BIOISOSTERISM: A STRATEGY OF MOLECULAR MODIFICATION · In 1925, Grimm’s formulated the Hydride Displacement Law, an empiric rule which states that the addition of a hydrogen atom

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Nidhi et al. World Journal of Pharmacy and Pharmaceutical Sciences

BIOISOSTERISM: A STRATEGY OF MOLECULAR MODIFICATION

Nidhi Kala1* and Sokindra Kumar

1

R V Northland Institute, Dadri, Greater Noida, G B Nagar, Uttar Pradesh, India.

ABSTRACT

Bioisosterism is a unique strategy of molecular modification of lead

compound to improve its pharmacodynamic & pharmacokinetic

properties. The aim of bioisosterism is to boost the physical, biological

& pharmacological properties as well as rectify the toxicity of lead

molecule. The present review highlight the vital role of in Structural

activity relationship of lead molecule. Bioisosterism has played a

central role in the development of drug molecules almost from the

outset of the pharmaceutical industry. The promise of bioisosterism is

that the properties of a compound can be fine-tuned without affecting

its underlying biological activity. This promise is not however without its challenges.

Successfully applying bioisosterism to achieve the desired molecular outcome is difficult

because of the fundamental problem that chemical structure is an unreliable indicator of

biological activity. Small changes in a molecule can have a profound impact on a

compound’s activity, specificity and toxicity, whilst completely different chemotypes may

have near identical biological activity profiles. More rigorous and reproducible methods for

suggesting relevant, non-obvious and yet synthetically intuitive bioisosteres would have wide

applicability.

KEYWORDS: Isosterism, Bioisosterism, SAR, Retroisosterism.

INTRODUCTION

Bioisosterism is a strategy of medicinal chemistry for the rational drug design as well as

molecular modification and optimization process aiming to improve pharmacodynamic and

pharmacokinetic properties of lead compounds.[4]

The lead is a prototype compound that has

the desired biological or pharmacological activity.[5]

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 7, Issue 3, 411-427 Review Article ISSN 2278 – 4357

Article Received on

07 Jan. 2018,

Revised on 27 Jan. 2018,

Accepted on 17 Feb. 2018

DOI: 10.20959/wjpps20183-11131

*Corresponding Author

Nidhi Kala

R V Northland Institute,

Dadri, Greater Noida, G B

Nagar, Uttar Pradesh, India.


412


Medicinal chemists have expanded and adapted the original concept to the analysis of

biological activity. The following definition has been proposed: "Bioisosteres are groups or

molecules which have chemical and physical properties producing broadly similar biological

properties". This definition might be reformed the concept of bioisosteres which may

produced the opposite biological effects, and these effects are frequently a reflection of some

action on the same biological process or at the same receptor site.[10]

Historical Development

The concept of bioisosterism derives from Langmuir's in 1919, ―Co molecules are thus

isosteric if they contain the same number and arrangement of electrons. The co molecules of

isosteres must, therefore, contain the same number of atoms. The essential differences

between isosteres are confined to charges on the nuclei of the constituent atoms‖.[9]

O-2

x F- x Ne x Na

+ x Mg

+2

ClO4- x SO4

-2 x PO4

-3

N=N x C=O

CO2 x NO2

N=N=N x N=C=O

In 1925, Grimm’s formulated the Hydride Displacement Law, an empiric rule which states

that the addition of a hydrogen atom with a pair of electrons (i.e. hydride) to an atom,

produces a pseudoatom presenting the same physical properties as those present in the

column immediately behind on the Periodic Table of the Elements for the initial atom (Table

1), showing that any atom belonging to groups 4A, 5A, 6A, 7A on the Periodic Table change

their properties by adding a hydride, becoming isoelectronic pseudoatoms.[21]

Table 1: Grimm’s Hydride Displacement Law.

Atomic Number 6 7 8 9 10 11

Elements C N O F Ne Na

Pseudoatoms - CH NH OH FH -

- - CH2 NH2 OH2 FH2+

- - - CH3 NH3 OH3+

- - - - CH4 NH4+

In 1932, Erlenmeyer et al. 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


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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.[27]

Hinsberg applied the concept of isosterism to entire molecules. He developed the concept of

"ring equivalents" groups that can be exchanged for one another in aromatic ring systems

without drastic changes in physicochemical properties relative to the parent structure.

Benzene, thiophene and pyridine illustrate this concept is shown as Figure 1.[5]

A -CH=CH- group in benzene is replaced by the divalent sulfur, -S-, in thiophene and a -

CH=CH- is replaced by the trivalent -N= to give pyridine. The physical properties of benzene

and thiophene are very similar. For example, the boiling point of benzene is 81.1°C and that

of thiophene is 84.4°C (at 760 mm Hg). Pyridine, however, deviates with a boiling range of

115-116°C. Hinsberg therefore concluded that divalent sulfur (-S- or thioether) must

resemble -C=C- in shape and these groups were considered to be isosteric which shown in

figure 1.[5,9]

The coining of the term bioisosterism goes back to the pioneer work of Friedman and

Thornber during the early 50s. Friedman in 1951, 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 actions. However, Friedman introduced the term bioisosterism

to describe the phenomenon observed between substances structurally related which

presented similar or antagonistic biological properties. Later, Thornber in 1979, proposed a

broadening of the term bioisosteres, defining them as subunits or groups or molecules which

possess physicochemical properties of similar biological effects.[26]

N

N

N(CH3)2

N

S

N(CH3)2

Tripelennamine Methaphenilene

Figure 1: Bioisosteric substitution of thiophene for benzene and benzene for pyridine.


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CLASSIFICATION OF BIOISOSTERES

In 1970, Alfred Burger classified and subdivided bioisosteres into two broad categories:

Classic and Non-Classic.[10,15,25]

Classical Bioisosteres are those which have similar steric and electronic features and have

the same number of atoms as the substituent moiety for which they are used as a replacement.

Nonclassical Bioisosteres are those which do not follow the strict steric and electronic

definition of classical isosteres and they do not have the same number of atoms as the

substituent moiety for which they are used as a replacement. These isosteres are capable of

maintaining similar biological activity by mimicking the spatial arrangement, electronic

properties, or some other physicochemical property of the molecule or functional group that

is critical for the retention of biological activity.[9]

Bioisosterism

Classic Non-Classic

Mono, Di, Tri, Tetravalent Functional Groups

Atoms or groups Non-Cyclic or Cyclic

Ring equivalent Retroisosterism

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 2), while non-classic bioisosteres were those which practically did not fit

the definitions of the first class (Table 3).

Table 2: Classic Bioisostere Groups and Atoms.

Monovalent Divalent Trivalent Tetravalent Ring Equivalent

-OH, -NH2, -CH3, -OR -CH2 =CH- =C=

-F -CI, -Br, - I, -SH, -PH2 -O- =N- =Si= N

-Si3, -SR -S- =P- =N+=

S

-Se- =As- =P+=

O

-Te- =Sb- =As

+=

=Sb+=


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Table 3: Non-Classic Bioisosteres.

-CO- -COOH -SO2NH2 -H -CONH- -COOR -CONH2

-CO2- -SO3 -PO(OH)NH2 -F -NHCO- -ROCO- -CSNH2

-SO2- -tetrazole

-SO2NR- -SO2NHR -SO2NH2

-OH -CH2OH

-catechol

-CON- -3-hydroxyisoxazole -benzimidazole

-CH(CN)- -2-hydroxychromones -NHCONH2 C4H4S

R-S-R -NH-CS-NH2 -C5H4N

(R-O-R’) =N- -C6H5

R-N-(CN)- C(CN)=R’ -NH-C(=CHNO2)-NH2

-NH-C(=CHCN)-NH2 -C4H4NH

-halides

-CF3

-CN

-N(CN)2

-C(CN)3

CLASSICAL BIOISOSTERISM

Monovalent atoms or groups: Substitution of a hydrogen atom by a fluorine atom is one of

the most common example of classical monovalent bioisosteric replacement. The

incorporation of fluorine into a drug allows simultaneous modulation of electronic, lipophilic

and steric parameters, all can influence both the pharmacodynamic and pharmacokinetic

properties of drug. Bioisosteric replacement of H in uracil by F gives 5-fluorouracil (anti-

cancer drug).[13,2]

Replacement of hydrogen with fluorine is one of the most common

example of monovalent isosteric replacements. Sterically H and F are quite similar with their

vander walls radii being 1.2 and 1.35A° respectively. F is most electronegative. H

replacement with F alter the biological activity as fluorine exerts strong field and inductive

effects. The strong inductive effect of F results in covalent linkage with thymidylate

synthetase, an enzyme involved in DNA synthesis.

HN

HNO

O

H

HN

HNO

O

F

Uracil 5-fluorouracil

Figure 2: Monovalent isosteric replacement of Uracil.


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In the antibiotic chloramphenicol, both the chlorine atoms of the dichloroacetic moiety and of

the p-nitrophenyl group yielded productive isosteric replacements (Table 4).[9]

X

HO OH

HN

O

Y

H

H

Table 4: Isosteric replacements in the amphenicol moiety.

COMPOUND X Y

Chloramphenicol -NO2 -CH-Cl2

Thiamphenicol CH3-SO2- -CH-Cl2

Cetophenicol CH3-CO- -CH-Cl2

Azidamiphenicol -NO2 -CH-N3

In 1997, Penning and coworkers suggested two classic bioisosteric monovalent group

replacements, represented by replacing the methyl group (CH3), by the amine group (NH2)

and replace the fluorine atom (F) with the CH3 group. In this research, found new anti-

inflammatory drugs acting through the selective inhibition of prostaglandin-H synthase-2

(PGHS-2) or cyclooxygenase-2 (COX-2), & investigated the effect of isosteric modifications

on the structure of lead compound SC-58125 (A), to improve its pharmacokinetic properties.

Both isosteric replacements, suggested allow introducing into the structure of the new

bioisosteric of SC-58125, vulnerable soft metabolic sites taking advantage of the effect of the

first passage through reactions of conjugation with glucuronic acid and the benzylic

hydroxylation catalyzed by CYP450, respectively (Figure 3).[12]

N N

CF

S

H3C

F

OO

N N

CF

S

H2N

OO

H3C

SC-58125 Celecoxib

PGHS-2 selectivity PGHS-2 selectivity

SI (COX-2/COX-1) = > 1000 SI (COX-2/COX-1) = 375

t1/2 = 211 h t1/2 = 8 to 12 h

Figure 3: Celecoxib: bioisosteric replacement of -CH3 group by -NH2 group.


417


Divalent atoms or groups: A first series of frequently interchanged divalent atoms or groups

is represented by O, S, NH and CH2 and many interesting examples are found in the

literature.

Bioisosteric replacement of carbonyl oxygen in hypoxanthine by S gives 6-mercaptopurine, a

potent anticancer antimetabolite.[13,1]

HN

NN

HN

O

HN

NN

HN

S

Hypoxanthine 6-mercaptopurine

Figure 4: Divalent isosteric replacement of Hypoxanthine.

The bioisosteric replacement of oxygen by sulfur in chlorpromazine to give the oxygen

isostere. This compound has 1/10 the soporific activity of the parent molecule.[3]

N

S

N

N

O

N

Cl Cl

Chlorpromazine Oxygen isostere of Chlorpromazine

Figure 5: Divalent isosteric replacement of Chlorpromazine.

Clonidine (A) (anti-hypertensive drug), having the greater selectivity for I1 imidazoline

receptors and less selectivity on α2-adrenoceptors and in the search for new anti-hypertensive

drugs Schann and coworkers in 2001 designed Rilmenidine (B), by the molecular

modifications in the structure of the lead compound. These modifications were based on

classical bioisosterism of divalent groups, by replacement of the divalent oxygen atom (O)

present in the oxazoline ring, by the methylene group (CH2), in the structure of new pyrroline


418


derivative (C); and between replacement of monovalent groups illustrated by the substitution

of hydrogen atoms (H) in C-4 and C-5 of derivative by the methyl group (CH3), originating

the cis/trans-4,5-dimethyl homologue (D). The binding tests with I1R and α2-adrenoceptors

evidence that the modifications occurring in the structure of rilmenidine, allow the attainment

of derivatives with affinities comparable to lead compound, although with a superior

selectivity for I1R and illustrated an example of the success of classic bioisosterism.[8]

HN

HN

N

Cl

Cl

HNO

N

Clonodine (A) Rilmenidine (B)

HN

N

HN

N

H3C

H3C

cis/trans (D) Pyrroline derivative (C)

Figure 6: Clonidine as an example of divalent bioisosterism.

Trivalent atoms or groups: The substitution of —CH= by —N= in aromatic rings has been

one of the most successful applications of classical isosterism. This type of interchanges are

found in proceeding from desipramine to nortriptyline and protriptyline or among the

antihistaminics, when comparing ethylenediamine derived compounds with the diaryl-

propylamines.[9]


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N

N

H

CH3

N

H

CH3

Desipramine Nortriptyline

CH

N

H

CH3

Protriptyline

Figure 7: Example of trivalent bioisosterism shown in aromatic ring.

Tetravalent atoms or groups: A tetravalent bioisosteric replacement study was done with a

series of α-Tocopherol has been shown in figure 8 to scavenge lipoperoxyl and superoxide

radicals and to accumulate in heart tissue. This is thought to be part of its mechanism of

action for reducing cardiac damage due to myocardial infarction. All of the biosiosteric

analogues were found to produce similar biological activity.[5]

HO

O

X

X= C14H29

X= N(CH3)3

X= P(CH3)3

X= S(CH3)3

α-Tocopherol

Figure 8: Tetravalent bioisosterism in α-Tocopherol.


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A well known tetra substituted atom is the replacement of quaternary ammonium ion in

acetyle choline by phosphonium and arsenoium. The bioisosteres so obtained are less potent

and enhanced toxicity, hence there is no further encouragement in the synthesis of direct

acting parasympathomimetic shown in figure 9. As the size of onium ion increased, the

pharmacological activity was decreased.[28]

O

N+

O

O

P+

O

O

As+

O

Acetyl Choline Phasphonium Aresonium

Figure 9: Tetravalent bioisosterism in Acetyl Choline.

Ring Equivalent: The substitution of —CH= by —N= or —CH=CH— by —S— in aromatic

rings has been one of the most successful applications of classical isosterism. Early examples

are found in the sulphonamide antibacterials with the development of sulphapyridine,

sulphapyrimidine, sulphathiazole, etc shown in table 5.[9]

H2N S

O

N

O

H

R

Table 5: Isosteric replacements in the Sulfonamides.

COMPOUND R

Sulfapyridine

N

Sulfapyrazine

N

N

Sulfathiazole

N

S

Sulfamethoxazole O

N

CH3


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Ring bioisosterism is Undoubtedly the most frequent relationship in drugs of different

therapeutic classes. The application of ring bioisosterism was also successfully explored by

Binder and coworkers in developing new NSAIDs of the oxican group.[22]

OH

NH

N

CH3SOO

O

N

OH

NH

NCH3S

OO

O

NS

Piroxican Tenoxican

Figure 10: Ring bioisosterism in NSAIDs.

NON-CLASSICAL BIOISOSTERISM

The majority example of non-classical bioisosteres includes the functional group

replacements in any moiety to improve its pharmacodynamics & pharmacokinetic. There are

many functional groups that contain necessary electronic and steric requirements for

biological properties. However, these functional groups can possess unwanted secondary

effects such as insufficient metabolic stability or toxicity.[5]

The term non-classical isosterism

refers to the concept in which functional groups that have similar physicochemical properties

may be interchangeable, resulting in similar biological properties. Furthermore, a non-

classical isostere may or may not have the same steric or electronic characteristics, nor even

the number of atoms, as the substituent for which it is used as a replacement.[7]

The landmark of the recognition of the importance of the bioisosterism of functional groups

is the discovery of the antibacterial properties of sulfanilamide. Sulfanilamide, an active

metabolite of Prontosil,[24]

revolutionized chemotherapy during the 30s and the later

elucidation of its mechanism of molecular action allowed evidence of the similarity of its

structure with p-aminobenzoic acid (PABA). These similarities, based on electronic and

conformational aspects, as well as the physicochemical properties such as pKa and logP,

denote an authentic bioisosteric relationship existing between the sulfonamide (SO2NH2) and

carboxylic acid functionalities (COOH) are shown in figure 11.[21]


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H2N S

O

NH2

OH2N C

O

OH

p-aminobenzoic acid (PABA) sulfonamide

Figure 11: Bioisosteric replacement of carboxylic acid in PABA by sulfonamide

functional group.

The tetrazole group mimics the carboxylate group, principally in terms of its physicochemical

properties related to acidity, although the former be more stable and lipophilic. These

differences allows this bioisostere to present a greater possibility of overcoming the blood-

brain-barrier, with the type of tropism favorable to the desired activity. An illustrative

example is described in the synthesis of a tetrazole bioisostere of γ-aminobutyric acid

(GABA), which presents important selective inhibitory properties of GABA-transaminase

(GABA-T) presenting a potential pharmacotherapeutic application as an anticonvulsant

agent.[19,21]

HO

NH2

O

NH2

NN

N

NH

GABA Tetrazole bioisostere of GABA

Figure 12: Replacement of carboxylic acid functional group by tetrazole in GABA.

Non-classic bioisosteric relationship can also exist in neurotransmitters like glutamate and

AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid).[4]

HO OH

O O

NH2

OH

O

NH2

O

N

CH3

OH

Glutamic acid AMPA(2-amino-3-(3-hydroxy-5-methyl-

isoxazol-4- yl)propanoic acid)

Figure 13: Non-classic bioisosteric replacement of Glutamic acid.


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Derivatives possessing a hydroxamic acid instead of a carboxylic acid function have been

developed as carboxylate bioisosteres. Among other examples, compounds with anti-allergic

properties presenting this function have been synthesized.[25]

Hydroxamic derivative designed

by modification in indomethacin, has proved to be metabolically stable.[20]

N

HOOC

Cl

O

CH3

O

OH

N

HOOC

Cl

O

CH3

O

N

H

OH

Indomethacin Hydroxamic derivative of

Indomethacin

Figure 14: Carboxylic functional group replaced by hydroxamic acid in Indomethacin.

Quinuclidine (B), designed by modifications in the natural alkaloid structure arecoline (A), is

an important non-selective muscarinics (M1 and M2) receptors agonist with marginal actions

on nicotinic receptors. However, the low selectivity associated with low therapeutic index

and inadequate bioavailability, have annulled its use for treating Alzheimer’s disease. In an

effort to optimize the pharmacotherapeutics profile of quinuclidine, Orlek and coworkers

proposed the exchange of the methyl ester group, present in quinuclidine, with the 3-methyl-

1,2,4-oxadiazole group in the structure of compound C shown in figure 15,[14]

being able to

identify electrostatic similarities between the methyl-oxadiazole and methyl ester groups, as

well as in the profile of muscarinic agonist activity of these derivatives. However, the

metabolic stability of methyl-oxadiazole bioisostere (C) was greater than to that found for the

quinuclidine lead compound (B), conferring to compound C a better oral bioavailability.

N

OCH3

O

CH3

N

OCH3

O

N

N

NO

CH3

Arecoline (A) Quinuclidine (B) 3-methyl-1,2,4-oxadiazole

(Bioisostere of Quinuclidine)

Figure 15: Bioisosteric replacement of ester functional group.


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Nonetheless, bioisosteric replacement of the ester with oxazole and other heteroaromatics

may not be universally effective, as demonstrated in the design and synthesis of a series of

highly selective and potent phenylalanine derived CCR2 antagonists as anti-inflammatory

agents. While compound A was highly effective in blocking both the binding and the

functional activity of a number of CCR3 agonists, compound B lacks all CCR affinity which

suggests a more subtle role for the ester moiety that the heterocycles were unable to mimic.[6]

NH

O

O

O

CH3

NO

NH

O

NO

N

O

A B

Figure 16: Bioisosteric replacement of the ester with oxazole.

Retroisosterism: Retroisosterism is based on the inversion of a determined functional group

present in the lead compound structure, producing an isostere with the same function. This

bioisosteric strategy aims to optimize the pharmacotherapeutic properties of the original lead

compound, thus aiding in optimizing the profile of interaction with the bioreceptor in

designing drugs with half-lives more adequate for therapeutic use and may even be used in

the attempt to avoid the formation of potentially toxic metabolic intermediates.

R O

R

O

R

O R

O

Retroisosterism

In 1998, Lages and coworkers described the existing retroisosteric relationship between the

methylsulfonylamine and methylsulfonamide functions present in the structures of new

selective COX-2 inhibitor lead compounds A and B. This type of retroisosteric relationship

confers metabolic susceptibility and distinct pKa values between compounds A and B, while

the greatest activity found for the methylsulfonamide derivative A may be explained

considering the profile of interaction of this group with the Arg513 and Ser353 amino acid

residues present at the catalytic site of COX-2, favored in A when compared to the B

retroisostere.[11]


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O

O

N

S H

H3C

OO

O

O

S

N

H3C

H

O

O

Retroisosterism

Methylsulfonylamine derivative (A) Methylsulfonamide derivative (B)

Figure 17: Retroisosteric relationship between the methylsulfonylamine and

methylsulfonamide functions.

CONCLUSION

Among these numerous examples which used in the strategy of bioisosterism for designing

new pharmacotherapeutically 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.

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Documents

BIOISOSTERISM: A STRATEGY OF MOLECULAR MODIFICATION · In 1925, Grimm’s formulated the Hydride Displacement Law, an empiric rule which states that the addition of a hydrogen atom