期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 10, 期 4, 页码 528-533出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00565
关键词
Trypanosoma brucei; flavonol-like compounds; SAR studies; ADME-tox properties; neglected tropical diseases
资金
- European Union's Seventh Framework Programme for research, technological development, and demonstration [603240]
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.
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