Benzoxaboroles: New Potent Inhibitors of the Carbonic Anhydrases of the Pathogenic Bacterium Vibrio cholerae

A series of urea/thiourea substituted benzoxaboroles was investigated for the inhibition of the three carbonic anhydrases encoded by Vibrio cholerae (VchCA alpha, VchCA beta, and VchCA gamma). In particular, benzoxaborole derivatives were here first assayed for the inhibition of a gamma-class CA, extending the panel of CA classes that benzoxaboroles efficiently target beyond alpha and beta. Inhibition profiles demonstrated that VchCA alpha was significantly more inhibited compared to VchCAy and, in turn, more efficientl gamma modulated than VchCA beta. Among the many selective benzoxaborole ligands detected against VchCA alpha over the off-target hCA II, compound 18, a p-NO2-phenylthiourea derivative, even exhibited a fully selective inhibition profile against the three VchCAs over hCA IL A comprehensive ligand/target interaction study was performed in silico for all three VchCA isoforms providing the first molecular modeling investigation with inhibitors of a gamma-class CA to the best of our knowledge. The present study reinforces the rationale behind the use of benzoxaboroles as innovative antibacterial agents with a new mechanism of action, furnishing suggestions for the rational design of new potent and selective inhibitors targeting V. cholerae CAs over human off-target ones.