Mapping Chromone-3-Phenylcarboxamide Pharmacophore: <i>Quid Est Veritas</i>?

Chromone-3-phenylcarboxamides
(Crom-1 and Crom-2) were identified as potent,
selective, and reversible inhibitors
of human monoamine oxidase B (hMAO-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 hMAO-B inhibitory
activity. From the study, N-(3-chlorophenyl)-4H-thiochromone-3-carboxamide (31) (hMAO-B IC50 = 1.52 ± 0.15 nM) emerged as
a reversible tight binding inhibitor with an improved pharmacological
profile. In in vitro ADME-toxicity studies, compound 31 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 31 also protected SH-SY5Y cells from iron­(III)-induced damage. Collectively,
these studies highlighted compound 31 as the first-in-class
and a suitable candidate for in vivo preclinical
investigation.