Coumarin-based Oximes Exert Monoamine Oxidase Inhibitory Activity

Coumarins (Benzopyran-2-one) are a broad class of compounds of both natural and synthetic origin with diverse pharmacological properties that have attracted intense interest in recent years. For example, the coumarin nucleus has emerged as a promising scaffold for monoamine oxidase (MAO) inhibitors (MAOIs), an essential target for developing drugs to treat neurodegenerative disorders. In the present study, we report the in vitro cytotoxic and MAO inhibitory activities of 3-acylcoumarin-oximes (7a-l) bearing various substituent groups on the core coumarin ring.

The cytotoxic activity was evaluated using crystal violet dye binding, MAO activity was assayed using the MAO-GloTM kit, and the Free radical scavenging activities of the most active compound were tested spectrophotometrically using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and hydrogen peroxide (H₂O₂) methods.

The in vitro cytotoxic activity indicated that all the synthesized compounds were non-cytotoxic against Neuroblastoma 2A (N2a) cells except compound 7k (cytotoxic concentration, CC₅₀=30.8±0.3 μM), bearing the hydroxy group at the carbon-7 and -8 positions. However, this cytotoxic compound showed the least MAO (hMAO-A and hMAO-B) inhibitory activity. Interestingly, the non-cytotoxic compound 7f, bearing the diethylamino group at the C-7 position, showed the highest MAO inhibitory activity (hMAO-A: IC₅₀=1.27±0.66 μM and hMAO-B: IC₅₀=4.65±0.52 μM), MAO (A/B), non-selectivity (selectivity index, SI=3.66), reversible inhibition against hMAO-A enzyme, neuroprotection in H₂O₂-treated N2a cells, and capability of neutralizing free radicals in DPPH assay.

The 7-diethylamino-substituted 3-acylcoumarin-oxime derivative (compound 7f, bearing a diethylamino group at the C-7 position of the coumarin ring) can be considered a promising scaffold for developing new and more potent MAOI drugs for treating neurodegenerative disorders.