Bioisosterism nonclassical

The oldest example of the use of nonclassical isosteres involves the replacement of the carboxamide in foUc acid by sulfonamide, to give the sulfanilamides. Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addition to the exploitation of auxiliary binding sites on dihydrofolate reductase. This concept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the same nnmber of atoms or identical electron structure — is really the classical structure modification approach. 

Bioisosteric Replacement and Nonisosteric Bioanalogs (Nonclassical Bioisosteres), 689... 

BIOISOSTERIC REPLACEMENT AND NONISOSTERIC BIOANALOCS (NONCLASSICAL BIOISOSTERES)... 

Replacement of the methyl ester moiety of the muscarinic partial agonist arecoline (16) by the putative nonclassical bioisosteric 1,2,4-oxadiazole ring system (18), where R = un-... 

Compounds (21-23) illustrate further examples of nonclassical bioisosteres. Compound (21) was reported to display antitrypanosomal activity (18). The analogs (22) and (23) also displayed antitrypanosomal activity (19). Compound (22) demonstrated the most impressive activity (IC50 values of 40 and... 

Conformational restriction was introduced into the side chain of a nonclassical serotonin bioisostere (28), a selective 5-HT and 5-HT receptor agonist) by its incorporation into a fused six-membered ring (29) (23). 

The preceding discussion on isosterism dealt mainly with the types of isosteres that may be considered classic (i.e., that is where the molecule bears a more or less readily apparent structural relationship to the parent compound). If one interprets bioisosteric relationships more broadly, less readily apparent similarities may result in useful new drugs. These might aptly be considered nonclassic isosteres. 

Fig. 13.3 An example of bioisosterism, or nonclassical isosterism GABA, isoguvacine and THIP are all agonists at the GABAa receptor. The 3-hydroxy-isoxazole ring has a comparable acidity to that of a carboxylic acid function. ...

Importantly, the nonclassical bioisosteres are preeisely the replaeements of functional groups not falling within the regimen by classical definitions. Although, several of these functional moieties practically just behave as one of the following characteristic specific features, such as ... 

Heterocycles as nonclassical bioisosteres of a-amino acids 13CMC205. 

Figure 9.3 Structural analogs of nonclassical bioisosteric replacement.

Analogously, the triazole derivatives 5 and 6 have been shown to act as a nonclassical bioisosteres of the ester group as in arecoline 4, a muscarinic agonist [20, 21]. 

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