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

• Type: Article in International Scientific Journal
• Date: 2016

Authors

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

Journal

Title: Journal of Medicinal Chemistry

Vol. 59

Pages: 5879-5893

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 82 Citations

Scopus - 84 Citations

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15