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

Malaria Journal

Research

Bruno Pradines¹  William Castro²  Maribel Navarro³  Nicolas Benoit⁴  Rémy Amalvict⁴  Marilyn Madamet⁴ 

[1] Aix Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, 1095, Inserm, Marseille, France;Centre National de Référence du Paludisme, Marseille, France;Unité de Parasitologie et d’Entomologie, Département des Maladies Infectieuses, Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France;Centro de Química, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela;Centro de Química, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela;Directoria de Metrologia Aplicada á ciências da vida, Instituto Nacional de Metrologia, Normalização e Qualidade Industrial, Rio de Janeiro, Brazil;Equipe Résidente de Recherche en Infectiologie Tropicale, Institut de Recherche Biomédicale des Armées, Hôpital d’Instruction des Armées Laveran, Marseille, France;Aix Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, 1095, Inserm, Marseille, France;Centre National de Référence du Paludisme, Marseille, France;

关键词: Malaria;    Plasmodium falciparum;    Anti-malarial;    in vitro;    Resistance;    Gold;    Platinum;    Chloroquine;    β-hematin;   

DOI  :  10.1186/1475-2875-13-471

 received in 2014-09-15, accepted in 2014-11-29,  发布年份 2014

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Navarro et al.; licensee BioMed Central Ltd. 2014