Identification of Novel Phthalimide 4, 5-dihydro oxazole amide Pyridine and Quinoline derivatives by Molecular Docking Studies as Potential anticonvulsant agents against GABA-Type A Receptor

Abstract

In this study, a series of novel N-(4-(2-(1,3-benzoxazole-2-carbonyl) hydrazono) ethyl)-2-pyridinecarboxamide derivatives and 2-[2-(1,3-Dioxoisoindolin-2-yl) acetyl]-N-(6-methylquinolin-4-yl) hydrazine-1-carboxamide Derivatives were designed and evaluated for their binding affinity against the GABA receptor using molecular docking studies.

The docking simulations were performed using AutoDock Vina against the diazepine binding site of the GABAA receptor. The compounds showed promising binding affinities, ranging from –6.7 to –7.3 kcal/mol, which are comparable or superior to diazepam (–6.6 kcal/mol), a standard GABAA modulator. The compounds exhibited favourable binding energies ranging from –6.8 to –7.8 kcal/mol against the benzodiazepine binding site of the GABA A receptor, indicating strong receptor-ligand interactions. Molecular interaction analysis revealed that the both derivatives formed stable hydrogen bonding and π–π stacking interactions with important residues in the GABA A binding pocket: Serine 205, Phenylalanine 100, Tyrosine 160, Histidine 102, Glutamate 189. The in silico ADMET profiling of the synthesized GP and GPQ derivatives reveals favorable drug-likeness and safety parameters, supporting their potential as CNS-active agents, particularly targeting the GABA-A receptor, In Phthalimide -4, 5-dihydro oxazole amide Pyridine Compound Gpy-12 Shows Least binding energy - and with pIC50 Concentration of 1.61 uM, In Phthalimide -4, 5-dihydro oxazole amide Quinoline Derivatives compound Gqu-7 shows binding energy   – 7.6 kcal /mol and With pIC50 value of 2.67 uM.