2. Academic Validation
  3. Shooting an Arrow against Convulsion: Novel Triazole-Grafted Benzenesulfonamide Derivatives as Carbonic Anhydrase II and VII Inhibitors

Shooting an Arrow against Convulsion: Novel Triazole-Grafted Benzenesulfonamide Derivatives as Carbonic Anhydrase II and VII Inhibitors

  • J Med Chem. 2025 Apr 24;68(8):8873-8893. doi: 10.1021/acs.jmedchem.5c00526.
Mohamed A Zeidan 1,  Mahmoud Abdelrahman Alkabbani 2,  Simone Giovannuzzi 3,  Eman F Khaleel 4,  Anwar A El-Hamaky 5,  Nourhan A Khattab 6,  Rehab Badi 4,  Abdelhameed Abubakr 7,  Abdallah M Hamdy 8,  Mohamed Fares 9 10,  Haytham O Tawfik 5,  Claudiu T Supuran 3,  Wagdy M Eldehna 11 12,  Moataz A Shaldam 11
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 2 Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
  • 3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, Firenze 50019, Italy.
  • 4 Department of Medical Physiology, College of Medicine, King Khalid University, Abha 61421, Asir, Saudi Arabia.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 6 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 7 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Egyptian Russian University, Badr City PO box 11829, Cairo, Egypt.
  • 8 Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr City PO box 11829, Cairo, Egypt.
  • 9 School of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
  • 10 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, ERU, Badr City, Cairo 11829, Egypt.
  • 11 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh P.O. Box 33516, Egypt.
  • 12 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt.
PMID: 40237575 DOI: 10.1021/acs.jmedchem.5c00526
Abstract

This study investigates new anticonvulsant substances that target the epilepsy-associated Carbonic Anhydrase isoforms II and VII. The 1,2,3-triazole with a benzenesulfonamide motif is present in the produced molecules. Of these, 5b and 5c exhibited remarkable selectivity and inhibitory efficacy toward hCA VII and hCA II over hCA I. The KI values of 5b and 5c were 6.3 and 10.1 nM, respectively, and 21.6 and 18.9 nM, respectively. In a pilocarpine-induced paradigm, in vivo assessments showed decreased seizure severity and susceptibility with delayed seizure onset and diminished intensity. The quick absorption and in vivo stability of 5b were demonstrated by pharmacokinetic investigations. Evaluations of toxicity showed no neurotoxic effects and a high safety margin (LD50 > 2000 mg/kg). Mechanistic research has shown effectiveness in maintaining neuronal integrity, reducing mTOR activation, and raising hippocampus KCC2 levels. Compound 5b's binding interactions with hCA II and hCA VII were clarified by docking and dynamics experiments.

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