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

Elshamsy A. M., Mustafa M., Nocentini A., Massardi M. L., Ali T. F. S., Rabea S. M., ...Daha Fazla

Journal of Medicinal Chemistry, 2025 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1021/acs.jmedchem.5c01392
  • Dergi Adı: Journal of Medicinal Chemistry
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, Veterinary Science Database
  • Sivas Cumhuriyet Üniversitesi Adresli: Evet

Özet

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.