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

作者：Reis Joana; Cagide Fernando; Chavarria Daniel; Silva Tiago; Fernandes Carlos; Gaspar Alexandra; Uriarte Eugenio; Remiao Fernando; Alcaro Stefano; Ortuso Francesco; Borges Fernanda^*

来源：Journal of Medicinal Chemistry, 2016, 59(12): 5879-5893.

DOI：10.1021/acs.jmedchem.6b00527

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 gamma-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.

• 出版日期2016-6-23