Design and synthesis of novel cyclohexanecarboxamides with anticonvulsant effect by activating Nrf2-ARE pathway

This study investigated a series of novel cyclohexanecarboxamide derivatives 4a-e, 5a-e and 6a-e as anticonvulsant and neuroprotective agents. Compounds 4a-e, 5a-e, and 6a-e were synthesized starting from cyclohexanone and aniline derivatives and evaluated for their anticonvulsant effects using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models. The most potent compounds 4b, 5c, and 6d demonstrated 83.33 % protection in the scPTZ test, while compounds 5a and 6b showed 100 % protection in the MES test. Further quantitative evaluation showed that compound 6d was the most active derivative in scPTZ test (ED₅₀ = 0.04 mmol/kg) and it was more potent than the two reference drugs phenobarbital and ethosuximide by 1.7 and 25.7-fold, respectively. Notably, all the compounds were free from neurotoxic side effects. Mechanistic studies indicated that the compounds 4b, 5c, and 6d exerted neuroprotective effects by modulating oxidative stress markers and activating the Nrf2/ARE pathway. Histopathological examination of brain of animals treated with compounds 4b, 5c, or 6d corroborated the neuroprotective properties. Additionally, molecular docking study and dynamic simulations were also carried out to study the mechanism of Nrf2 activation by the most active compound 6d. These results spotlight the potential of these derivatives as promising candidates for further development as anti-epileptic and neuroprotective agents.