title: Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi.
abstract: Chagas disease is a neglected tropical disease caused by the flagellated protozoan Trypanosoma cruzi. The current drugs used to treat this disease have limited efficacy and produce severe side effects. Quinolines, nitrogen heterocycle compounds that form complexes with heme, have a broad spectrum of antiprotozoal activity and are a promising class of new compounds for Chagas disease chemotherapy. In this study, we evaluated the activity of a series of 4-arylaminoquinoline-3-carbonitrile derivatives against all forms of Trypanosoma cruzi in vitro. Compound 1g showed promising activity against epimastigote forms when combined with hemin (IC50<1 μM), with better performance than benznidazole, the reference drug. This compound also inhibited the viability of trypomastigotes and intracellular amastigotes. The potency of 1g in combination with heme was enhanced against epimastigotes and trypomastigotes, suggesting a similar mechanism of action that occurs in Plasmodium spp. The addition of hemin to the culture medium increased trypanocidal activity of analog 1g without changing the cytotoxicity of the host cell, reaching an IC50 of 11.7 μM for trypomastigotes. The mechanism of action was demonstrated by the interaction of compound 1g with hemin in solution and prevention of heme peroxidation. Compound 1g and heme treatment induced alterations of the mitochondrion-kinetoplast complex in epimastigotes and trypomastigotes and also, accumulation of electron-dense deposits in amastigotes as visualized by transmission electron microscopy. The trypanocidal activity of 4-aminoquinolines and the elucidation of the mechanism involving interaction with heme is a neglected field of research, given the parasite's lack of heme biosynthetic pathway and the importance of this cofactor for parasite survival and growth. The results of this study can improve and guide rational drug development and combination treatment strategies.
authors.affiliation: Laboratório de Interação celular e molecular, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense, Rua Outeiro São João Batista, 24020-141, Niterói, Rio de Janeiro, Brazil.
authors.forename: Guilherme Curty
authors.initials: GC
authors.lastname: Lechuga
authors.affiliation: Departamento de Química Orgânica, Universidade Federal Fluminense, Rua Outeiro São João Batista, 24020-141, Niterói, Rio de Janeiro, Brazil; Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Campus Nilópolis, 26530-060, RJ, Brazil.
authors.forename: Júlio Cesar
authors.initials: JC
authors.lastname: Borges
authors.affiliation: Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil 4365, 21040-360, Rio de Janeiro, RJ, Brazil.
authors.forename: Claudia Magalhães
authors.initials: CM
authors.lastname: Calvet
authors.affiliation: Departamento de Imunologia, Instituto Nacional de Controle de Qualidade em Saúde, Fundação Oswaldo Cruz, Avenida Brasil 4365, 21040-360, Rio de Janeiro, RJ, Brazil.
authors.forename: Humberto Pinheiro
authors.initials: HP
authors.lastname: de Araújo
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373-bloco G. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, Brazil.
authors.forename: Aline Araujo
authors.initials: AA
authors.lastname: Zuma
authors.affiliation: Laboratório de Interação celular e molecular, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense, Rua Outeiro São João Batista, 24020-141, Niterói, Rio de Janeiro, Brazil.
authors.forename: Samara Braga
authors.initials: SB
authors.lastname: do Nascimento
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373-bloco G. Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, Brazil.
authors.forename: Maria Cristina Machado
authors.initials: MCM
authors.lastname: Motta
authors.affiliation: Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Campus Nilópolis, 26530-060, RJ, Brazil.
authors.forename: Alice Maria Rolim
authors.initials: AMR
authors.lastname: Bernardino
authors.affiliation: Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil 4365, 21040-360, Rio de Janeiro, RJ, Brazil. Electronic address: mirian@ioc.fiocruz.br.
authors.forename: Mirian Claudia de Souza
authors.initials: MCS
authors.lastname: Pereira
authors.affiliation: Laboratório de Interação celular e molecular, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense, Rua Outeiro São João Batista, 24020-141, Niterói, Rio de Janeiro, Brazil. Electronic address: saulocb@globo.com.
authors.forename: Saulo Cabral
authors.initials: SC
authors.lastname: Bourguignon
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006418:Heme / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure
chemical_list: D000634:Aminoquinolines; D014344:Trypanocidal Agents; D006418:Heme; C001920:4-aminoquinoline
keywords: Chagas disease; Chemotherapy; Heme; Quinoline; Trypanosoma cruzi