title: Design, Synthesis and Evaluation of New Fluoroamodiaquine Analogues.
abstract: Malaria is one of the most important tropical diseases; the use of amodiaquine as a current chemotherapy in the treatment of malaria has shown some problems such as hepatotoxicity and agranulocytosis. In this work we present the rational design, synthesis, and biological evaluation (antimalarial activity, cytotoxicity and genotoxicity) of four new fluoroamodiaquine analogues. The results showed significant correlation between MolDock score and IC50 values. The molecules 7b and c were the most active of the planned compounds, with lower IC50 against Plasmodium falciparum W2 strain (0.9 and 0.8 µM, respectively) and an excellent cytotoxicity profile. The present study revealed no mutagenicity or genotoxicity for the analogues. Confirming our docking results, the molecular dynamics showed that compound 7b remains stably bound to the heme group by means of π-stacking interactions between quinoline and the porphyrin ring. Based on these findings, this study may prove to be an efficient approach for the rational design of hemozoin inhibiting compounds to treat malaria.
authors.affiliation: Laboratório de Tecnologia Industrial Farmacêutica (LabTIF), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro.
authors.forename: Ana Carolina Corrêa de
authors.initials: AC
authors.lastname: Sousa
authors.forename: Gil Mendes
authors.initials: GM
authors.lastname: Viana
authors.forename: Nuria Cirauqui
authors.initials: NC
authors.lastname: Diaz
authors.forename: Marianne Grilo
authors.initials: MG
authors.lastname: Rezende
authors.forename: Filipe Fernandes de
authors.initials: FF
authors.lastname: Oliveira
authors.forename: Raquel Pinto
authors.initials: RP
authors.lastname: Nunes
authors.forename: Monica Farah
authors.initials: MF
authors.lastname: Pereira
authors.forename: André Luiz Lisboa
authors.initials: AL
authors.lastname: Areas
authors.forename: Marianos Gustavo
authors.initials: MG
authors.lastname: Zalis
authors.forename: Valber da Silva
authors.initials: Vda S
authors.lastname: Frutuoso
authors.forename: Hugo Caire de Castro
authors.initials: HC
authors.lastname: Faria
authors.forename: Thaisa Francielle Souza
authors.initials: TF
authors.lastname: Domingos
authors.forename: Marcelo de
authors.initials: Md
authors.lastname: Pádula
authors.forename: Lucio Mendes
authors.initials: LM
authors.lastname: Cabral
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
mesh_terms: D000655:Amodiaquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D000655:Amodiaquine