Exploring aliphatic sulfonamides as multiclass inhibitors of the carbonic anhydrases from the pathogen bacterium Vibrio cholerae

This study investigates aliphatic sulfonamide derivatives as inhibitors of the alpha-, beta-, and gamma-class carbonic anhydrase (CA) isoforms from Vibrio cholerae (VchCAs). A series of 26 compounds bearing a triazole linker and urea- or ether-based tails were described and evaluated for their inhibitory action using a stopped-flow CO2 hydrase technique. These inhibitors demonstrated a preferential efficacy against VchCA beta. Specifically, the ureido derivatives showed the highest inhibitory potency with inhibition constants (KIs) in the submicromolar range (0.67-0.93 mu M). Selectivity indices were calculated to assess the selective inhibition of VchCA beta over human CA I and II, as well as other VchCA isozymes. Urea-linked compounds demonstrated a significant 25- to 125-fold selectivity for VchCA beta over hCAs and 14- to 26-fold over other VchCAs. Molecular modeling elucidated the interactions contributing to the efficacy and selectivity of aliphatic sulfonamides as VchCA inhibitors, aligning with and reinforcing the experimental results. The latter suggests that aliphatic sulfonamides could serve as valid targeted therapeutics to treat V. cholerae infections.