title: Discovery of a new antileishmanial hit in 8-nitroquinoline series.
abstract: A series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward Leishmania donovani promastigotes. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an IC(50) value of 6.6 μM and CC(50) values ≥ 100 μM, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference (amphotericin B, miltefosine and pentamidine). Compound 21 also appears as an efficient in vitro antileishmanial molecule against both Leishmania infantum promastigotes and the intracellular L. donovani amastigotes (respective IC(50) = 7.6 and 6.5 μM). Moreover, hit quinoline 21 does not show neither significant antiplasmodial nor antitoxoplasmic in vitro activity and though, presents a selective antileishmanial activity. Finally, a structure-activity relationships study enabled to define precisely the antileishmanial pharmacophore based on this nitroquinoline scaffold: 2-hydroxy-8-nitroquinoline.
authors.affiliation: Infections Parasitaires, Transmission, Physiopathologie et Thérapeutique, UMR MD3, Faculté de Pharmacie, Aix-Marseille Université, 27 Boulevard Jean Moulin, CS 30064, 13385 Marseille cedex 05, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Paloque
authors.forename: Pierre
authors.initials: P
authors.lastname: Verhaeghe
authors.forename: Magali
authors.initials: M
authors.lastname: Casanova
authors.forename: Caroline
authors.initials: C
authors.lastname: Castera-Ducros
authors.forename: Aurélien
authors.initials: A
authors.lastname: Dumètre
authors.forename: Litaty
authors.initials: L
authors.lastname: Mbatchi
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hutter
authors.forename: Manel
authors.initials: M
authors.lastname: Kraiem-M'rabet
authors.forename: Michèle
authors.initials: M
authors.lastname: Laget
authors.forename: Vincent
authors.initials: V
authors.lastname: Remusat
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.forename: Pascal
authors.initials: P
authors.lastname: Rathelot
authors.forename: Nadine
authors.initials: N
authors.lastname: Azas
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D056945:Hep G2 Cells; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development; D008018:Life Cycle Stages / Q000187:drug effects; D051379:Mice; D009600:Nitroquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D009600:Nitroquinolines