A New scaffold for selective inhibition of human monoamine oxidase B

Monoamine oxidases (MAOs) are mitochondrial FAD-containing enzymes that catalyze the oxidative deamination of biogenic amine neurotransmitters and xenobiotic amines. Being involved in the catabolism of neurotransmitters, MAOs are well-known and always attractive pharmacological targets in various neurological, psychiatric and neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD)1,2. As the ideal drug has not been achieved so far, researchers continue to explore this field3, in particular in search for reversible MAO B inhibitors. In the frame of a screening campaign of a huge library of natural and synthetic compounds, 2-phenyloxazole emerged as potential scaffold and a library of twelve derivatives was prepared. Most of the compounds were found to act as competitive inhibitors of MAOs: compounds 4a, 4g and 4m were found to be the most potent inhibitors (Ki = 0.5-1M), with a good selectivity toward MAO B (KiMAO-A/KiMAO-B> 45). Molecular docking analysis allowed rationalizing the experimentally observed binding affinity and selectivity. Compound 4a was also able to inhibit MAO activity in NGF–differentiated PC12 cells. Our results indicate that 4a may be considered a promising scaffold for the design of novel effective and selective MAO-B inhibitors, with potential pharmacological applications.