Benzenesulfonamide derivatives as Vibrio cholerae carbonic anhydrases inhibitors: a computational-aided insight in the structural rigidity-activity relationships

Vibrio cholerae causes life-threatening infections in low-income countries due to the rise of antibacterial resistance. Innovative pharmacological targets have been investigated and carbonic anhydrases (CAs, EC: 4.2.1.1) encoded by V. cholerae (VchCAs) emerged as a valuable option. Recently, we developed a large library of para- and meta-benzenesulfonamides characterised by moieties with a different flexibility degree as CAs inhibitors. Stopped flow-based enzymatic assays showed strong inhibition of Vch alpha CA for this library, while lower affinity was detected against the other isoforms. In particular, cyclic urea 9c emerged for a nanomolar inhibition of Vch alpha CA (K-I = 4.7 nM) and high selectivity with respect to human isoenzymes (SI >= 90). Computational studies revealed the influence of moiety flexibility on inhibitory activity and isoform selectivity and allowed accurate SARs. However, although VchCAs are involved in the bacterium virulence and not in its survival, we evaluated the antibacterial activity of such compounds, resulting in no direct activity.

Automated summary

Vibrio cholerae, a pathogen responsible for life-threatening infections in low-income countries, has developed resistance to antibacterial drugs. Researchers have identified carbonic anhydrases (CAs) encoded by V. cholerae as potential pharmacological targets. They have developed a large library of CAs inhibitors with different flexibility degrees and found compounds with strong inhibition against Vch alpha CA. Computational studies have provided insights into the inhibitory activity and isoform selectivity of these compounds.