Nonclassical isosteres

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. 

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. ...

Arecoline is of historical interest, because its structure, like those of many other early medicinal agents, viras determined and confirmed by a 19th-century German pharmacist, E. Jahns (2). Xanomeline may be viewed as a nonclassical bio-isostere of the ester moiety of arecoline. It is a muscarinic M1/M4 agonist that is showing promise in clinical trials for the treatment of Alzheimer s disease (35). Although it is not tolerated at orally effective doses, transdermal delivery systems are showing promise. 

Besides the perhaps trivial examples of isomers, such as the regiospedfic thiophene, pyridine, and phenyl exchanges, the nine remaining isosteric replacements include mostly nonclassical ones, that is, substituents that are structurally distinct, exhibiting different steric electronic properties [6]. 

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