Synthesis, Docking and Antiepileptic Activity of New 2-((1,5-Diphenyl-1H-1,2,4-Triazol-3-yl)Thio)-N-Phenylacetamide Derivatives

Abstract

In this work, a new series of 2-((1,5-diphenyl-1H-1,2,4-triazol-3-yl)thio)-N-phenylacetamide derivatives (9a–k) were synthesized and then evaluated for their antiepileptic activity against pentylenetetrazole (PTZ)-induced seizures in mice. The most potent synthesized compound was 3-chloro derivative, 9e, with an average latency time of 825 ± 281 seconds (mean ± SEM) and zero mortality. Moreover, compound 9e was more active than phenytoin (p < 0.1) but weaker than phenobarbital (p < 0.05) in the PTZ test. Further, a molecular docking study was performed to investigate the modes of interactions between the GABA_A receptor and the synthesized compounds. Docking results indicate that all of the synthesized compounds place well into the active site of the GABA_A receptor. In addition, compound 9e, with the highest anticonvulsant properties, demonstrates proper interactions and forms strong hydrogen bonds with key amino acid residues in the active site of the GABA_A receptor. Additionally, it has exhibited higher binding energy in the docking study compared to phenobarbital and phenytoin as the standard antiepileptic agents.

Keywords:

• Antiepileptic
• seizures
• molecular docking
• synthesis
• pentylenetetrazole
• 1,2,4-triazole

Acknowledgments

The authors would like to acknowledge Dr. Mehdi Gholami at the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran, for kind assistance in providing laboratory facilities for this research.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Financially supported by the Research Council of AJA University of Medical Sciences gratefully acknowledged.