Novel coumarin benzamides as potent and reversible monoamine oxidase-B inhibitors: Design, synthesis, and neuroprotective effects.

[Display omitted] • New coumarin benzamides 3a – j were designed and synthesized. • Selective MAO-B inhibition (IC 50 = 95 nM, K i = 46 nM) was elicited by compound 3i. • The 6-amidocoumarins 3i and 3j showed a safe cytotoxicity profile. • Compounds 3i and 3j showed neuroprotective effects in SH-SY5Y neuroblastoma cells. • Docking and MD simulations highlighted the favorable binding mode of 3i with MAO-B. A series of new 6-amidocoumarin derivatives, 3a – j, was synthesized and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase. All compounds, except 3 g , showed higher inhibitory activity towards MAO-B than MAO-A. Compound 3i most potently inhibited MAO-B with an IC 50 value of 0.095 μM, followed by 3j (0.150 μM), 3b (0.190 μM), and 3c (0.204 μM). Compound 3i demonstrated the highest selectivity index (>421.05) for MAO-B. The remarkable MAO-B inhibitory activity of compounds 3i , 3j , 3b , and 3c highlighted the substantial role of the substituents at the 3,4-position of the terminal phenyl group in achieving optimal MAO-B inhibition, especially 3-Cl (3i) > 3-CF 3 (3b). In the kinetic study, the K i value of 3i for MAO-B was 0.046 ± 0.010 μM with a competitive reversible mode. Moreover, compounds 3i and 3j were nontoxic to normal (MDCK), cancer (HL-60), and neuroblastoma (SH-SY5Y) cells and showed protective effects against damage induced by reactive oxygen species in SH-SY5Y neuroblastoma cells. Moreover, molecular docking and molecular dynamics simulations highlighted the tight interactions of 3i with Tyr398 at the binding site of MAO-B. These findings suggest that 3i is a potent, reversible, and selective MAO-B inhibitor that could potentially treat neurological disorders. [ABSTRACT FROM AUTHOR]