Metal-chloroquine derivatives as possible anti-malarial drugs: evaluation of anti-malarial activity and mode of action

Abstract

BackgroundMalaria still has significant impacts on the world; particularly in Africa, South America and Asia where spread over several millions of people and is one of the major causes of death. When chloroquine diphosphate (CQDP) lost its efficiency as a first-line anti-malarial drug, this was a major setback in the effective control of malaria. Currently, malaria is treated with a combination of two or more drugs with different modes of action to provide an adequate cure rate and delay the development of resistance. Clearly, a new effective and non-toxic anti-malarial drug is urgently needed.MethodsAll metal-chloroquine (CQ) and metal-CQDP complexes were synthesized under N2 using Schlenk techniques. Their interactions with haematin and the inhibition of β-haematin formation were examined, in both aqueous medium and near water/n-octanol interfaces at pH 5. The anti-malarial activities of these metal- CQ and metal-CQDP complexes were evaluated in vitro against two strains, the CQ-susceptible strain (CQS) 3D7 and the CQ-resistant strain (CQR) W2.ResultsThe previously synthesized Au(CQ)(Cl) (1), Au(CQ)(TaTg) (2), Pt(CQDP)2Cl2 (3), Pt(CQDP)2I2 (4), Pd(CQ)2Cl2 (5) and the new one Pd(CQDP)2I2 (6) showed better anti-malarial activity than CQ, against the CQS strain; moreover, complexes 2, 3 and 4 were very active against CQR strain. These complexes (1–6) interacted with haem and inhibited β-haematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) and other known metal-based anti-malarial agents.ConclusionsThe high anti-malarial activity displayed for these metal-CQ and metal-CQDP complexes (1–6) could be attributable to their effective interaction with haem and the inhibition of β-haematin formation in both aqueous medium and near water/n-octanol interfaces at pH 5.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-471) contains supplementary material, which is available to authorized users.

Chloroquine-containing organoruthenium complexes are fast-acting multistage antimalarial agents

“…An improvement in the potency against intraerythrocytic stages of P. falciparum was observed in most cases, in comparison with metalfree CQ. An interesting finding is that the antiparasitic potency is not superior to complexes containing two CQ molecules in the structure, which indicates that metal complexes are not mere drug delivery systems that act by releasing CQ and that, instead, the entire chemical structure is involved in the antiparasitic activity (Sánchez-Delgado et al 1996;Goldberg et al 1997;Lewis et al 1997;Navarro et al 1997Navarro et al , 2004Navarro et al , 2011aNavarro et al , b, 2014Rajapakse et al 2009). Given this promising outlook, CQ analogs have been employed in the metal complex composition in the last years and given rise to many successful outcomes (Dubar et al 2011(Dubar et al , 2013Glans et al 2012a, b;Salas et al 2013;Ekengard et al 2015).…”

<i>In Silico</i> Evaluation of Anti-Malarial Agents from <i>Hoslundia opposita</i> as Inhibitors of <i>Plasmodium falciparum</i> Lactate Dehydrogenase (P<i>f</i>LDH) Enzyme

“…Thus, identifying new drug targets with new mechanisms of action of the drug may help in fighting the disease [4] [8]. Today, many other natural products and synthetic anti-malaria agents have been designed to target different enzymes involved in parasitic life cycle [6] [10]- [15].…”

Effective-Loading of Platinum–Chloroquine into PEGylated Neutral and Cationic Liposomes as a Drug Delivery System for Resistant Malaria Parasites

“…PtCQ-Loaded Liposomes Prepared Using the Thin Drug-Lipid Film Method Navarro et al mentioned the high lipophilicity of metal chloroquine complexes 28) and Khokhar et al demonstrated the preparation of highly stable lipophilic cisplatin complex/liposomes with high encapsulation ratios. 29) Consequently, in this study we succeeded in loading the PtCQ complex into neutral and cationic liposomes at reasonable drug-to-lipid ratios by incorporating the drug into the lipid phase using the thin drug-lipid film method.…”