Design, synthesis and evaluation of piperazine clubbed 1,2,4-triazine derivatives as potent anticonvulsant agents

Abstract

The new series of N-(5,6-diphenyl-1,2,4-triazin-3-yl)-2-(4-substituted piperazin-1-yl) acetamide (RP1–5) and 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-1-(4- substituted piperazin-1-yl)-ethan-1-one (RP6–10) derivatives were designed and synthesised by clubbing substituted 5,6-diphenyl-1,2,4-triazine with different substituted piperazines. The synthesized compounds were tested for anticonvulsant activity and various biochemical toxicity parameters. Among the series, two compounds (2-(4-benzylpiperazin-1-yl)-N-(5,6-diphenyl-1,2,4-triazin-3-yl)acetamide (RP4), and 2‑chloro-1-(4-substituted piperazin-1-yl)ethan-1-one (RP5) were found to demonstrate the most potent anticonvulsant activity in both MES and scPTZ convulsion mice models. The most active compound RP5 was effective at median doses (ED50) of 14.82 mg/kg in MES and 14.61 mg/kg in scPTZ model. The median toxic dose (TD50) was > 600 which provided the compound RP5 with high protective index of 40.48 in the MES test and 41.06 in scPTZ test. Further, both the compounds were also found to possess significant antidepressant activity. The compounds did not show any adverse effect in various parameters such as grip-strength test (skeletal muscular strength), actophotometer, and rotarod test (locomotor) as compared to the control groups. In biochemical estimation, RP4 and RP5 were found nontoxic and showed no sign of any pathological changes in blood chemistry, liver, and nephrology of the kidney. The GABA level estimation in the whole brain of mice was performed to predict the mechanistic study of the selected compounds.