The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6: Structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces

Abstract

The mechanism of antimalarial action of [Au(CQ)(PPh 3 )] PF 6 (1), which is active in vitro against CQ-resistant P. falciparum and in vivo against P. berghei, has been investigated in relation to hemozoin formation and DNA as possible important targets. Complex 1 interacts with heme and inhibits β-hematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) or other known metal-based antimalarial agents; the higher inhibition activity is probably related to the higher lipophilicity observed for 1 through partition coefficient measurements at low pH, with respect to CQDP. The interactions of complex 1 with DNA were explored using spectrophotometric and fluorimetric titrations, circular dichroism spectroscopy, viscosity and melting point studies, as well as electrophoresis and covalent binding assays. The experimental data indicate that complex 1 interacts with DNA predominantly by intercalation and electrostatic association of the CQ moiety, similarly to free CQDP, while no covalent metal-DNA binding seems to take place. The most likely antimalarial mechanism for complex 1 is thus heme aggregation inhibition; the high activities observed against resistant parasites are probably due to the structural modification of CQ introduced by the presence of the gold-triphenylphosphine fragment, together with the enhanced lipophilic character.

Synthesis and Anticancer Activity of Gold(I)-Chloroquine Complexes

“…Complexes 1 and 2 both exerted some degree of growth inhibition on four of the tumor cell lines and total growth inhibition on the HT-29 and LoVo lines at concentrations below 30 µM. Their general activity was greater than that shown by CQ and cisplatin control compounds, but not as marked as the lead compound 3 [29,64], which was included here for comparison. The low activity of cisplatin seen in these assays, when compared to its well-known cytotoxicity as reported in the literature, is probably due to the relatively short incubation times used here (48 h).…”

“…Putting together all the results of the gold-chloroquine -DNA experimental data, we propose that complexes 1 and 2 displayed two types of interaction with DNA, the first showing covalent binding through the metal center, with an additional non-covalent interaction, which, from the data, appears to be electrostatic, while complex 2 appears to intercalate, in a manner similar to that displayed by free CQ. The interaction of complex 3 with DNA has been evaluated in a previous study [64], showing mainly intercalation and electrostatic association associated with the CQ moiety. However, no covalent metal-DNA binding was observed.…”

Potential of Casiopeínas® Copper Complexes and Antituberculosis Drug Combination against <b><i>Mycobacterium tuberculosis</i></b>

“…Many efforts have been made in medicinal chemistry to develop metal-based drugs for the treatment of several diseases, such as AIDS [4], cancer [5], metabolic syndrome [6], tropical neglected diseases (e.g. Chagas' disease, leishmaniasis, malaria, sleeping sickness, and amebiasis) [7,8] and bacterial diseases, such as TB [9,10]. …”

The role of nanogold in human tropical diseases: research, detection and therapy

“…The highest activity for this series was obtained for [Au(CQ)(PEt 3 )]PF 6 . More recently, Navarro et al [65] studied the mechanism of antimalarial action of [Au(CQ)(PPh 3 )] PF 6 . This compound seems to avoid heme aggregation (which allows accumulation of toxic levels of compound, resulting in parasite death).…”