Reversal of functional groups

FIGURE 15.43 Inhibition of IGF-IR and other kinases by AG 538 bioisosteres and analogs. 

FIGURE 15.45 Replacement of the phenolic function of serotonine by various functions able to serve as H-bond acceptors. 

CHAPTER 15 Molecular Variations Based on Isosteric Replacements 

TABLE 15.16 Displacement of [3H -5-HT to 5-HTl D Recognition Sites in Pig Caudate Membranes by N-Linked Imidazoles, Triazoles and Tetrazoles and Standard 5-HTl D Agonists 

FIGURE 15.46 Selective COX-2 inhibitors and their azido bioisosteres. 

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F. The bioisosterism concept F. Reversal of functional groups C. Bioisosteries involving... 

Fig. 13.22 Reversal of functional groups in practolol yields atenolol.

The transformation of carboxylic acids with CDI into imidazolides has a wide range of applicability. CDI reacts with aliphatic, aromatic, and heterocyclic carboxylic acids under very mild conditions, and these reactions are not affected by the presence of functional groups unless the latter are strongly nucleophilic and themselves react with CDI in such cases a reversible protection of the functional groups is necessary. The reaction of CDI also works in such specific cases as trifluoro- and trichloroacetic acids, leading to the very reactive Af-trifluoro- and N-trichloroacetylimidazoles. 1 111... 

One can in principle combine different exchange reactions in the same system in order to further increase the structural diversity accessed by the library. However, as this compounds the problem of selectivity (i.e., one now has two or more reactions that must exclusively involve one pair of functional groups), there are very few examples thus far of the practical implementation of this concept. An early, highly intriguing example was described by Lehn and coworkers in 2001 [68]. In this system, imine exchange (acyl hydrazone formation) and reversible metal coordination were employed in library generation. 

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