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.