Thiosemicarbazone-benzenesulfonamide Derivatives as Human Carbonic Anhydrases Inhibitors: Synthesis, Characterization, and In silico Studies

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.