SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti-Trypanosoma brucei Agent

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Borsari, C (Author) Other; Santarem, N (Author) Other; Macedo, S (Author) Other; Dolores Jimenez Anton, MD (Author) Other; Torrado, JJ (Author) Other; Isabel Olias Molero, AI (Author) Other; Corral, MJ (Author) Other; Tait, A (Author) Other; Ferrari, S (Author) Other; Costantino, L (Author) Other; Luciani, R (Author) Other; Ponterini, G (Author) Other; Gul, S (Author) Other; Kuzikov, M (Author) Other; Ellinger, B (Author) Other; Behrens, B (Author) Other; Reinshagen, J (Author) Other; Maria Alunda, JM (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Costi, MP (Author) Other

Journal

Title: Acs Medicinal Chemistry Letters

Vol. 10

Pages: 528-533

ISSN: 1948-5875

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 3 Citations

Other information

Authenticus ID: P-00Q-F80

DOI: 10.1021/acsmedchemlett.8b00565

Abstract (EN): Chemical modulation of the flavonol 2-(benzo[d] [1,3]dioxo1-5-y1)-chromen-4-one (1), a promising anti-Trypanosomatid agent previously identified, was evaluated through a phenotypic screening approach. Herein, we have performed structure activity relationship studies around hit compound 1. The pivaloyl derivative (13) showed significant anti-T. brucei activity (EC50 = 1.1 1iM) together with a selectivity index higher than 92. The early in vitro ADME-tox properties (cytotoxicity, mitochondria] toxicity, cytochrome P450 and hERG inhibition) were determined for compound 1 and its derivatives, and these led to the identification of some liabilities. The 1,3-benzodioxole moiety in the presented compounds confers better in vivo pharmacokinetic properties than those of classical flavonols. Further studies using different delivery systems could lead to an increase of compound blood levels.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11