Identification of 7,8-dihydroxy-3-phenylcoumarin as a reversible monoamine oxidase enzyme inhibitor.

We herein report the biological evaluation of 3-arylcoumarin derivatives (3a-l) as potential human monoamine oxidase-A and -B (hMAO-A and hMAO-B) inhibitors. The result indicated that 7,8-dihydroxy-3-(4-nitrophenyl)coumarin (3j) was most effective against MAO-A (inhibition concentration [IC50 ] = 6.46 ± 0.02 µM) and MAO-B (IC50  = 3.8 ± 0.3 µM) enzymes than other synthesized compounds and reference compounds (pargyline and moclobemide). Furthermore, compound (3j) showed (a) nonselectivity against hMAO enzymes, (b) reversible hMAO enzymes inhibition, and (c) neuroprotection against H2 O2 -treated human neuroblastoma (N2a) cells. Finally, a molecular modeling study revealed that the hMAO enzymes inhibitory activity of the compound (3j) may be due to the orientation where the nitro (NO2 ) group lies deep into the receptor and the phenyl ring directed toward flavin adenosine dinucleotide via hydrogen bond interaction, and possible π-π interaction with various important residues. Thus, the results of the present study demonstrate that compound (3j) can be considered as a promising scaffold for the development of hMAO-A and hMAO-B inhibitors.