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 IC 50 values. The molecules 7b and c were the most active of the planned compounds, with lower IC 50 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.Key words docking; molecular dynamics; molecular modeling; antimalarial Malaria is one of the most important tropical diseases, affecting 97 countries. It is an infectious disease caused by five species of Plasmodium genus protozoa, from which the P. falciparum is the most lethal in humans. There were approximately 198 million cases of malaria reported in 2013, and an estimated number of 584000 deaths, mainly in African subSaharan countries.1)The chemotherapy combination of artesunate and amodiaquine (ASAQ) is currently the treatment recommended by WHO. However, recent reports show that P. falciparum has become resistant to these chemotherapeutic agents. In addition, the use of amodiaquine (AQ) (Fig. 1) has shown some problems such as hepatotoxicity and agranulocytosis.2-4) This is a result of the biotransformation that occurs in the liver by CYP450 enzymes, which generates a reative quinoneimine metabolite, the amodiaquine quinone imine (AQQI) 5) (Fig. 1). This metabolite binds irreversibly to cellular macromolecules, leading to cell death by oxidation and, probably, to direct toxicity as well as immune-mediated hypersensitivity reactions.6,7) The mechanism of action of AQ and other 4-aminoquinolines is based on the inhibition of the parasite's mechanism of detoxification of heme, namely, the inclusion of free heme into hemozoin. By doing so, AQ increases the concentration of free heme inside the host cell acidic digestive vacuole, killing the parasite by oxidative stress. [8][9][10][11][12][13] The design of new amodiaquine derivatives with reduced toxicity and increased activity is a current matter of study.14-17) It's already well established in the literature that the fluorine insertion in this series is favorable to reduce the hepatotoxicity, by forming new compounds that are more resistant to oxidation and hence less likely to form toxic quinone imine metabolites in vivo. 2,3,17,18) O'Neill et al. demonstrated that the 4′-hydroxyl group could b...

Hybridization of Fluoro-amodiaquine (FAQ) with Pyrimidines: Synthesis and Antimalarial Efficacy of FAQ–Pyrimidines

“…Similar strategy was adopted to synthesize fluoro-tebuquine analogues, but it resulted in diminished antimalarial activity compared to both AQ and tebuquine. , FAQ-4 (4′-fluoro- N - tert -butylamodiaquine) was later identified as a candidate for further development studies based on its activity profile (comparable to AQ), low toxicity, and an acceptable safety profile . More recently, Sousa et al reported the synthesis of FAQ-piperazines (Figure ), but these analogues exhibited a 16–106-fold reduction in antiplasmodial activity.…”

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines

“…The interaction of the 2,8-trifluoromethyl bisquinoline with hematinf alls into an anticipated order of stability from singlecrystal diffraction studies with hydrogen-bonding [63] and covalent interactions dominating. [62,63] Hence, p···p interactions are often assumed to be the preferred orientation geometry [68] between drug and porphyrin but, to our knowledge, only one study compares the thermodynamics of ar ange of all three competing geometries, [62] which are essential for understanding antimalarialdrug action. [62,63] Hence, p···p interactions are often assumed to be the preferred orientation geometry [68] between drug and porphyrin but, to our knowledge, only one study compares the thermodynamics of ar ange of all three competing geometries, [62] which are essential for understanding antimalarialdrug action.…”

“…[56b, 57-59] This evidencec ontradicts currently accepted models of antimalariald rug receptor interaction(s)b ecause if the interactions betweenr eceptor and ligand were based on frequency of appearancei ng raphical forms, then p···p depictions [22, 23, 34n, 67] are most common and axial, covalent,a nd coordination adducts [52, 56b, 57-61] are fewer in number.E dge-type interactions between drug and ligand are currently restricted to afew studies only. [62,63] Hence, p···p interactions are often assumed to be the preferred orientation geometry [68] between drug and porphyrin but, to our knowledge, only one study compares the thermodynamics of ar ange of all three competing geometries, [62] which are essential for understanding antimalarialdrug action.…”

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

“…Among them, hybrid 55d (IC 50 : 94.3 nM) which was greater than twofolds more active than CQ and PQ (IC 50 : 213 and 643 nM, respectively) against CQR K1 strain, showed low cytotoxicity toward L6 cells (IC 50 : 17.6 μM), and SI was 186.6. The quinoline‐benzoimidazole 57 also displayed low cytotoxicity (CC 50 : >80 μM) toward VERO cells, as well as considerable activity (IC 50 : 800 nM) against CQR W2 strain, but it was less potent than AQ (IC 50 : 50 nM) …”