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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2016

Autores

Reis, J (Autor) Outra; Fernando Cagide (Autor) FCUP; Chavarria, D (Autor) Outra; Silva, T (Autor) Outra; Fernandes, C (Autor) Outra; Gaspar, A (Autor) Outra; Uriarte, E (Autor) Outra; Fernando Remiao (Autor) FFUP; Alcaro, S (Autor) Outra; Ortuso, F (Autor) Outra; Fernanda Borges (Autor) FCUP

Revista

Título: Journal of Medicinal Chemistry

Vol. 59

Páginas: 5879-5893

ISSN: 0022-2623

Editora: American Chemical Society

Indexação

ISI Web of Knowledge - 82 Citações

Scopus - 84 Citações

Outras Informações

ID Authenticus: P-00K-KBZ

DOI: 10.1021/acs.jmedchem.6b00527

Abstract (EN): 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 15