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

International audienceBackground: Malaria 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. Methods: All metal-chloroquine (CQ) and metal-CQDP complexes were synthesized under N 2 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. Results: The previously synthesized Au(CQ)(Cl) (1), Au(CQ)(TaTg) (2), Pt(CQDP) 2 Cl 2 (3), Pt(CQDP) 2 I 2 (4), Pd(CQ) 2 Cl 2 (5) and the new one Pd(CQDP) 2 I 2 (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. Conclusions: The 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