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SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti-Trypanosoma brucei Agent
- Publication Year :
- 2019
-
Abstract
- Chemical modulation of the flavonol 2-(benzo[d][1,3]dioxol-5-yl)-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 μM) together with a selectivity index higher than 92. The early in vitro ADME-tox properties (cytotoxicity, mitochondrial 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.
- Subjects :
- Stereochemistry
Phenotypic screening
hERG
Trypanosoma brucei
01 natural sciences
Biochemistry
03 medical and health sciences
In vivo
Drug Discovery
Moiety
Cytotoxicity
neglected tropical diseases
030304 developmental biology
0303 health sciences
biology
010405 organic chemistry
Chemistry
Organic Chemistry
Cytochrome P450
ADME-tox properties
biology.organism_classification
In vitro
0104 chemical sciences
3. Good health
flavonol-like compounds
SAR studies
biology.protein
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....455b808d33574d4d1e3e13d9c8209afd