title: Quinoline derivatives: Synthesis, leishmanicidal activity and involvement of mitochondrial oxidative stress as mechanism of action.
abstract: Leishmaniasis comprise a spectrum of diseases caused by protozoa parasites from the genus Leishmania, affecting millions of people worldwide, mainly in subtropical countries. Most antileishmanial drugs are highly toxic, present resistance issues or require long-term treatment. Consequently, new drugs are urgently needed. Quinoline-containing compounds have displayed an impressive array of biological properties over the years, including antileishmanial activity. In the present study, we report the synthesis and evaluation of novel quinoline derivatives (QuinDer) against Leishmania species and cytotoxic effect on mammalian cells. The ROS production and mitochondrial membrane potential analyses were also studied. The compound QuinDer1 showed activity on L. amazonensis and L. braziliensis promastigotes and this compound exhibited a strong inhibition of the proliferation of L. amazonensis amastigotes at nM concentration (IC50of 0.0911 μM), being 139 times more active than miltefosine (IC50of 12.7 μM), used as reference drug. This compound presents low cytotoxicity toward murine macrophages and human erythrocytes. In addition, promastigotes of L. amazonensis treated with the compound QuinDer1 present high generation of ROS levels with low alterations in mitochondrial membrane potential and maintenance of parasite membrane integrity. No substantial NO production in infected-macrophages treated with this compound was detected. These results suggest that the compound QuinDer 1 is a potent and selective antileishmanial agent by mitochondrial oxidative stress.
authors: Departamento de Parasitologia, Microbiologia e Imunologia, I.C.B., Universidade Federal de Juiz de Fora, Juiz de Fora, MG, 36036-900, Brazil. Electronic address: elaine.coimbra@ufjf.edu.br.
authors: Elaine S
authors: ES
authors: Coimbra
authors: Departamento de Parasitologia, Microbiologia e Imunologia, I.C.B., Universidade Federal de Juiz de Fora, Juiz de Fora, MG, 36036-900, Brazil.
authors: Luciana M R
authors: LM
authors: Antinarelli
authors: Departamento de Parasitologia, Microbiologia e Imunologia, I.C.B., Universidade Federal de Juiz de Fora, Juiz de Fora, MG, 36036-900, Brazil.
authors: Natália P
authors: NP
authors: Silva
authors: Departamento de Química, I.C.E., Universidade Federal Juiz de Fora, Juiz de Fora, MG, 36036-900, Brazil.
authors: Isabela O
authors: IO
authors: Souza
authors: Departamento de Química, I.C.E., Universidade Federal Juiz de Fora, Juiz de Fora, MG, 36036-900, Brazil.
authors: Raissa S
authors: RS
authors: Meinel
authors: Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz/FIOCRUZ, 30190-002 Belo Horizonte, MG, Brazil.
authors: Marcele N
authors: MN
authors: Rocha
authors: Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz/FIOCRUZ, 30190-002 Belo Horizonte, MG, Brazil.
authors: Rodrigo P P
authors: RP
authors: Soares
authors: Departamento de Química, I.C.E., Universidade Federal Juiz de Fora, Juiz de Fora, MG, 36036-900, Brazil. Electronic address: david.silva@ufjf.edu.br.
authors: Adilson D
authors: AD
authors: da Silva
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D011804:Quinolines; D017382:Reactive Oxygen Species
keywords: Chemotherapy; Leishmania; Mitochondrial membrane potential; Oxidative stress; Quinolines; ROS production