2. Academic Validation
  3. Novel N-(3-(1-(4-sulfamoylphenyl)triazol-4-yl)phenyl)benzamide Derivatives as Potent Carbonic Anhydrase Inhibitors with Broad-Spectrum Anticancer Activity: Leveraging Tail and Dual-Tail Approaches

Novel N-(3-(1-(4-sulfamoylphenyl)triazol-4-yl)phenyl)benzamide Derivatives as Potent Carbonic Anhydrase Inhibitors with Broad-Spectrum Anticancer Activity: Leveraging Tail and Dual-Tail Approaches

  • J Med Chem. 2025 Feb 13;68(3):3764-3781. doi: 10.1021/acs.jmedchem.4c02830.
Ashraf K El-Damasy 1 2,  Hyun Ji Kim 1,  Muhammad Faisal 1 3,  Andrea Angeli 4,  Ahmed E Elsawi 5,  Wagdy M Eldehna 5 6,  Claudiu T Supuran 4,  Gyochang Keum 1 3
Affiliations

Affiliations

  • 1 Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 3 Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea.
  • 4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, Firenze 50019, Italy.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, P.O. Box, Kafrelsheikh 33516, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt.
PMID: 39818802 DOI: 10.1021/acs.jmedchem.4c02830
Abstract

Carbonic anhydrases (CAs) IX and XII are crucial for the survival and metastasis of solid tumors under hypoxic conditions. We designed compounds 7a-s, integrating triazole and benzenesulfonamide scaffolds known for inhibiting tumor-associated CAs IX/XII. Initial synthesis included compounds 7a-e, followed by diversification with small hydrophobic groups (7f-m) and hydrophilic heterocyclic secondary amines (7n-s). Compounds were evaluated against CA II, IX, and XII to assess activity and selectivity. Chlorinated derivative 7l exhibited the highest efficacy against CA IX (KI = 0.317 μM) and ditrifluoromethylated 7j against CA XII (KI = 0.081 μM). Subsequent testing on 60 Cancer cell lines at 10 μM revealed promising Anticancer activity, especially for dimethylated derivative 7h (CA IX, KI = 1.324 μM; CA XII, KI = 0.435 μM), with GI50 values ranging from 0.361 to 9.21 μM. Molecular docking analyses elucidated binding mechanisms, highlighting potential inhibitory actions of compound 7h on CAs IX and XII.

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