represents an approach used by the medicinal chemist for the rational modification Keywords: Bioisostere, Isostere, Drug design, Replacement, Pseudoatoms. A Review on Bioisosterism: A Rational Approach for Drug Design and Why eed For Bioisosteric Replacements [5]? There are many reasons for the use of. Bioisosterism: A Rational Approach in Drug Design Nonclassical Bioisosteres A. Cyclic vs Noncyclic Nonclassical Bioisosteric Replacements B.

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Skip to main content. Log In Sign Up. A Review on Bioisosterism: A Prime Approach Keywords: Vandana Sharma Assistant Professor Dept.

Summary Several methods for drug designing have been employing from many decades. Development of novel drug molecule with improved with high efficacy, potency and undesirable side effects have been the aim of the scientists. Bioisosterism represents one such approach used by the medicinal chemist for the rational bbioisosteres of lead compounds into safer and more clinically effective agents. This review will show the role of bioisosterism in the molecular modification as well as in rational drug design and optimization process with the aim to improve pharmacodynamic and pharmacokinetic properties of lead compounds.

Introduction A lead compound LC with a desired pharmacological activity may have associated with it undesirable side effects, characteristics that limit its bioavailability, or structural features which adversely influence its metabolism and excretion from the body.

Taking consideration of the structure of lead molecule, it is always the priority of medicinal chemist to design safer drug molecule. Isosterism played good role in designing of bioisozteres drugs. Isosteres are molecules or ions with the same number of atoms and bioisostwres same number of valence electrons.

The term [1] isosterism was introduced in by the physicist Irving Langmuir. This definition has now been broadened to include groups that produce compounds that can sometimes have similar biological activities.

The term bioisosterism, introduced by Friedman in [2] is used, bipisosteres along with physicochemical analogy, compounds share some dgug biological properties.

Bioisosterism is a strategy of Medicinal Chemistry for the rational design of new drugs, applied with a lead compound LC as a special process of molecular modification [3]. The LC should be of a completely well known chemical structure and possess an equally well known mechanism of action. Furthermore, the pathways of metabolic inactivation[4], as well as the main determining structural factors of the physicochemical properties which regulate the bioavailability, and its side effects, whether directly or not, should be known.

The success of this strategy in developing new substances which are therapeutically attractive has observed rqtional significant growth in distinct therapeutic classes, being amply used by the pharmaceutical industry to discover new analogs of therapeutic innovations commercially attractive and also as a tool useful in the molecular modification.

There are many reasons for the use of bioisosterism: Development of the isosterism concept [6] InAllen defined the molecular dessign of a compound in a same way to the atomic number: Compare ammonium NH4 and sodium Na cations as an example. The atomic number of NH4 cation and Na cation is Two compounds, with identical molecular numbers shows at least some similar physical properties.

Examples of various atoms and molecules are [8]: According to Grimm, each vertical column Table 1 would represent a group of isosteres. Grimm’s hydride displacement law [12] InErlenmeyer broadened Grimm’s classification and redefined isosteres as elements, molecules or ions which present the same number of electrons at the valence level.

C, Si and Ge Table 2 and the development of a deug of electronically equivalent rings, later lead to the term ring bioisosterism. A plan designed to achieve molecular modeling The most appropriate application of bioisosterism insist on physical, chemical, electronic and conformational parameters involved in bioisosteric substitution, carefully analyzed so as to predict, although theoretically, any alterations occurs in terms of the pharmacodynamic and pharmacokinetic properties.

Following parameters should be appropriately considered while making any bioisosteric replacement [15]. Classic and Non- Classic [16]. Z Bioisosteres Table 1 1. Classical Bioisosteres Groups and Atoms 1.


Univalent atoms and groups a. Cl PH2 SH bioisosterea. Bivalent atoms and groups a. Trivalent atom and groups a. Azomethine CN N C Thus, difference in electronic effects fluorine being the most electronegative element in the periodic table form the major differences in the bilisosteres properties of agents where fluorine has been substituted for hydrogen.

Bioisosterism: A Rational Approach in Drug Design.

Due to electronegativity of fluorine, it exerts a strong field and inductive effects electron-withdrawing effect on the adjacent carbon atom. Fluorine substitution exerts a diminished electron-withdrawing effect at distal sites.

This is commonly referred to as its mesomeric effect.

The antineoplastic agent 5- [18] fluorouracil 5-FU is biochemically transformed in vivo into 5-fluoro-2′-deoxyuridylic acid. This biochemically altered form of 5-FU 15-fluoro-2′-deoxyuridylic acid, is ultimately responsible for the inhibition of thymidylate synthase, an enzyme involved in the conversion of uridylic acid to thymidylic acid and critical for DNA synthesis Figure 1. The increased reactivity of 5-fluoro-2′-deoxyuridylic acid relative to 2′-deoxyuridylic acid is due to the inductive effect of fluorine which results in its covalent binding to thymidylate synthase.

This greater receptor binding affinity is also due to the inductive effect of the fluorine atom facilitating a stronger interaction with the receptor. H3C H3C O O N N F H 2 3 Figure 2 b Interchange of Hydroxyl and Amino Groups The functional groups having similar steric size, spatial arrangement, and the ability to act as either hydrogen bond acceptors or donors is likely responsible for their successful use as bioisosteres.

OH NH2 4 5 Figure 3 An example where change in biological activity occurs when hydroxyl group is replaced by amino group is represented by 4-aminodeoxy derivative [16]aminopterin and its Nmethyl derivative methotrexate amethopterin Figure 4 6an anti-metabolite anticancer. A classical illustration of this replacement is shown by guanine 8 and 6- thioguanine 7 both are purine analogous Figure 5 [21]. By inhibition of epithelial neutral endopeptidase NEP that cause inactivation of endogenous atrial natriuretic peptide ANPeffects of diuretic and natriuretic effects can be mediated.

Inhibition of angiotensin II formation occurs by inhibition of endothelial angiotensin-converting enzyme ACE. A series of dual metallopeptidase inhibitors 9 have been designed on the basis of the characteristics of the active sites of both enzymes. Monovalent substitution by fluorine, hydroxyl, and amino in place of hydrogen has been used in the design of these metallopeptidase inhibitors Fig. However due to increase in the effective van der Waal’s radii of the isosteric substituents resulted in a decrease in activity, thus with these bioisosteres, no significant alteration in preferential activity with either of the peptidases, ACE or NEP observed.

An example is illustrated by guanosine analogues having a monovalent isosteric replacements. C8-substituted guanosine analogues Fig. Both -NH- and -CH2- bioisosteric linkers have similar bond angles and electronegativities result in analogues which retain activity. Use of an oxygen atom as a bioisosteric linker, which has smaller bond angle and much greater electronegativity, results in an analogue 12 with increased potency. This pattern of pharmacological effects is not achieved by conventional, tertiary amine, anti-histaminic drugs of which mepyramine is typical and has led to the definition of burimamide as an H2-receptor antagonist and mepyramine as an H1-receptor antagonist [27].

Bioisosterism: A Rational Approach in Drug Design.

Although burimamide has sufficient [28] pharmacological activity but seemed to lack the combination of specific activity with adequate oral bioavailability.

Therefore it needs to modify the structure of burimamide. In the side carbon chain of burimamide 13electron withdrawing bivalent sulphur atom was [29] introduced which reduce the ring p Ka. The resulting compound, metiamide 14 had excellent oral absorption and was ten times more active than burimamide Figure Arsenicals have received considerable attention due to their therapeutic significance. The oxidation of arsenic compounds to arsenoxides is important in the bioactivation of a number of chemotherapeutic arsenicals.

One of the first drugs used clinically was arsphenamine. Oxophenarsine metabolite of arsphenamine contribute to its activity against the syphilis organism.

Bioisosterism: A Rational Approach in Drug Design | javier vera –

Due to the lack of selective toxicity associated with these arsenicals, analogy is drawn to prontosil 17 Figure 12 which is found to be metabolized to p- aminobenzenesulfonamide Prontosil is inactive against microorganisms in vitro but active in vivo. Such replacements resulted in less potent analogues with greater toxicity. Activity decreased as size of the onium ion increased. The decreased potency and greater toxicity of these higher elements has diminished interest in replacements of this type for the development of direct-acting cholinergic agonists.

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Ring [33] bioisosterism, is the most frequent relationship in drugs of different therapeutic classesas can be seen in Fig. Examples of ring bioisosterism between drugs belonging to different therapeutic classes.

One of the successful uses of this replacement resulted in the potent antihistamine 22 mepyramine Figure 15 by the replacement of the phenyl moiety in antegran by a pyridyl group. X H3CO 23 Figure 16 The search for novel cardio-tonic agents resulted in the successful development of two clinically useful agents, amrinone [35] 24 and milrinone [36] 25 Figure This prompted the [38] design and synthesis of analogues with general structure Divalent isosteric ring substitutions of the pyrazino[2,1-a][2]benzazepine system Figure 18 resulted in derivatives 27 containing different heterocyclic systems.

All these bioisosteres exhibited anthelmintic [38] activity. Replacement of the methylene with a sulfur or oxygen atom resulted in analogues with decreased potency relative to the carbocyclic analogue.

Replacement of the carbon atom on [41] the oxazolidinone ring with nitrogen resulted in the carbamate analogue 29 Figure 19 which was equipotent with pilocarpine. This analogue bypasses the problem associated with epimerization as seen with pilocarpine. Bioisosteres of the indole ring, presenting affinity and selectivity by the serotonin receptors similar to lead compound. Regioisomeres formation occurs in this replacement.

Both derivatives act by the same mechanism of action, at the same receptor level, i. Pharmacological activity profile of tenoxican proved to be comparable to that of piroxican [46]. Molecular design of 37 could be carried out from the opening of rings B and C of the steroidal skeleton of estradiol 36 Figure Central bond of diethylstilbestrol is important for the correct orientation of the phenolic and ethyl groups for [48] [49] binding to the estrogenic receptor. Structurally or conformationally rigid analogues are equipotent as estradiol.

Nonrigid analogues have little or no estrogenic activity [50, 51]. P-aminosulfanilamide 42an active metabolite of Prontosil which was able to provide cures of streptococcal infections in mice revolutionized chemotherapy and on later elucidation of its mechanism of action shows similarity of its structure with p-aminobenzoic bioisosferes PABA, These similarities based on electronic and conformational aspects as well as the physicochemical properties such as p Ka and log P.

Sulfonamides act as competitive inhibitors of the incorporation of p-aminobenzoic acid associated with the formation of dihydropteroic acid, thereby, ultimately inhibiting the biosynthesis of dihydrofolic acid [56].

Bioisosteric replacement of —COOH by a tetrazole group resulted in druf potency due to the reduced hydrophilicity [57, 58]. The tetrazole group mimics the carboxylate group, principally in terms of its physicochemical properties related to bioisostere.

Oxatolrestat 46 [62], represent a classic bioisostere of tolrestat 45 Figure 26a potent aldose reductase inhibitor [63]. Retroisosterism Retroisosterism dezign based on the inversion of a determined functional group present in the lead compound structure, producing an isostere with the same function Figure Main aim is 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.