Design, Synthesis, and In Vitro Anticancer Evaluation of Thiazole-Based Chalcones Linked to Sulfanilamide as Tumor-Associated Carbonic Anhydrase IX and XII Inhibitors.

Human carbonic anhydrases IX and XII (hCA IX/XII) are overexpressed in various solid tumors and play critical roles in tumor survival and progression, particularly under hypoxic conditions. In this study, a tail-focused design strategy was employed to synthesize thiazole-based chalcone derivatives bearing a sulfanilamide moiety as the zinc-binding group for selective inhibition of tumor-associated CA isoforms. Compound 5u emerged as the most potent, exhibiting strong inhibition of hCA IX/XII, outperforming acetazolamide and SLC-0111. In the NCI-60 panel, 5u showed broad-spectrum anticancer activity, with GI50 values below 2 μM in melanoma, breast, and colon cancer cell lines. Under hypoxic conditions, 5u demonstrated enhanced cytotoxicity in A375, A2058, SKMEL-2, and MDA-MB-231 cells. Molecular docking confirmed favorable binding to hCA IX/XII active sites. ADME predictions indicated good solubility and oral bioavailability, while DFT calculations supported its electronic stability. These results highlight 5u as a promising lead for dual hCA IX/XII-targeted cancer therapy.