Thiosemicarbazone-benzenesulfonamide Derivatives as Human Carbonic Anhydrases Inhibitors: Synthesis,...

Carbonic anhydrases (CAs) are widespread metalloenzymes with the core function of catalyzing the interconversion of CO₂ and HCO₃ -. Targeting these enzymes using selective inhibitors has emerged as a promising approach for the development of novel therapeutic agents against multiple diseases.

A series of novel thiosemicarbazone-containing derivatives were synthesized, characterized, and tested for their inhibitory activity against pharmaceutically important human CA I (hCA I), II (hCA II), IX (hCA IX), and XII (hCA XII) using the single tail approach.

The compounds generally inhibited the isoenzymes at low nanomolar concentrations, with compound 6b having K_i values of 7.16, 0.31, 92.5, and 375 nM against hCA I, II, IX and XII, respectively. Compound 6e exhibited K_i values of 27.6, 0.34, 872, and 94.5 nM against hCA I, II, IX and XII, respectively.

To rationalize the inhibition data, molecular docking studies were conducted, providing insight into the binding mechanisms, molecular interactions, and selectivity of the compounds towards the isoenzymes.