Electrostatic potential map carboxylic acid derivatives

Electronically, we find that strongly polarized acyl compounds react more readily than less polar ones. Thus, acid chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic add derivatives indicate the differences by the relative blueness on the C-O carbons. Acyl phosphates are hard to place on this scale because they are not used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters. 

In further SAR study for C-3 heterocycle-substituted derivatives of squalestatins 1 and 3 [61], the inhibitory activities of squalestatin 3 analogs showed a greater dependence on the nature of the C-3 substituent, which is different from those of squalestatin 1 analogues. Potent squalene synthase inhibitory activities equivalent to those of squalestatins 1 and 3 were retained in C-3 analogues substituted with a tetrazol-5-yl functionality which closely mimics the parent carboxylic acid (see Table 1). Also, electrostatic potential maps studies showed that squalene synthase inhibitory activity similar to that of the methyl ester (IC50 = 220 nM) was retained only in those C-3 heterocycle-substituted squalestatin 3 analogues for which electrostatic potential maps of the C-3 substituent were closely similar to that of a methyl ester [61]. Squalene synthase inhibitory activities of several analogues substituted with a heterocyclic moiety at C-3 are shown in Table 1. 

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