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

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Mesiti, F (Author) Other; Gaspar, A (Author) Other; Chavarria, D (Author) Other; Maruca, A (Author) Other; Rocca, R (Author) Other; Martins, EG (Author) Other; Barreiro, S (Author) Other; Silva, R (Author) Other; Fernandes, C (Author) Other; Gul, S (Author) Other; Keminer, O (Author) Other; Alcaro, S (Author) Other; Fernanda Borges (Author) FCUP

Journal

Title: Journal of Medicinal Chemistry

Vol. 64

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 9 Citations

Other information

Authenticus ID: P-00V-5MW

DOI: 10.1021/acs.jmedchem.1c00510

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14