Synthesis, in silico ADME, toxicity prediction and molecular docking studies of N-substituted [1,2,4]triazolo[4,3-a]pyrazine derivatives as potential anticonvulsant agents

Two new series of N-substituted [1,2,4]triazolo[4,3-a]pyrazine derivatives, 2a-e and 3a-e were synthesized by coupling substituted acid chlorides/benzyl chlorides with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine and investigated for antioxidant, anticonvulsant effect and neurotoxicity. The in vitro antioxidant activity was assessed using the DPPH and hydroxyl radical scavenging assays. The anticonvulsant potential of the synthesised molecules was assessed using MES and PTZ tests, and their neurotoxicity was evaluated using a rotorod test in mice. Compounds 2a, 2b, 2e, and 3d were identified to have a good anti-seizure action while causing minimal neurotoxicity. The most effective anticonvulsants were compounds 2a, 2b, and 2e, with median effective dosages of 0.38, 0.36, and 0.25 mg/kg, respectively. A computational analysis was also conducted, which included drug-likeness and docking studies, as well as prediction of pharmacokinetic parameters. Docking studies of potent compounds in the binding pocket of the 4-aminobutyrate aminotransferase protein (PDB ID: 10HV) reveal strong binding interactions and high docking scores. From these findings, the potent compounds 2a, 2b, and 2e might be a promising lead in the quest for safer and more effective anticonvulsants with neuroprotective properties. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

Two new series of pyrazine derivatives were synthesized and evaluated for their antioxidant, anticonvulsant, and neurotoxicity properties. Compounds 2a, 2b, and 2e showed good anticonvulsant activity and minimal neurotoxicity. Computational analysis revealed strong binding interactions of these compounds in the binding pocket of a specific protein. The results suggest that compounds 2a, 2b, and 2e have potential as safer and more effective anticonvulsant drugs with neuroprotective properties.