Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors

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• 作者：Joana Reis ; Fernando Cagide ; Daniel Chavarria ; Tiago Silva ; Carlos Fernandes ; Alexandra Gaspar ; Eugenio Uriarte ; Fernando Remião ; Stefano Alcaro ; Francesco Ortuso ; Fernanda Borges
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 23, 2016
• 年：2016
• 卷：59
• 期：12
• 页码：5879-5893
• 全文大小：627K
• 年卷期：0
• ISSN：1520-4804

文摘

The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure–activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3′-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC₅₀ = 403 pM) and N-(3′,4′-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC₅₀ = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme–inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood–brain barrier permeability, thus being a valid candidate for subsequent animal studies.