%0 Journal Article
%9 ACL : Articles dans des revues avec comité de lecture répertoriées par l'AERES
%A Pedron, J.
%A Boudot, C.
%A Bourgeade-Delmas, Sandra
%A Sournia-Saquet, A.
%A Paloque, L.
%A Rastegari, M.
%A Abdoulaye, M.
%A El-Kashef, H.
%A Bonduelle, C.
%A Pratviel, G.
%A Wyllie, S.
%A Fairlamb, A. H.
%A Courtioux, B.
%A Verhaeghe, P.
%A Valentin, A.
%T Antitrypanosomatid pharmacomodulation at position 3 of the 8-nitroquinolin-2(1h)-one scaffold using palladium-catalysed cross-coupling reactions
%D 2018
%L fdi:010074329
%G ENG
%J Chemmedchem
%@ 1860-7179
%K 8-nitroquinolin-2(1H)-ones ; antikinetoplastid pharmacomodulation ; palladium-catalysed cross-coupling ; parasitic nitroreductases ; trypanosomatids
%M ISI:000448061600009
%N 20
%P 2217-2228
%R 10.1002/cmdc.201800456
%U https://www.documentation.ird.fr/hor/fdi:010074329
%> https://www.documentation.ird.fr/intranet/publi/2018/11/010074329.pdf
%V 13
%W Horizon (IRD)
%X An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56V) than the initial hit (-0.45V). Compound 21 displays micromolar antitrypanosomal activity (IC50=1.5m) and low cytotoxicity on the human HepG2 cell line (CC50=120m), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L.infantum and is not efficiently bioactivated by T.brucei brucei typeI nitroreductase, which suggests the existence of an alternative mechanism of action.
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