Synthesis and pharmacological activity studies of 5-substituted-2-methylbenzenesulfonamide derivatives

The discovery of dual-target compounds aimed at two different molecular mechanisms has become a popular approach in anticancer drug development studies. In this regard, carbonic anhydrase IX enzyme and vascular endothelial growth factor receptor-2 tyrosine kinase have emerge as important therapeutic targets in the discovery of new anticancer compounds. In this study, a total of thirty-two new compounds were synthesized, including 4-thiazolidinone/2,4-thiazolidinedione derivatives carrying 2-methylbenzenesulfonamide, which are targeted to have dual inhibitory effects on CAIX and VEGFR-2 enzymes and their structures were elucidated using IR, 1H-/13C-NMR, and HRMS spectral analysis methods. The inhibitory effects of the compounds on the CAIX enzyme were investigated by comparing them to the reference compounds dorzolamide and acetazolamide. The inhibitory activities of the six compounds (3a, 3b, 3o, 6d, 6g and 6i) with the most powerful CAIX inhibitory effect on VEGFR-2 enzyme were tested by comparing them with sorafenib, and their cytotoxic effects on the MCF-7 breast cancer cell line and 3T3 mouse fibroblast cell line were evaluated. The 4-thiazolidinone derivative 3b (CAIX IC50 = 0.035 µM, VEGFR-2 IC50 = 0.093 µM) and the 2,4-thiazolidindione derivative 6i (CAIX IC50 = 0.041 µM, VEGFR-2 IC50 = 0.048 µM) were identified as the most potent dual inhibitors of the CAIX and VEGFR-2 enzymes. Molecular modeling studies were conducted to identify possible protein-ligand interactions in the active sites of the CAIX and VEGFR-2 enzymes for compounds 3b and 6i. Additionally, the physicochemical properties of all target compounds were evaluated in silico.