Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/7321
Title: Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites
Authors: Aguiar, Anna Caroline Campos
Santos, Raquel de Meneses
Figueiredo, Flavio Junior Barbosa
Cortopassi, Wilian Augusto
Pimentel, Andre Silva
França, Tanos Celmar Costa
Meneghetti, Mario Roberto
Krettli, Antoniana Ursine
Affilliation: Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG Brazil/Universidade Federal de Minas Gerais. Faculdade de Medicina. Programa de Pos Graduação em Medicina Molecular. Belo Horizonte, MG, Brazil
Universidade Federal do Alagoas. Instituto de Quımica e Biotecnologia. Maceio, Alagoas, Brazil
Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG Brazil
Instituto Militar de Engenharia. Laboratorio de Modelagem Molecular Aplicada a Defesa Quımica e Biologica . Rio de Janeiro, RJ, Brazil/ Pontifıcia Universidade Catolica do Rio de Janeiro. Departamento de Quımica. Rio de Janeiro, RJ, Brazil
Pontifıcia Universidade Catolica do Rio de Janeiro. Departamento de Quımica. Rio de Janeiro, RJ, Brazil
Instituto Militar de Engenharia. Laboratorio de Modelagem Molecular Aplicada a Defesa Quımica e Biologica . Rio de Janeiro, RJ, Brazil,
Universidade Federal do Alagoas. Instituto de Quımica e Biotecnologia. Maceio, Alagoas, Brazil,
Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG Brazil/ Universidade Federal de Minas Gerais. Faculdade de Medicina. Programa de Pos Graduação em Medicina Molecular. Belo Horizonte, MG, Brazil
Abstract: Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak Pf LDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.
Keywords: Malaria
Issue Date: 2012
Publisher: Public Library Of Science
Citation: AGUIAR, Anna Caroline Campos et al. Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites. Plos One. 2012, vol.7, pp. e37259
DOI: 10.1371/journal.pone.0037259
ISSN: 1932-6203
Copyright: open access
Appears in Collections:MG - IRR - Artigos de Periódicos




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