Synthesis and biological evaluation of sulfonamide-based compounds as inhibitors of carbonic anhydrase from Vibrio cholerae

Abstract

This study reports our continued efforts to identify inhibitors capable of targeting carbonic anhydrases (CAs) expressed in bacteria. Based on previously identified chemotypes, we designed and synthesized new analogs that were screened toward the α, β, and γ classes encoded in Vibrio cholerae (Vch). The K_i values measured in the stopped-flow hydrase assay revealed that very simple structural modifications might induce a relevant impact on the inhibitory effects as well as the selectivity profile over ubiquitous human isozymes (hCA I/II). Unfortunately, the best active VchCA inhibitors demonstrated a dramatic loss of hCA II selectivity when compared to previously reported compounds. Among the new series of sulfonamides, several molecules proved to be about sevenfold more potent against VchCAγ than the reference compound acetazolamide, thus furnishing new insights for further development of inhibitors targeting CAs expressed in bacteria.

Keywords: Vibrio cholerae; carbonic anhydrases; enzyme inhibitors; sulfonamides.