Novel Indole-Based Hydrazones as Potent Inhibitors of the α-class Carbonic Anhydrase from Pathogenic Bacterium Vibrio cholerae

Abstract

Due to the increasing resistance of currently used antimicrobial drugs, there is an urgent problem for the treatment of cholera disease, selective inhibition of the α-class carbonic anhydrases (CA, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae (VcCA) presents an alternative therapeutic target. In this study, a series of hydrazone derivatives, carrying the 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold, have been evaluated as inhibitors of the VcCA with molecular modeling studies. The results suggest that these compounds may bind to the active site of VcCA. To verify this, VcCA enzyme inhibition studies were performed and as predicted most of the tested compounds displayed potent inhibitory activities against VcCA with three compounds showing KI values lower than 30 nM. In addition, all these compounds showed selectivity for VcCA and the off-targets hCA I and II.

Investigation on Hydrazonobenzenesulfonamides as Human Carbonic Anhydrase I, II, IX and XII Inhibitors

“…Hydrazones have been extensively studied due to their wide biological activities [20][21][22][23][24][25][26][27] while a urea group is a commonly incorporated tailing linker in benzenesulfonamide CA inhibitors. The hydrazone group is a urea-bioisostere, thus different groups have reported successful approaches to inhibit CA by hydrazone-based compounds [28][29][30][31][32][33][34][35][36].…”

Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes

“…The existence of a link between CAs and microorganism metabolism represents a challenge in discovering antibacterials, especially in the era of antibiotic resistance [ 18 ]. In this Special Issue, Akdemir and coworkers demonstrated that selective inhibition of the α-class CA from the pathogenic bacterium Vibrio cholerae (VcCA) with a series of hydrazone derivatives, carrying the 2-(hydrazinocarbonyl)-3-phenyl-1 H -indole-5-sulfonamide scaffold, presents an alternative therapeutic target to contrast the acute diarrheal infection provoked by Vibrio cholera [ 19 ]. These groups also tested 26 thiazolidinones against the Candida glabrata β-CA (CgNce103) and the Candida spp., demonstrating that these compounds had selective antifungal activity with a potency like fluconazole and clotrimazole [ 20 ].…”