title: Antileishmanial pharmacomodulation in 8-nitroquinolin-2(1H)-one series.
abstract: An antileishmanial pharmacomodulation at position 4 of 8-nitroquinolin-2(1H)-one was conducted by using the Sonogashira and Suzuki-Miyaura coupling reactions. A series of 25 derivatives was tested in vitro on the promastigote stage of Leishmania donovani along with an in vitro cytotoxicity evaluation on the human HepG2 cell line. Only the derivatives bearing a phenyl moiety at position 4 of the quinoline ring displayed interesting biologic profile, when the phenyl moiety was substituted at the para position by a Br or Cl atom, or by a CF3 group. Among them, molecules 17 and 19 were the most selective and were then tested in vitro on the intracellular amastigote stage of both L. donovani and Leishmania infantum, in parallel with complementary in vitro cytotoxicity assays on the macrophage cell lines THP-1 and J774A.1. Molecule 19 showed no activity on the amastigote stages of the parasites and some cytotoxicity on the J774A.1 cell line while molecule 17, less cytotoxic than 19, showed anti-amastigote activity in L. infantum, being 3 times less active than miltefosine but more active and selective than pentamidine. Nevertheless, hit-molecule 17 did not appear as selective as the parent compound.
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille cedex 05, France.
authors.forename: Charline
authors.initials: C
authors.lastname: Kieffer
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille cedex 05, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Université Paul Sabatier, Faculté des Sciences Pharmaceutiques-CNRS UPR 8241, Laboratoire de Chimie de Coordination, 205 Route de Narbonne, 31077 Toulouse cedex 04, France. Electronic address: pierre.verhaeghe@univ-tlse3.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verhaeghe
authors.affiliation: Université Paul Sabatier, Faculté des Sciences Pharmaceutiques, UMR 152 IRD-UPS PHARMA-DEV, Equipe BIOCID, 35 chemin des Maraîchers, 31062 Toulouse cedex 9, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Paloque
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille cedex 05, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hutter
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille cedex 05, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Castera-Ducros
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille cedex 05, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Laget
authors.affiliation: Université de Caen Basse Normandie, Faculté des Sciences Pharmaceutiques, UPRES EA 4258, CERMN, boulevard Becquerel, 14032 Caen cedex, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.affiliation: Université Paul Sabatier, Faculté des Sciences Pharmaceutiques, UMR 152 IRD-UPS PHARMA-DEV, Equipe BIOCID, 35 chemin des Maraîchers, 31062 Toulouse cedex 9, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Valentin
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille cedex 05, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Rathelot
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille cedex 05, France. Electronic address: nadine.azas@univ-amu.fr.
authors.forename: Nadine
authors.initials: N
authors.lastname: Azas
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille cedex 05, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000254:growth & development; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development; D008018:Life Cycle Stages / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D009600:Nitroquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D009600:Nitroquinolines; D010767:Phosphorylcholine; C039128:miltefosine; D010419:Pentamidine
keywords: 8-Nitroquinolin-2(1H)-one; Leishmaniasis; SARs; Sonogashira; Suzuki–Miyaura