Monoamine Oxidase Inhibitors: Benzylidene-prop-2-ynyl-amines Analogues

A new series of benzylidene-prop-2-ynyl-amines analogues have been synthesized and evaluated for their monoamine oxidase A and B inhibitory activity by determination of IC50 and selectivity index (SI). Among these inhibitors, benzhydrylidene-prop-2-ynyl-amine (2, IC50 = 32 nM) and (3, 4-dimethoxy-benzylidene)-prop-2-ynyl-amine (10, IC50 = 14 nM) provide the highest inhibitory potency toward monoamine oxidase (MAO) A and B respectively. (3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-prop-2-ynyl-amine (1, SI = 58.96) and compound (2, SI = 0.34) were proved to be the superior selective inhibitors toward MAO-A and MAO-B respectively. Docking studies show that the imine moiety is located in hydrophobic pocket, bringing the propargyl group close to FAD which indicates that the different inhibitory potency toward MAO-A may be ascribable to both the distance between alkynyl group and N5 of FAD, and hydrogen bonding interactions between inhibitors and enzymes.