Carbonic anhydrase inhibitors. The nematode alpha-carbonic anhydrase of Caenorhabditis elegans CAH-4b is highly inhibited by 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides

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 evaluated as inhibitors of an alpha-carbonic anhydrase (CA, EC 4.2.1.1) of the nematode model organism Caenorhabditis elegans (CAH-4b, or ceCA). The substitution pattern at the 3- phenyl ring highly influenced the ceCA inhibitory activity of these heterocyclic sulfonamides, with best inhibitors (K(I)s in the range of 6.0 - 13.4 nM) incorporating 3- methyl-, 4- methyl-, 2-/3-/4-fluoro-, 4chloro- and 3-/4-bromo-phenyl such moieties. Some of these sulfonamides also showed a good selectivity pro. le for the inhibition of the nematode over the human isozymes CA I and II ( selectivity ratios in the range of 1.78 - 4.95 for the inhibition of ceCA over hCA II). These data can be used for the design of possibly new antihelmintic drugs, since the genome of many parasitic nematodes encode for a multitude of orthologue CA isozymes to ceCA investigated here. (C) 2009 Elsevier Ltd. All rights reserved.