S.P.Sethy et al. / AJPSR volume 3 issue 1, Jan.

2013

Available online at www.ordonearresearchlibrary.com ISSN 2249 - 4898

Review- Article

ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH

THE ROLE OF BIOISOSTERISM IN MOLECULAR MODIFICATION

AND DRUG DESIGN: A REVIEW

S.P.Sethy*1, C.P.Meher1, S.Biswal1 ,U.Sahoo1, S.K.Patro1

Department of Medicinal Chemistry, Institute of Pharmacy and
Technology,Salipur,Cuttack,Odisha-754202

Received: 26 Nov. 2012; Revised: 19 Dec. 2012; Accepted: 14 Jan. 2013; Available online: 5 Feb. 2013

ABSTRACT
This review aim to demonstrate the role of bioisosterism in rational drug design as well as in the
molecular modification and optimization process aiming to improve pharmacodynamic and
pharmacokinetic properties of lead compounds
Keywords:- bioisosterism, pharmacodynamic

INTRODUCTION

Bioisosterism is a statergy of medicinal chemistry for the rational design of drugs, applied to a
lead compound as a special process of molecular modification.The lead compound should be a
completely well known chemical stracture and possess an equally well known mechanism of
action.The success of this statargy in developing a new drug molecules which are
therapeutically active has observed a significant growth in distinct therapeutic class used by the
pharmaceutical industry to discover new analogue of therapeutic inventions commertially
attractive,and also serve a tool useful in molecular modification. There are many reasons for the
use of bioisosterism to design new drug including the necessicity to improve pharmacological
activity,gain selectivity for determined receptor or enzymatic isoform sub type with simultaneous
reduction of adverse effect or even optimize the pharmacokinetics. In this review we will
highlight bioisosterism as a statargy of molecular modification showing its importance in
building a new series compounds designed as candidate of new drug.

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DEFINATION:

Replacement/modification of a functional group by an another group having similar

physicochemical properties known as bioisosterism. Isosteres are of vital importance to
medicinal chemist because the biological characteristics of isosteres appear to be similar more
frequently than their physicochemical characteristics.
3.BACKGROUND:
In 1919 langmuir, studying the chemical behavior and the reactivity of determined substances
possessing atoms and groups with same no of valance electron, i.e isoelectronic,created the
concept of isosterism to defined atoms or organic or inorganic molecules or atoms which
possess the same number and arrangement of electrons.
FIGURE-1

1 Cu+2,Zn+2

2 N3,NCO

3 N2,COCN

4 CH4,NH4

5 CO2,N2O,N3,CNO

(Langmuir law)

In 1925 Grimm formulated the hydride displacement law,an empirical rule which of a hydrogen
atom with a pair of electron (i.e hydride) to an atom produces a pseudo atom states that the
addition presenting the same physical properties as those present in the column immediately
behind on the periodic table of the elements for the initial atom (Fig. 2), showing that any atom
belonging to groups 4A, 5A, 6A &7A on the Periodic Table change their properties by adding a
hydride, becoming isoelectronic pseduoatom.

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FIGURE-2

(Grimm’s Hydride Displacement Law)

In 1932, Erlenmeyer proposed a broadening of the term isosterism, defining isosteres as

elements, molecules or ions which present the same number of electrons at the valence level. His
contribution includes the proposition that elements of the same column on the Periodic Table are
isosteres among themselves (e.g. C x Si x Ge) and the creation of a concept of rings
electronically equivalent, later broadened to the term ring bioisosterism.

FIGURE-3
4 5 6 7 8
N+ P S Cl ClH
P+ As Se Br BrH
S+ Sb Te I IH
As+ Ph SH SH2

The coining of the term bioisosterism goes back to the pioneer work of Friedman and Thornber
during the early 50s. Friedman recognizing the usefulness of the concept isosterism to design
bioactive molecules, defined bioisosters as compounds which fit the definitions of isosteres and
which exercise their biological activity of bioreceptor, whether through agonist or antagonist
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actions. However, Friedman introduced the term bioisosterism to describe the phenomenon
observed between substances structurally related which presented agonist or antagonist
biological properties. Later, Thornber proposed a broadening of the term bioisosteres, defining
them as subunits or groups or molecules which possess physicochemical properties of similar
biological effects. broadened to the term ring bioisosteres,. defining them as subunits or groups
or molecules which possess physicochemical properties of similar biological effects.

Over the years, innumerous bioisosteric relations have been identified in compounds
both natural and synthetic origin. In nature, we have identified many examples of isosterism as a
form of broadening chemodiversity (Scheme 1),striking among which are the classic bioisosteric
relation existing between the essential amino acids serine (1) and cysteine (2), tyrosine (3) and
histidine (4) among the pyrimidine and purine bases cytosine (5) and uracile (6), adenine (7) and
guanine (8), among the xanthines caffeine (9) and theophyline (10); and among the salicylic (11)
and anthranilic (12) acids, which originated two important classes of non-steroid anti-
inflammatory drugs, e.g. acetylsalicylic acid and mefenamic acids, respectively. Furthermore,
examples of the application of non-classic bioisosterism are also found in nature - such as the
bioisosteric relationship existing between γ-aminobutyric acid (GABA) (13) and) muscimol (14),
between the neurotransmittors glutamate (15) and AMP(16).

SCHEME-1
O O
O
OH
OH
HO OH
NH2
NH2 HS NH2 HO
(1) (2) (3)
NH2 OH O

O
N N HN

HN OH
O N O N O N
N H2N H H H

(4) (5) (6-a) (6-b)

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O O
H2N CH3 H
H3C
O H3C N N
N N
N N
N HN
N N N
O N O
N N H2N N N
H H CH3 CH3

(7) (8) (9) (10)

O O

OH OH N O
O
H2N NH2
NH2 OH
HO
OH

(11) (12) (13) (14)

OH OH

OH
O O
N
O
H2N NH2
O
OH H3C

(15) (16)

So bioisosteres are the functional groups that have similar spatial and electronic character.in
many case replacement of a group with a bioisosteres result in a new compound that retains the
activity of the parent. Thus this approach is common in pharmaceutical industry,since it allows
them to generate marketable analogue of a known drug that has a patentable composition of
matter.The common isosteric replacement are,
R
R H 3C
NH O
O H3C

≡ N ≡ S , HO ≡ OH
O O
H3C
O S R R CH2
R ≡ R , H3C ≡

CLASSIFICATION OF BIOISOSTERISM: CLASSICAL AND NON-CLASSICAL

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In 1970, Alfred Burger classified and subdivided bioisoteres into two broad categories: Classical
and Non- Classical.
BIOISOSTERES
CLASSICAL NON CLASSICAL
Monovalent atoms Cyclic Vs Non cyclic
Divalent atoms Functional groups
Trivalent atoms Retroisosterism
Tetravalent atoms

Burger’s definition significantly broadened this concept, now denominating those atoms or
molecular subunits or functional groups of the same valence and rings equivalents as classic
bioisosteres. (Table 1) while non-classic bioisosteres(Table 2) were those which practically did
not fit the definitions of the classical bioisosteres.

 Classic Bioisosteres(Table 1)
1.1 Monovalent atoms or groups.
1.2 Divalent atoms or groups.
1.3 Trivalent atoms or groups.
1.4 Tetrasubstituted atoms.
 .Non-Classic Bioisosteres(Table 2)
2.1 Cyclic vs Noncyclic.
2.2 Functional groups
2.3 Retroisosterism.
 CLASSICAL BIOISOSTERIC GROUPS AND ATOMS .(TABLE-1)
Monovalent Divalent Trivalent Tetravalent
-F, -Cl, -Br -CH2-, =CH- =C=
-I, -SH, -PH2 -O- =N- =Si=
-Si3, -SR, -S- =P- =N+ =
-OH, -NH2 -Se- =As- =P+ =
-CH3, -OR -Te- =Sb- =As+ =

 NON CLASSICAL BIOISOSTERIC GROUPS.(TABLE-2)

--CO- -COOH -SO2NH2 -H -CONH -COOR
--CO2- -SO3H -- -F -NHCO- -ROCO- -
PO(OH)NH2
-SO2- -tetrazole
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-SO2NR- -SO2NHR -OH -

-SO2NH2 -CH2OH catechol
-CON- -3-hydroxyisoxazole -- 3hydroxyisoxazole
benzimi-
dazole
- - -NHCONH2
CH(CN)- 2hydroxychromones
R-S-R -NH-CS-NH2
(R-O-R’) =N-
R- C(CN)=R’ -NH-C(=CHNO2)NH2,
N(CN)- -NH-C(=CHCN)-NH2
-halides
-CF3
-CN

BIOISOSTERISM AS A STRATEGY OF MOLECULAR MODIFICATION.

Among the most recent numerous examples used in the strategy of bioisosterism for designing
new pharmaco therapeutically attractive substances, there is a significant predominance on non-
classic bioisosterism distributed in distinct therapeutic categories, be they selective receptor
antagonist or agonist drugs, enzymatic inhibitors or anti-metabolites. The use of classic
bioisosterism for the structural design of new drugs, while less numerous, has also been carried
out successfully.The correct use of bioisosterism demands physical, chemical, electronic and
conformational parameters involved in the planned bioisosteric substitution, carefully analyzed
so as to predict, although theoretically, any eventual alterations in terms of the pharmacodynamic
and pharmacokinetic properties which the new bioisosteric substance presents.Thus any
bioisosteric replacement should be rigorously preceded by careful analysis of the following
parameters.

a) size, volume and electronic distribution of the atoms or the considerations on the degree
of hybridization polarizability, bonding angles and inductive and mesomeric effects when
fitting;

b) degree of lipidic and aqueous solubility, so as to allow prediction of alteration of the

physicochemical properties such as logP and pKa.

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c) chemical reactivity of the functional groups or bioisosteric structural subunits, mainly to

predict significant alterations in the processes of biotransformation, including for the
eventual alteration of the toxicity profile relative to the main metabolites.

d) conformational factors, including the differential capacity formation of inter- or

intramolecular hydrogen bonds.

BIOISOSTERISM AND ALTERATIONS OF PHYSICOCHEMICAL PROPERTIES.

Some bioisosteric groups dramatically alter the physicochemical properties of substances and,
therefore, their activities. This can be easily understood by comparing classic isosteres resulting
from bioisosteric replacement between hydroxyl (–OH) and amine (–NH2), an example of
classic bioisosterism of monovalent groups according to Grimm’s Rule. In this case, considering
the bioisosteric replacement of aromatic amine present in aniline(18) by hydroxyl, we have
phenol (17) resulting in a significant change in the acid-base properties of isosteres, with
dramatic modification of the pKa of the compounds. in question molecular recognition of a given
receptor site, we have a change form one positively charged function (-NH3+) originating from
basic aromatic amine function (pKb = 9,30) by another acid (pKa = 10.0) present in phenol,
which may, quite probably, abolish the original activity. Thus, in this example, we may predict
that the use of bioisosterism, even the classic type, can promote severe alterations of even the
classic type, can promote severe alterations of even the classic type, can promote severe
alterations of even the classic type, can promote severe alterations of even the classic type, can
promote severe alterations of even the classic type, can promote severe alterations of even the
classic type, can promote severe alterations of molecular properties, as much in terms of lipidic-
aqueous molecular properties as much in terms of lipidic-aqueous solubility as well as chemical
reactivity, among others, which, broadly speaking, is not observed in the same homologue
carbonic series. Otherwise, the system’s enzymatic capacity for hepatic detoxification of
xenobiotics, involving the microsomal mixed function oxidase also called cytochrome P-450
system , is distinct in the presence of these functional isosteric groups, which does not allow a
simplistic comparison between the lead compound aniline (18) and the hydroxylated isostere
(17) in terms of metabolism, altering, therefore, the pharmacokinetic phase as well as the
pharmacodynamics of the isosteres.

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OH NH2

PHENOL ANILINE
(17) (18)

Another classic example of isosteric replacement involving phenol (PhOH), can be found in the
search for adrenergic derivatives, structurally related to catecholamines.
O
O
NH
NH O CH3
CH3 H3C
S
NH
HO O
(19) (20)

This example illustrates the exchange of phenolic hydroxyl group present in compound (19) with
the arilsulfonamide unit in compound(20), through the use of non-classic bioisosterism of
functional groups.Thus, when bioisosteric replacement occurs in functional groups involved in
the pharmacophore subunit of a certain bioactive substance, the relative activity of the resulting
compounds may be dramatically modified. However, bioisosteric replacement which
successfully occurs in a series of compounds acting as a type of bioreceptor, will not necessarily
be successful in another therapeutic series acting through other receptors.

CLASSICAL BIOISOSTERISM

 APPLICATION OF CLASSICAL BIOISOSTERISM IN DRUG DESIGN.

 Replacement of monovalent atom.
 EXAMPLE-1
H H
N O N O

NH NH
H F
O O
URACIL 5- FLURO URACIL

 EXPLANATION:The substitution of hydrogen atom by fluorine is the one of the most

commonly employed monovalent isosteric replacement. Steric parameter for hydrogen and
fluorine are similar.Their vanderwall redii is 1.2 & 1.35A.

 The substitution of’ H’ atom by ‘F’ atom result in the formation of 5-fluro uracil which is
having Anti neoplastic activity.

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 EXAMPLE-2
NH2 CH3

O O
S S
O O
HN HN
NH NH
O O
CH3 CH3
CARBUTAMIDE
TOLBUTAMIDE

 EXPLANATION: The replacement of NH2 group in carbutamide by CH3 group gives

tolbutamide. Both are oral hypoglycemic agent,but tolbutamide having extended biological
half life & reduced toxicity.

 EXAMPLE-3
F F

N
N
F H3C
F

N F
N
F
O
S O S O
H3C NH2
O
COMPOUND-1 CELECOXIB
SI(COX-2/COX-1)>1OOO SI (COX2/COX1) =375
t1/2 = 211h t1/2 = 8 to 12 h

 EXPLANATION: In spite of the high rate of selectivity by PGHS-2(Prostagladin-H

Synthase-2)(SI> 1000) and good inhibitory potential, the compound-1 ,exhibited a half-life
of over 200 h, thus reflecting its low susceptibility in the presence of the complex enzyme
involved in the hepatic metabolism of xenobiotics.

 Here are two classic monovalent bioisosteric group replacement,represented by Replacing

the CH3 group(in compound-1) byNH2 group & the F atom(in compound-1) with CH3
group. Both the isosteric replacement allows the introduction of a new bioisostere of
compound 1,i.e CELECOXIB.
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 Taking the advantage of the effect first passage through reaction of conjugation with
glucoronic acid & benzylic hydroxylation catalysed by CYP450. The new bioisostere
optimized by compound 1 is CELECOXIB.

 EXAMPLE-4

O
H CH3 O
N CH3
HN
O N
O N

HO O HO O

- +
N N N HO
ZIDOVUDIN(AZT) THIAMINE

 EXPLANATION: Zidovudin; (AZT) an important chemotherapeutic agent for the

treatment of AIDS. It is a powerfull inhibitor of RTs(Reverse Transcyyptase enzyme)
 Thiamine which is used for normal biosynthesys of DNA&RNA,isosteric replacement of
OH( in thiamine) by N3 gives AZT.
 EXAMPLE-5
OH

N
N

H2N N N
H
SH

N
N

H2N N N
H
GUANINE 6- THIO
GUANINE

 EXPLANATION: The replacement of OH group(in Guanine) by SH group to produce 6-

THIO GUANINE which is based on the ability of SH group to form HYDROGEN
BOND with the receptor. The anti neoplastic agent 6-thio guanine inhibit the enzyme
HGPT(Hypoxanthene Guanine Phosphorybosyl Transferase).

Replacement of divalent atoms or groups.

 EXAMPLE-6
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Cl
H
N NH

N
Cl
O
NH
N
H

CLONIDIN(1)
RILMENIDIN(2)

H
NH
N
H H

H3C
NH
N
H3C H

COMPOUND(3)
COMPOUND(4)

 EXPLANATION: Search for a new anti-hypertensive drug analogus to CLONIDINE,

Schann and coworkers describe the attainment of a new anti-hypeertensive drug designed
by molecular modification in the stracture in the lead compound RILMENIDIN
 Replacement of the bivalent O atom present in the oxazoline ring of Rilmenidin by the
CH2 group in the stracture of new pyrrolidine derivative(3) & the substitution of
monovalent H(in compound -3) at C-4 & C-5 position by the methyl group originating
the cis/trans 4,5 di methyl derivative(compound-4).
 The binding test with I.R(imidazole receptor) and the alpha2 adreno receptor evident that
the modification occurring in the stracture of Rilmenidin allow the attachment of
derivative with affinity compairable to the lead compound(i.e. Rlmenidin).

 EXAMPLE-7

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O
O
O S
+
S N
O O NH
CH3
OH
NH2

CH3
AMPRENAVIR(1)

NH2
O S O
O
S
O NH N
O
OH CH3

CH3
COMPOUND(2)

 EXPLANATION: To develop a new protease inhibitor Rocheblave and co worker

describe the bioisosteric changes between CH2 group present in the stracture of the lead
Amprenavir for a sulphar atom in compound(2).
 The newer isosteres were synthesized and its stereoisomers were duly separated by HPLC
& tested as recombinant HIV protease inhibitor.
 The result revailed that the 4 diastereoisomer tested were only weak inhibitor if HIV
protease.
 This result could explain by the high sensitivity to hydrolysys of the isosteres.
 EXAMPLE-8
CH3 CH3
O
N
N CH3
O CH3 NH
H2N
O H2N
PROCAIN
PROCAINAMIDE

 EXPLANATION: The replacement of the oxygen atom by NH group in the procain gives
procainamide. The local anesthetic activity of procain is more than
procainamide due to higher lipid solubility.
 EXAMPLE-9

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CH3

HO NH2 HO N

HO HO CH3
DOPAMINE(1) COMPOUND(2)
HO

CH3
HO N

CH3

N
HO
O
HO
COMPOUND(3)
COMPOUND(4)
CH3

O
N
HO
O
HO
CH3

S
N
HO
O
HO
COMPOUND(5) COMPOUND(6)
 EXPLANATION: Bioisosteric replacement of oxygen atom by the sulphar atom results
in significant alteration in lipophilicity & it may be used in the design of a new drug to
act on CNS.
 The molecular target for design of a new anti-psychotic drug, modification in the
HEXAHYDRONAPTHOXAZINE system present tn the lead compound (3) an analog
conformationally restricted to dopamine(1), of high potency and low selectivity.
 The structural modification based on the isosteric changes of CH2 group in compound( 4)
by oxygen atom results in the generation of compound(5) & the sulphar atom in

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compound 6 respectively results in two new D3 receptor agonist.The compound 5&6

shows a significant increase in lipophilicity.

7.3 Replacement of Trivalent atoms or groups.

 EXAMPLE-10
CH3
N

N N CH3

O
H3C
H3C
N CH3
N

Cl

MEPYRAMINE CHLORPHENIRAMINE
 EXPLANATION: Subsitution of pyridinyl amino (-N=) by the (-CH=) in Mepyramine
gives Chlorpheniramine,valued for its short,powerful & freedom from sedationwhich are
the considerable effect of anti-histaminics.
 EXAMPLE-11
H3C CH3
CH3 CH3
N CH3 N CH3
HN

Cl N Cl N

( A) CHLOROQUINE

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CH3
CH3
N CH3
HN

Cl
(B)

 EXPLANATION: To understand the contribution of 4-amino quinoline subunit present

in the stracture of the first generation anti malarial(CLOROQUINE).
 Here a change in NH & N in Chloroqquine by CH2 & CH group respectively gives a
compound A&B observing the loss of anti-malarial activity.

7.4 Replacement of Tetravalent atoms or groups.

 EXAMPLE-12
CH3 CH3 CH3
O O + O O + O O +
N P As
CH3 CH3 CH3
CH3 H3C CH3 H3C CH3 H3C
ACETYLCHOLINE PHOSPHONIUM ION ARSENIUM ION
 EXAPLANATION: The interchange of quarternary charged atom with a tertiary carbon
atom has been attempted in case of cholinergic agonist.
Replacement of quarternary ammonium group with phosphonium and arsenium analegus
has resulted greater toxicity.

NON CLASSICAL BIOISOSTERES

Cyclic vs Non cyclic
 EXAMPLE-13
An example of cyclic vs noncyclic structure is diethyl stilbesterol and 17-B estrodiol.

CH3 OH OH
CH3

HO H3C HO

(Trans-Diethyl Stilbesterol) ( 17-B Estradiol)

 EXPLANATION: Diethyl stilbesterol having potency as that of naturally occurring
estradiol.The central double bond in diethyl stilbesterol is highly important for the correct
orientation of phenolic and ethyl group.

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 EXAMPLE-14

S
Cl O OH

Cl
O
H2C

O
H3C Cl O
Cl OH

COMPOUND(2)
COMPOUND(1)

S
OH

O O
O

COMPOUND(3)

 Explanaton-In the category of diuretic compounds of phenoxy acetic acid classes,

etacrinic acid compound (1) is the main representative.
 The compound(3) is a bioisostere of compound(2).The structure of compound (3) was
defined based upon the attachment of phenoxy acetate chain of compound(2) which in
turn arous by the replacement of ethylinic function present in the compound(1) by the
thiophen nucleus of compound (2).
 The uric potential of compound (3) compaired to compound(2) is even greater.

 EXAMPLE-15

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O
CH3
OH
O
CH3
N

O Cl

H O

OH
N
H3C CH3

Cl

INDOMETHACIN(1)
COMPOUND(2)

H3C O O

OH OH
N N
H3C CH3 CH3

O O

Cl CH3

COMPOUND(3) TOLMETIN(4)

O
OH

H3C N

CETROPLAC(5)

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 EXPLANATION: Bioisosteric modification leads to development of new NSAIDs called

cetroplac(5),designed from cyclic nonclassical bioisosterism stratergy taking lead
compound tolmetin(4),only tolmetin was developed by the molecular modification of
indomethacin(1).

 EXAMPLE-16
H2N

O N CH3

S
NH S
O
CH3
S
O NH
H2N S NH
O
SULPHATHIAZOLE DERIVATIVE THIOUREA
H3C

O O
S
NH NH CH3
DERIVATIVE O
CH3
O
O NH
H2N S NH
O
TOLBUTAMIDE
CARBUTAMIDE

 EXPLANATION: Sulphathiazole derivative lower the blood sugar to a fatal

level.Modification done by opening the thiazole ring to give thiourea derivative, where
the sulphur atom is replaced by oxygen atom to yield carbutamide which was latter
replaced by less toxic tolbutamide by replacing the NH2 group by CH3 in carbutamide.

 EXAMPLE-17

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O F
O

O
O
S
NH
CH3
F

O F

O
O S CH3
NH
O
FULSOLIDE(1)
COMPOUND(2)
 EXPLANATION: A bioisosteric relation between indanone ring present in the structure
of prototype fulsolide(1) and benzodiaxole unit present in the compound(2).both
compound having similar PGHS-2(Prostaglandin-H Synthase-2) or COX-2 inhibitory
property.
 EXAMPLE-18
CH3 O

NH N

CH3

CH3
CH3 CH3
O
N CH3
NH
CH3
BUPIVACAIN
LIGNOCAIN
 EXPLANATION:The local anesthetic agent bupivacaine arises from the similar
modification of side chain lignocaine,having greater lipophilic property than lignocain.

Non-Classic Bioisosterism of Functional Groups.

 EXAMPLE-19

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OH

N
N
N
N
N N
H
NICOTINIC ACID TETRAZOLE
DERIVATIVE
 EXPLANATON: The tetrazole analogue of nicotinic acid was found to be 3 times more
active in lowering the blood cholesterol level than nicotinic acid.
 EXAMPLE-20
O

NH

O S
HO CH3
O N
CH3

HO O
CH3
CH3
S
O O

N
NH OH
HN
N O
N
N
CARBENICILLIN 5’TETRAZOYL
DERIVATIVE
 EXPLANATION: Carbenicillin a broad spectrum semisynthetic antibiotic can not be
administrated orally.since the Beta carboxylic acid rappidely de carboxylate in the acidic
environment of stomach.
 That’s why the 5’tetrazole derivative of carbenicillin represents an attempt to overcome
this instability.

 EXAMPLE-21
N CH3
HN NH
S
NH S
H3C

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METIAMIDE
N CH3
HN NH
S
NH NH
H3C
COMPOUND(1)
CH3
HN

N
NH
N S
N
HN

CH3
CIMETIDINE
HN
H3C S CH3
O NH
N NH
H3C +
H N
+ O
N
-
O
RANITIDINE
 EXPLANATION:-Thiourea bioisosteres have been successfully employed in the
development of H2 receptor antagonist.
 The early drug metiamide was the first compound to show H2 receptor antagonist
property,but it produce agranulocytosis.
 The replacement with guanidine group in metiamide give compound(1),but results in
absorption problem.
 Further isosteric compound (1) with cyanoguanidine group produce cimetidine.
 Further the isosteric modification of imidazole nucleus in cimetidine gives ranitidine.

RETRO ISOSTERISM

 Retro isosterism is based on the inversion of a determine functional group present in the
lead compound structure produced an isostere with same function.
O
O
R O O
1 1
R R R
Retro isosterism
 EXAMPLE-22

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CH3
O
S H3C NH
O O
HN S
O

O O

O O

COMPOUND(1) RETRO ISOSTERISM COMPOUND(2)

 EXPLANATION:-Retro isosterism relationship between methylsulphonylamine(2) and

methyl sulphonamide(1) function present in the newer selective COX-2 inhibitor.The
greatest activity is found in methyl sulphonamide(1) derivative.
 EXAMPLE-23
CH3 CH3
O OH
N
N
O OH O O
H3C H3C
COMPOUND(1)
COMPOUND(2)

 EXPLANATION:- it was demonstrated that hydroxamic acid derivatives (1) are rapidly
metabolized to corresponding inactive carboxylic acid derivatives, which are unable to
block leukotriene synthesis. Taken together these results suggest the pharmacophoric
profile of hydroxamic acid subunit (CON(OH)CH3).

 Later, Summers and coworkers demonstrated that hydroxamic acids with 5-LOX
inhibitor activity have small substituents (hydrogen or methyl) attached to the
hydroxamic acid nitrogen and relatively large groups (aryl ring system) appended to the
carbonyl group. Based on this observation, the authors proposed the attainment of the
retroisostere(2) through the application of retroisosterism strategy in the structure of lead
compound(1).

 The study of the pharmacokinetic behavior of retroisosters (2) revealed that when
administered orally to rats, this retroisostere produced higher plasma concentrations and
longer duration.

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CONCLUSION:
As we have demonstrated in this paper, through comments made on selected examples, the
bioisosterism represents in rational drug design a successful strategy, useful in the molecular
modification and design of new therapeutically attractive substances of different
pharmacological classes including the design of drugs.The correct use of the strategy of
molecular modification also allows the identification of new classes of lead compound with
attractive pharmacotherapeutic activity, minimizing the efforts of synthetic work and,
consequently maximizing the chances for success in discovering medications both more efficient
and of safer use. In this paper, we have also demonstrated that drug discovery may be planned
when determined theoretic principles of Medicinal Chemistry are carefully applied, thus
allowing a prediction of the structural effects which govern phramacokinetic factors, such as
absorption and biotransformation; consequently, in theoretical terms we are able to predict the
expected bioavailability for the new bioactive compound designed as new drug candidate.

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