Shooting an Arrow against Convulsion: Novel Triazole-Grafted Benzenesulfonamide Derivatives as Carbonic Anhydrase II and VII Inhibitors
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, <b>5b</b> and <b>5c</b> exhibited remarkable selectivity and inhibitory efficacy toward hCA VII and hCA II over hCA I. The <i>K</i><sub>I</sub> values of <b>5b</b> and <b>5c</b> were 6.3 and 10.1 nM, respectively, and 21.6 and 18.9 nM, respectively. In a pilocarpine-induced paradigm, <i>in vivo</i> assessments showed decreased seizure severity and susceptibility with delayed seizure onset and diminished intensity. The quick absorption and <i>in vivo</i> stability of <b>5b</b> were demonstrated by pharmacokinetic investigations. Evaluations of toxicity showed no neurotoxic effects and a high safety margin (LD<sub>50</sub> > 2000 mg/kg). Mechanistic research has shown effectiveness in maintaining neuronal integrity, reducing mTOR activation, and raising hippocampus KCC2 levels. Compound <b>5b</b>'s binding interactions with hCA II and hCA VII were clarified by docking and dynamics experiments.
Authors
- Simone Giovannuzzi (ORCID: https://orcid.org/0000-0002-0669-7481)
- Abdallah M Hamdy (ORCID: https://orcid.org/0009-0000-4340-0483)
- Moataz A. Shaldam (ORCID: https://orcid.org/0000-0002-0420-4364)
- Rehab Mustafa Badi (ORCID: https://orcid.org/0000-0003-3320-6091)
- Abdelhameed Abubakr (ORCID: https://orcid.org/0000-0002-5256-599X)
- Eman F. Khaleel (ORCID: https://orcid.org/0000-0002-3499-1186)
- Claudiu T. Supuran (ORCID: https://orcid.org/0000-0003-4262-0323)
- Haytham O. Tawfik (ORCID: https://orcid.org/0000-0001-6455-5716)
- Mahmoud Abdelrahman Alkabbani (ORCID: https://orcid.org/0000-0002-2871-2603)
- Wagdy M. Eldehna (ORCID: https://orcid.org/0000-0001-6996-4017)
- Mohamed Farès (ORCID: https://orcid.org/0000-0003-0589-3955)
- Anwar A El-Hamaky (ORCID: https://orcid.org/0000-0001-8887-2310)
- Nourhan A. Khattab (ORCID: https://orcid.org/0009-0006-2149-6895)
- Mohamed A. Zeidan
Institutions
- The University of Sydney (AU)
- Kafrelsheikh University (EG)
- Pharos University in Alexandria (EG)
- Tanta University (EG)
- Estonian Association for Applied Linguistics (EE)
- Institute of Pharmacology (CZ)
- University of Florence (IT)
- Egyptian Russian University (EG)
- King Khalid University (SA)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00526
- Citations
- 14
- Primary Topic
- Enzyme function and inhibition
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- King Khalid University