Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?

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 th...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-08, Vol.64 (15), p.11169-11182
Main Authors: Mesiti, Francesco, Gaspar, Alexandra, Chavarria, Daniel, Maruca, Annalisa, Rocca, Roberta, Gil Martins, Eva, Barreiro, Sandra, Silva, Renata, Fernandes, Carlos, Gul, Sheraz, Keminer, Oliver, Alcaro, Stefano, Borges, Fernanda
Format: Article
Language:English
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00510