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.

SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti- Trypanosoma brucei Agent / C. Borsari, N. Santarem, S. Macedo, M.D. Jimenez-Anton, J.J. Torrado, A.I. Olias-Molero, M.J. Corral, A. Tait, S. Ferrari, L. Costantino, R. Luciani, G. Ponterini, S. Gul, M. Kuzikov, B. Ellinger, B. Behrens, J. Reinshagen, J.M. Alunda, A. Cordeiro-Da-Silva, M.P. Costi. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 10:4(2019 Jan 29), pp. 528-533. [10.1021/acsmedchemlett.8b00565]

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

C. Borsari;
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.
ADME-tox properties; flavonol-like compounds; neglected tropical diseases; SAR studies; Trypanosoma brucei
Settore CHIM/08 - Chimica Farmaceutica
   New Medicines for Trypanosomatidic Infections
   NMTRYPI
   European Commission
   SEVENTH FRAMEWORK PROGRAMME
   603240
29-gen-2019
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1012751
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