Synthesis, Biological Evaluation and Molecular Modeling Studies of Propargyl‐Containing 2,4,6‐Trisubstituted Pyrimidine Derivatives as Potential Anti‐Parkinson Agents

Abstract

Monoamine oxidase B (MAO‐B) inhibitors are potential drug candidates for the treatment of various neurological disorders including Parkinson's disease. A total of 20 new propargyl‐containing 2,4,6‐trisubstituted pyrimidine derivatives were synthesized and screened for MAO inhibition using Amplex Red assays. All the synthesized compounds were found to be reversible and selective inhibitors of the MAO‐B isoform at sub‐micromolar concentrations. MVB3 was the most potent MAO‐B inhibitor with an IC50 value of 0.38±0.02 μμ, whereas MVB6 (IC50=0.51±0.04 μμ) and MVB16 (IC50=0.48±0.06 μμ) were the most selective for MAO‐B with a selectivity index of more than 100‐fold. In cytotoxic studies, these compounds were found to be nontoxic to human neuroblastoma SH‐SY5Y cells at concentrations of 25 μm. MVB6 was found to decrease the intracellular level of reactive oxygen species to 68 % at 10 μm concentration, whereas other compounds did not produce significant changes in reactive oxygen species levels. In molecular modeling studies, MVB3 displayed strong binding affinity for the MAO‐B isoform with a dock score of −10.45, in agreement with the observed activity. All the compounds fitted well in the hydrophobic cavity of MAO‐B. Thus, propargyl‐substituted pyrimidine derivatives can be promising leads in the development of potent, selective and reversible MAO‐B inhibitors for the treatment of Parkinson's disease.