Exploring new cyclohexane carboxamides based GABA agonist: Design, synthesis, biological evaluation, in silico ADME...

The new series of 5a-e, 6a-e and 7a-e derivatives were designed, synthesized and tested for their anticonvulsant activity using "gold standard methods" ScPTZ and MES model, neurotoxicity, liver enzymes and neurochemical assay. Screening of the synthesized analogues exhibited variable anticonvulsant potential especially in chemically induced seizures. Quantification study showed that compounds 6d and 6e were the most potent analogues with ED₅₀ 44.77 and 11.31 mg/kg, respectively in ScPTZ test. Compound 6e (0.031 mmol/kg) was about 2 fold more potent than phenobarbital (0.056 mmol/kg) and was 30 folds more potent than Ethosuximide (0.92 mmol/kg) as reference standard drug. Moreover, all the synthesized compounds were screened for acute neurotoxicity using the rotarod method to recognize motor impairment, whereas all compounds devoid from neurotoxicity except compound 5a, 5b, 7a and 7e. The most active compounds were examined for acute toxicity and the estimates for LD₅₀ were stated. Further neurochemical study was performed to investigate the effect of the most active compounds in ScPTZ test on GABA level in brain of the mice; a significant elevation in GABA level was obvious for compound 6d compared to control group confirming GABAergic modulating activity. Docking study was accomplished to examine the binding interaction of the newly synthesized analogues with GABA-AT enzyme. Additionally, physicochemical and pharmacokinetic parameters were predicted. The attained results indicate that the newly target compounds are considered a promising scaffolds for further development of newly anticonvulsants.