Rational design and synthesis of pyrazole-based sulfonamides as dual carbonic anhydrase and PRAK-targeting anticancer agents

  • Bioorg Chem. 2026 Jun 25:180:110170. doi: 10.1016/j.bioorg.2026.110170.
Mariam M Fakhry  1 ,  Mohamed A Said  2 ,  Noha Zeidan  3 ,  Andrea Ammara  4 ,  Jalloul Bouajila  5 ,  Mahmoud Abdelrahman Alkabbani  6 ,  Alessandro Bonardi  7 ,  Paola Gratteri  7 ,  Mohamed Fares  8 ,  Claudiu T Supuran  9 ,  Hatem A Abdel-Aziz  10 ,  Sahar M Abou-Seri  11
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt; Laboratoire de Génie Chimique, Université de Toulouse, CNRS, INP, UT, Toulouse F-31062, France. Electronic address: [email protected].
  • 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, University of Kut, Waist 52001, Iraq.
  • 3. School of Natural Sciences, Faculty of Science, Business and Enterprise, University of Chester, Chester CH1 4BJ, United Kingdom.
  • 4. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Firenze, Italy.; NEUROFARBA Department, Laboratory of Molecular Modeling, Cheminformatics & QSAR, University of Florence, Firenze, Italy.
  • 5. Laboratoire de Génie Chimique, Université de Toulouse, CNRS, INP, UT, Toulouse F-31062, France.
  • 6. Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
  • 7. NEUROFARBA Department, Laboratory of Molecular Modeling, Cheminformatics & QSAR, University of Florence, Firenze, Italy.
  • 8. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt; Sydney Pharmacy School, The University of Sydney, Sydney, New South Wales 2006, Australia.
  • 9. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Firenze, Italy.
  • 10. Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt. Electronic address: [email protected].
  • 11. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. Electronic address: [email protected].
PMID: 42372456 DOI: 10.1016/j.bioorg.2026.110170
Abstract

Herein, a novel series of pyrazole-based derivatives 5a-f, 6a-f, 7a,b, and 8a-f was rationally designed, synthesized, and evaluated as potential Anticancer agents targeting tumor-associated Carbonic Anhydrase (hCA) isoforms IX and XII. Sulfonamide derivatives 5d,e, and 8d-f displayed potent inhibitory activity against hCA IX (Ki = 2.2-34.9 nM) and XII (Ki = 9.9-51.9 nM). The structure of representative compound 8d was confirmed by single crystal X-ray crystallography. In vitro Anticancer screening against the NCI-60 human tumor cell lines revealed that compounds 8d-f exhibited broad-spectrum cytotoxicity, with 8d inducing G0/G1 cell cycle arrest and suppressing DNA synthesis in MDA-MB-231 breast Cancer cells. Kinase profiling of compound 8d against 140 kinases at 10 μM uncovered additional inhibitory activity against key cancer-related kinases, particularly YES1, Btk, MAP4K3, and most intriguingly, PRAK, suggesting a potential multitarget mechanism. To the best of our knowledge, this study represents the first dual Carbonic Anhydrase Inhibitor capable of engaging PRAK. The concurrent inhibition of pH regulator-hCA IX and PRAK signaling by compound 8d disrupted hypoxia-driven survival pathways and promoted cell death in therapy-resistant tumor cells. Molecular docking studies supported these findings, demonstrating stable binding within the active sites of hCA IX and XII. Additionally, docking studies demonstrated that compound 8d adopts a stable binding pose within the ATP-binding cleft of PRAK, establishing favorable interactions with key active-site residues.

Keywords
Carbonic anhydrase; Molecular docking; PRAK inhibitor; Pyrazole; X-ray crystallography.
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