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

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.