Design and Synthesis of Bis-Triazole-Linked Benzenesulfonamides as Selective Carbonic Anhydrase IX/XII Inhibitors with Chemosensitizing Activity

  • J Med Chem. 2026 May 14;69(9):11365-11381. doi: 10.1021/acs.jmedchem.6c00547.
Eslam Roshdy  1  2 ,  Ahmet Kilic  3 ,  Muhamad Mustafa  4 ,  Ismail Celik  5 ,  Zeynep Betül Sarı  3  6 ,  Ender Simsek  3  6 ,  Alessio Nocentini  7 ,  Simone Giovannuzzi  7 ,  Claudiu T Supuran  7 ,  Özen Özensoy Güler  3  6 ,  Jean-Yves Winum  4 ,  Manabu Abe  1  8
Affiliations
  • 1. Department of Chemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
  • 2. Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
  • 3. Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University (AYBU), 06800 Ankara, Turkey.
  • 4. IBMM, University of Montpellier, CNRS, ENSCM, 34293 Montpellier, France.
  • 5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey.
  • 6. Yenimahalle Education and Research Training Hospital, Yenimahalle, Ankara 06370, Turkey.
  • 7. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Polo Scientifico, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
  • 8. Research Center for Photo-Drug-Delivery Systems (Hi-PDDS), Hiroshima University, Higashi-Hiroshima 739-8526, Hiroshima, Japan.
PMID: 42059120 DOI: 10.1021/acs.jmedchem.6c00547
Abstract

Carbonic Anhydrase hCA IX and hCA XII are cancer-associated Enzymes involved in tumor pH regulation, hypoxia-driven survival, and therapeutic resistance. Here, we report the rational design, synthesis, and biological evaluation of bis-triazole-linked benzenesulfonamides as novel Carbonic Anhydrase inhibitors. Several compounds exhibited potent and selective inhibition of hCA IX/XII, with compounds 2g and 4g showing nanomolar activity (hCA IX KI = 25.1 and 28.1 nM; hCA XII KI = 35.2 and 11.6 nM, respectively) and reduced activity against off-target isoforms hCA I/II, indicating favorable selectivity profiles. Lead compounds 2g and 4g significantly enhanced the antiproliferative effects of azacitidine and sorafenib in breast and pancreatic Cancer cells under both normoxic and hypoxic conditions. Molecular modeling and simulation studies further supported productive zinc coordination and stable active-site interactions. Overall, these findings highlight bis-triazole benzenesulfonamides as promising scaffolds for targeting hCA IX/XII-expressing tumors and improving chemosensitivity to conventional chemotherapeutics to overcome Cancer resistance.

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