Bioisosteric mimicking

A substance class of particular importance as intermediates in most central metabolic processes and also as chemical messengers in many signal cascades are organophosphates [64], Despite of their pivotal biochemical role they are often only short-lived species which are rapidly hydrolyzed either spontaneously or by ubiquitous phosphatases. To make use of phosphates as bioactive compounds of pharmaceutical interest, the hydrolytically labile phosphate bond has to be stabilized [65]. 

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Introducing a sulfur atom to the carbonyl significantly increased the activity of the resulting compounds (B) on JHE and some but not all other esterases, possibly by bioisosterically mimicking Q5) the a,ft double bond of the natural JHs. Based on this finding, a series of aliphatic, aromatic (2,8.) and terpenoid (9) derivatives were synthesized. The most active compound of these series was 3-octylthio-l,1,l-trifluoro-2-propanone (OTFP). 

All the previous examples can be applied to the catechol family. Many of these bioisosteres share with the catechols the ability to chelate metal atoms and to form hydrogen-bonded second rings. In benzimidazole this H-bond ring is mimicked by way of a covalent ring structure (Figure 15.42). 

Some of the bioisosteres identified for the phenol group in CDK2 are shown in Figure 10.7, along with the ways in which they mimic the hydrogen bonding properties of the phenol moiety. This information could be used to bias the selection of bioisosteres for test, either on the grounds that the interactions to be mimicked are known or such that a diverse set of potential bioisosteres is picked to explore different combinations of interactions. 

In addition to the potential of triazoles in mimicking the amide moiety and consequently the peptide bond, their capability to act as bioisosteres of the acyl phosphate and h ns-olefinic moieties has also been predicted [18]. The... 

Another interesting and important use of triazoles was in the generation of non-classical bioisosteres of potentially labile groups (ester, amide) with heterocycles capable of mimicking the same electrostatic potential maps [19] (Figure 2.2). 

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