In-silico Screening and Synthesis of Benzo[c]Pyridazines Targeting N-Methyl D-Aspartate Glutamate Receptor for the Treatment of Seizures

Abstract

This study focuses on synthesizing novel benzopyridazine compounds with an evaluation of their anti-epileptic activity by in-silico screening and MES test. The compounds were synthesized under controlled conditions by the reaction of the substituted anilines with sodium nitrite, followed by the reaction with cyanoacetamide, substituted urea, ethanol, and water. The final compounds (5a-d; 6a-d) were tested for antiepileptic activity by in-silico screening targeting N-Methyl D-Aspartate glutamate receptor (PDB ID:5IPV). The screened compounds are also evaluated by in vivo test (MES) by taking phenytoin as a standard drug. The results of the whole study were satisfactory with the yield of the compounds in the range of 88 % to 96 %. The results of in- silico, screening showed that compounds 6a and 6c have far more binding energy compared with standard phenytoin (6a -7.5 Kcal/mol. ; 6c -7.6 Kcal/mol. and Phenytoin -6.5 Kcal/mol.). The TD₅₀ values of synthesized compounds (6a-6d) are observed to be significantly higher than those of standard phenytoin. The PI values of several synthetic compounds (6a and 6c) were found to be higher (55.8 % and 58.0 %) than the current antiepileptic medicine phenytoin (55.6 %), demonstrating the synthesized compound's safety potential.

Keywords: 5IPV; Anti-epileptic; Benzopyridazine; In-silico; N-Methyl D-Aspartate glutamate receptor.