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

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

  • J Med Chem. 2025 Jul 24;68(14):15151-15164. doi: 10.1021/acs.jmedchem.5c01392.
Ali M Elshamsy 1,  Muhamad Mustafa 2,  Alessio Nocentini 3,  Maria Luisa Massardi 4,  Taha F S Ali 5,  Safwat M Rabea 5,  Burak Tüzün 6,  Michael Smietana 2,  Serkan Kapancık 7,  Mohamed Abdel-Aziz 5,  Roberto Ronca 4,  Claudiu T Supuran 3,  Jean-Yves Winum 2,  Hamada Hashem 8
Affiliations

Affiliations

  • 1 Medicinal Chemistry Department, Faculty of Pharmacy, Deraya University, Minia 61519, Egypt.
  • 2 IBMM, CNRS, ENSCM, University of Montpellier, Montpellier 34293, France.
  • 3 Department of NEUROFARBA─Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Firenze 50019, Italy.
  • 4 Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy.
  • 5 Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • 6 Plant and Animal Production Department, Technical Sciences Vocational School of Sivas, Sivas Cumhuriyet University, Sivas 58140, Turkey.
  • 7 Department of Biochemistry, Cumhuriyet University School of Medicine, Sivas 58140, Turkey.
  • 8 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
PMID: 40623264 DOI: 10.1021/acs.jmedchem.5c01392
Abstract

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.

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