1,3,4-Oxadiazole as a Privileged Scaffold for Anticonvulsant Activity: Design, Syntheses and ADMET Studies
摘要
The compounds with an –N=C–O– linkage have been widely used in the drug development. In the 1,3,4-oxadiazole ring, substitutions made at position 2 and position 5 make the molecule behave as an anchor for lipophilic groups. The present study focuses on the synthesis of a novel series of 2,5-disubstituted 1,3,4-oxadiazoles using a two-step reaction. The first step involves the synthesis of acid hydrazides from substituted methyl esters, followed by reaction with aromatic carboxylic acids using POCl3 as the cyclizing agent to form the title compounds. All the synthesized compounds were characterized using physicochemical and spectral methods. The compounds were tested for anti-convulsant potential using maximal electroshock seizure and Isoniazid-induced seizure models. The 2-(4-bromophenyl)-5-(2,3-dichlorophenyl)-1,3,4-oxadiazole was found to be the best in the series, with percentage inhibition of 61 and 75% in the MES and the INH models, respectively. Molecular docking study was also carried against the GABA-selective protein, PDB ID 6HUP. The binding energy was predicted in the range of –6.59 to –7.91 kcal/mol. The partition coefficient for the compounds was found to be coordinated with the in vivo experimental results and with the molecular docking prediction data. The in silico ADMET data suggested the compounds to be safe anti-convulsant agents. Thus, 1,3,4-oxadiazole may be a promising pharmacophore for designing effective and safe anticonvulsant agents.