%0 Journal Article
%9 ACL : Articles dans des revues avec comité de lecture répertoriées par l'AERES
%A Fersing, C.
%A Basmaciyan, L.
%A Boudot, C.
%A Pedron, J.
%A Hatter, S.
%A Cohen, A.
%A Castera-Ducros, C.
%A Primas, N.
%A Laget, M.
%A Casanova, M.
%A Bourgeade-Delmas, Sandra
%A Piednoel, M.
%A Sournia-Saquet, A.
%A Mbou, V. B.
%A Courtioux, B.
%A Boutet-Robinet, E.
%A Since, M.
%A Milne, R.
%A Wyllie, S.
%A Fairlamb, A. H.
%A Valentin, A.
%A Rathelot, P.
%A Verhaeghe, P.
%A Vanelle, P.
%A Azas, N.
%T Nongenotoxic 3-nitroimidazo[1,2-a]pyridines are NTR1 substrates that display potent in vitro antileishmanial activity
%D 2019
%L fdi:010074883
%G ENG
%J ACS Medicinal Chemistry Letters
%@ 1948-5875
%K Leishmania ssp ; imidazopyridine ; nitroaromatic ; nitroreductases ; Ames ; test ; comet assay
%M ISI:000455561600005
%N 1
%P 34-39
%R 10.1021/acsmedchemlett.8b00347
%U https://www.documentation.ird.fr/hor/fdi:010074883
%> https://horizon.documentation.ird.fr/exl-doc/pleins_textes/divers19-01/010074883.pdf
%V 10
%W Horizon (IRD)
%X Twenty nine original 3-nitroimidazo[1,2-a]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. In vitro evaluation highlighted compound 5 as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC50 > 100 mu M) alongside good antileishmanial activities (IC50 = 1-2.1 mu M) against L. donovani, L. infantum, and L. major; and good antitrypanosomal activities (IC50 = 1.3-2.2 mu M) against T. brucei brucei and T. cruzi, in comparison to several reference drugs such as miltefosine, fexinidazole, eflornithine, and benznidazole (IC50 = 0.6 to 13.3 mu M). Molecule 5, presenting a low reduction potential (E degrees = -0.63 V), was shown to be selectively bioactivated by the L. donovani type 1 nitroreductase (NTR1). Importantly, molecule 5 was neither mutagenic (negative Ames test), nor genotoxic (negative comet assay), in contrast to many other nitroaromatics. Molecule 5 showed poor microsomal stability; however, its main metabolite (sulfoxide) remained both active and nonmutagenic, making 5 a good candidate for further in vivo studies.
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