Mapping Chromone-3-Phenylcarboxamide Pharmacophore: ?

Chromone-3-phenylcarboxamides ( and ) were identified as potent, selective, and reversible inhibitors of human monoamine oxidase B (MAO-B). Since they exhibit some absorption, distribution, metabolism, and excretion (ADME)-toxicity liabilities, new derivatives were synthesized to map the chemical structural features that compose the pharmacophore, a process vital for lead optimization. Structure-activity relationship data, supported by molecular docking studies, provided a rationale for the contribution of the heterocycle's rigidity, the carbonyl group, and the benzopyran heteroatom for MAO-B inhibitory activity. From the study, -(3-chlorophenyl)-4-thiochromone-3-carboxamide () (MAO-B IC = 1.52 ± 0.15 nM) emerged as a reversible tight binding inhibitor with an improved pharmacological profile. In ADME-toxicity studies, compound showed a safe cytotoxicity profile in Caco-2, SH-SY5Y, HUVEC, HEK-293, and MCF-7 cells, did not present cardiotoxic effects, and did not affect P-gp transport activity. Compound also protected SH-SY5Y cells from iron(III)-induced damage. Collectively, these studies highlighted compound as the first-in-class and a suitable candidate for preclinical investigation.