3-Phenyl-1H-Indole-5-Sulfonamides: Structure-Based Drug Design of a Promising Class of Carbonic Anhydrase Inhibitors

Abstract

A series of 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides possessing various 2-, 3- or 4-substituted phenyl groups with methyl-, halogeno- and methoxy-functionalities, as well as the perfluorophenyl moiety have been synthesized and evaluated as inhibitors of both alpha- and beta-class carbonic anhydrases (CAs, EC 4.2.1.1). All human isoforms with medicinal chemistry applications were included in such studies, among which CA I, II, VA, VB, VII, IX and XII. Several low nanomolar, sometimes isoform-selective compounds were thus detected. Two beta-CAs from the pathogenic bacterium Mycobacterium tuberculosis encoded by the genes Rv1284 Rv3588c were also highly inhibited (sometimes in the sub-nanomolar range) by some pyridinium derivatives incoprorating this scaffold, obtained from the corresponding 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides by reaction with pyrylium salts. The fungal beta-CAs from Candida albicans (Nce103) and Cryptococcus neoformans (Can2) were also investigated for their inhibition with this family of sulfonamides and some highly effective inhibitors detected. As the X-ray crystal structure of one such sulfonamide with the human isoform CA II is also known, the 3-substituted-phenyl-1H-indole-5-sulfonamides represent a totally new class of inhibitors obtained by structure-based drug design, which show efficiency in inhibiting both alpha- and beta-CAs from several species.