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

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 IC value of 0.38±0.02 μμ, whereas MVB6 (IC =0.51±0.04 μμ) and MVB16 (IC =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.