Design, Synthesis and Evaluation of New Fluoroamodiaquine Analogues

• Published in: Chemical & pharmaceutical bulletin Vol. 64; no. 6; pp. 594 - 601
• Main Authors: Ana Carolina Corrêa de Sousa, Viana, Gil Mendes, Diaz, Nuria Cirauqui, Rezende, Marianne Grilo, Oliveira, Filipe Fernandes de, Nunes, Raquel Pinto, Pereira, Monica Farah, Areas, André Luiz Lisboa, Zalis, Marianos Gustavo, Frutuoso, Valber da Silva, Hugo Caire de Castro Faria, Domingos, Thaisa Francielle Souza, Pádula, Marcelo de, Cabral, Lucio Mendes, Rodrigues, Carlos Rangel
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 2016; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: Amodiaquine - analogs & derivatives; Amodiaquine - chemical synthesis; Amodiaquine - pharmacology; Animals; antimalarial; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Cell Survival - drug effects; Cercopithecus aethiops; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; docking; Dose-Response Relationship, Drug; Drug Design; Life Sciences & Biomedicine; molecular dynamics; Molecular Dynamics Simulation; molecular modeling; Molecular Structure; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Physical Sciences; Plasmodium falciparum; Plasmodium falciparum - drug effects; Science & Technology; Structure-Activity Relationship; Vero Cells; ASSAY; MECHANISM; AMODIAQUINE; BIOACTIVATION; molecular dynamics; antimalarial; docking; IN-VITRO; HEMATIN; CYTO-TOXICITY; METABOLISM; molecular modeling; ANTIMALARIAL ACTIVITY; FLUORINE SUBSTITUTION
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c15-01001

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.