muscle. Hydrolysis occurs in the immediate
vicinity of the nerve ending. At the neuromuscular junction, hydrolysis occurs at the end
plate region after acetylcholine has initiated the muscle twitch. In the autonomic ganglia,
cholinesterase is usually present in the preganglionic fibre. While serum esterase is present
in glial cells, plasma, liver and at other sites.
Cholinesterase enzymes are present in two different forms.
(i) Simple oligomers of a 70,000 dalton catalytic subunit, and
(ii) Elongated forms of complex structure.
The cholinesterases are not very selective enzymes. Both these types hydrolyse a large
number of esters, both of, choline and other carboxylic acids. Cholinesterase is one of the
most efficient enzyme present in the body. It can hydrolyse about 3 × 105 acetylcholine
molecules per mole per minute.