1. Academic Validation
  2. Identification of Benzenesulfonamide-Containing Thiazolidine-2,4-Dione Derivatives as Novel Carbonic Anhydrase II and VII Inhibitors with Anti-Epileptic Activity

Identification of Benzenesulfonamide-Containing Thiazolidine-2,4-Dione Derivatives as Novel Carbonic Anhydrase II and VII Inhibitors with Anti-Epileptic Activity

  • J Med Chem. 2025 Dec 25;68(24):26280-26297. doi: 10.1021/acs.jmedchem.5c02403.
Mohamed M Eldesouki 1 Mahmoud Abdelrahman Alkabbani 2 Mohammed S Taghour 3 Andrea Ammara 4 Diaaeldin M Elimam 5 Alaa Elwan 3 Rehan Monir 6 Kamyar Afarinkia 7 Alessio Nocentini 4 Claudiu T Supuran 4 Haytham O Tawfik 8 Wagdy M Eldehna 9
Affiliations

Affiliations

  • 1 Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 2 Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
  • 3 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11884, Egypt.
  • 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 Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
  • 6 Clinical Biochemistry Department, College of Medicine, King Khalid University, Asir, Abha 61421, Saudi Arabia.
  • 7 Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, U.K.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, P.O. Box Kafrelsheikh 33516 Egypt.
Abstract

We report new anticonvulsant thiazolidine-2,4-diones with pendant benzenesulfonamide group that target epilepsy-associated Carbonic Anhydrase isoforms II and VII. Among these, 6b, 6c, 6e, and 6g exhibited remarkable inhibitory efficacy toward hCA II (KI values of 4.1, 47.8, 9.6, and 6.9 nM, respectively) and hCA VII (KI values of 9.4, 3.6, 41.6, and 98.3 nM, respectively), and selectivity over hCA I. 6c was found to significantly reduce seizure severity and susceptibility, delay seizure onset, and lower seizure intensity in in vivo study of pilocarpine (PIL)-induced seizure model. Its superior in vivo stability and quick absorption were validated by pharmacokinetic studies. According to toxicological evaluations, there was no indication of neurotoxicity and a large safety margin (LD50 > 2000 mg/kg). According to mechanistic research, 6c increased expression of KCC2 in the hippocampus, maintained neuronal integrity, and reduced mTOR activity. Molecular docking clarified 6c interactions with hCA II and hCA VII.

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