Premium
Antitrypanosomatid Pharmacomodulation at Position 3 of the 8‐Nitroquinolin‐2(1 H )‐one Scaffold Using Palladium‐Catalysed Cross‐Coupling Reactions
Author(s) -
Pedron Julien,
Boudot Clotilde,
BourgeadeDelmas Sandra,
SourniaSaquet Alix,
Paloque Lucie,
Rastegari Maryam,
Abdoulaye Mansour,
ElKashef Hussein,
Bonduelle Colin,
Pratviel Geneviève,
Wyllie Susan,
Fairlamb Alan H.,
Courtioux Bertrand,
Verhaeghe Pierre,
Valentin Alexis
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800456
Subject(s) - trypanosoma brucei , chemistry , stereochemistry , cytotoxicity , leishmania infantum , axenic , stille reaction , amastigote , combinatorial chemistry , in vitro , biochemistry , biology , leishmania , catalysis , visceral leishmaniasis , genetics , leishmaniasis , bacteria , immunology , gene , parasite hosting , world wide web , computer science
Abstract An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3‐bromo‐8‐nitroquinolin‐2(1 H )‐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(1 H )‐one ( 21 ) with a lower reduction potential (−0.56 V) than the initial hit (−0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC 50 =1.5 μ m ) and low cytotoxicity on the human HepG2 cell line (CC 50 =120 μ m ), 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 type I nitroreductase, which suggests the existence of an alternative mechanism of action.