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

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 (CAs) emerged as a valuable option. Recently, we developed a large library of - and -benzenesulfonamides characterised by moieties with a different flexibility degree as CAs inhibitors. Stopped flow-based enzymatic assays showed strong inhibition of αCA for this library, while lower affinity was detected against the other isoforms. In particular, cyclic urea emerged for a nanomolar inhibition of αCA ( = 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 CAs are involved in the bacterium virulence and not in its survival, we evaluated the antibacterial activity of such compounds, resulting in no direct activity.