Docking, synthesis, and characterization of novel heterocyclic ring system and their evaluation for mGlu8 receptor agonist as anticonvulsant agents

Abstract

This research work involves the synthesis of a series of substituted 1-(4-methoxy-1-phenyl/methyl-2-thioxo-1,2- dihydroquinolin-3-yl)ethanone [IVa/b(1-5)] derivatives by dimerization at third position and evaluation of their anticonvulsant activity. The starting material 3-acetyl-4-hydroxy-1-phenyl/methylquinolin-2(1H)-one Ia/b has been treated with P4S10:Al2O3 to yield compound 1-(4-hydroxy-1-phenyl/methyl-2-thioxo-1,2-dihydroquinolin-3-yl)ethanone (IIa/b). Compound IIa/b has been methylated to yield compound 1-(4-methoxy-1-phenyl/methyl-2-thioxo-1,2-dihydroquinolin-3-yl)ethanone (IIIa/b) which, on condensation with ketones forms dimers giving the title compounds IVa-b (1-5). All the synthesized compounds are satisfactorily characterized by spectral data. The in silico pharmacophore modeling of the title compounds has been performed using Molegro Virtual Docker (MVD-2007 software and mGlu8 is the target and in vivo anticonvulsant activity by phenylenetetrazole (PTZ) induced convulsion method. The results of docking have revealed that the synthesized compounds exhibit well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of metabotropic glutamate receptor mGluR8 complexed with (S)-3,4-dicarboxyphenylglycine (DCPG) (PDB ID:6E5V)LY341495 antagonist (PDB ID: 3MQ4). The MolDock Score of compound 2,6-bis(4-methoxy-1-phenyl-2-thioxo-1,2-dihydroquinolin-3-yl)hepato-2,5-dien- 4-one (IVa-1) has been found to be −141.617. The in vivo anticonvulsant activity results show that compound 2,6-bis(4- methoxy-1-phenyl-2-thioxo-1,2-dihydroquinolin-3-yl)hepato-2,5-dien-4-one (IVa-1), 2,7-bis(4-methoxy-1-phenyl-2-thioxo- 1,2-dihydroquinolin-3-yl)octa-2,6-dien-4,5-dione (IVa-2), 2,6-bis(4-methoxy-1-methyl-2-thioxo-1,2-dihydroquinolin-3- yl)hepato-2,5-dien-4-one (IVb-2) and (2E,6E)-2,6-bis(4-methoxy-1-phenyl-2-thioxo-1,2-dihydroquinolin-3-yl) cyclohexanone (IVb-4) have been found to be most potent against pentylenetetrazole induced convulsion.