Tail approach synthesis of novel benzenesulfonamides incorporating 1,4-disubstituted triazole hybrids as potent inhibitors of carbonic anhydrase I, II, IX and XII isoenzymes.

A series of twenty novel 1,4-disubstituted-1,2,3-triazole containing benzenesulfonamides were designed, synthesized and evaluated for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX and XII. Most of the newly synthesized sulfonamides moderately inhibited the physiologically important and off-target isoform hCA II while the cytosolic isoform hCA I was weakly inhibited with inhibition constants (KIs) in the low nanomolar range (KI = 65.2 nM-2.590 μM). Cytotoxicity studies were also carried out for all synthesized compounds, along with in-silico ADMET and drug-likeness evaluation to assess their pharmacokinetic potential. Additionally, molecular docking and Molecular Dynamics (MD) simulation studies were performed for the most potent compounds to elucidate their binding interactions and confirm the stability of the ligand-protein complexes. These findings offer useful guidance for designing future carbonic anhydrase inhibitors and highlight promising lead compounds for further biological and preclinical evaluation.