Synthesis, characterisation and evaluation of some 1,5-benzodiazepine quinolin-2-one derivatives as possible hypnotic agents

Abstract

A series of novel 3-(2-(phenyl/substituted phenyl)-1H-benzo[b] [1,5]-diazepin-4-yl)-4-methoxy-1-phenyl/methylquinolin-2(1H)-one [IV-a(1-6)/IV-b(1-6)] derivatives are synthesised by condensation of 3-substituted cinnamoyl-4-methoxy-1-phenyl/methylquinolin-2(1H)-one [III-a(1-6)/III-b(1-6)] with o-phenylenediamine. The results of the docking studies reveal that the synthesised compounds exhibited well conserved hydrogen bonding with one or more amino acid residues in the active pocket of alpha1beta3gamma2L GABA(A) Receptor (PDB ID: 6HUO) using Molegro Virtual Docker Software (MVD-2013, 6.0). The title compounds exhibit Mol Dock Score in the range of -124.502 to -149.448 with score more or comparable to the standard ligand score of -127.4127 and better than the standard drug -92.3878. All the synthesized compounds were satisfactorily characterized by spectral analysis and were tested for in vivo hypnotic activity based on the potentiation of barbiturate (phenobarbitone) sleeping time in miceusing diazepam as reference standard. All the compounds, except 4-methoxy-1-methyl-3-(2-(3-nitrophenyl)-1H-benzo[b][1,5]-diazepin-4-yl) quinolin-2(1H)-one (IV-b4), significantly decrease the sleep latency, prolonged the duration of sleep and also showed good muscle relaxation property. Among the synthesised compounds, 4-methoxy-3-(2-(3-methoxyphenyl)-1H-benzo[b][1,5]-diazepin-4-yl)-1-phenylquinolin-2(1H)-one (IV-a3) is found to be the most potenthypnotic agentwith sleep latency of 26.67 ± 2.629 min and sleeping time of 111.00 ± 6.028 minutesand matches with pharmacophore mapping of the designed molecule with the MolDock score.