Design, Synthesis, Biological Evaluation, and Computational Studies of Novel 1,4‐Diketopiperazines as GABA Agonist

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A novel series of 1,1-disubstituted cyclohexane 7a-e, 8a-e, and 9a-e were designed, synthesized, and evaluated for their anticonvulsant activities. Compounds 7c, 8c, 8d, and 9a displayed significant anticonvulsant activity in both maximum electroshock seizure (MES) and pentylenetetrazol (PTZ) induced seizure during the preliminary screening with no neurotoxicity. The phase II quantitative anticonvulsant activity revealed that compound 8c demonstrated the most potent activity as compared to the conventional drugs phenobarbital. The expression of nuclear factor erythroid 2-related factor- antioxidant response element (Nrf2-ARE) signaling pathways, oxidative stress parameters were also observed. Additionally, histopathological examination of brain of animals treated with compounds 7c, 8c, 8d, and 9a was performed and the results were corroborated the neuroprotective properties. Further neurochemical investigation was performed to unravel the effect of the most active compounds, compounds 7c, 8c, 8d, and 9a demonstrated significant protection by ameliorating GABA levels, which were initially reduced to 61% by PTZ administration, suggesting enhanced GABAergic neurotransmission. Computational parameters including docking analysis on GABAA exhibiting good binding on the active site, Moreover, In silico prediction was carried out indicating that most of compounds have favorable oral bioavailability and BBB permeability they might be viewed as helpful models for future research and derivatization.

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