Potency of copper(II) complexes towards drug-sensitive and -resistant Plasmodium falciparum: Structure-activity relationship, ROS-generation and proteasome inhibition

Abstract

The use of copper in medicine has a long history and copper-containing compounds have multiple applications, such as in treating heart disease, arthritis, cancer, parasitic as well as other inflammatory diseases. Here, we investigate structural factors, structure-activity relationship and two mechanisms of action of a series of copper(II) complexes with 1,10-phenanthroline (phen) and/or amino acid ligands towards Plasmodium falciparum (Pf) 3D7 and artemisinin-resistant Pf5202. To achieve this, the following set of copper(II) complexes, viz. [Cu(phen)Cl2] 1, [Cu(phen)2Cl]Cl·2H2O 2, [Cu(phen)(gly)Cl]·2H2O 3, [Cu(phen)(edda)]·5H2O 4, cis-[Cu(gly)2(H2O)] 5 and [Cu(edda)] 6, (gly = glycine; edda = ethylenediamine-N,N’-diacetic acid) were selected, synthesized and characterized by FTIR, elemental analysis, UV-Visible spectroscopy, molar conductivity measurement and magnetic moment. Herein, we report comparison of aqueous copper(II) species, CuCl2 and ligands in inhibiting proteolytic sites of 20S proteasome, generation of reactive oxygen species, hemolysis and antimalarial property. Factors affecting their antimalarial potency are different from those affecting proteasome inhibition and ROS production. Complexes 1 – 4, with IC50 values of about 3 µM towards Pf3D7, were more effective against artemisinin-resistant strain Pf5202 than chloroquine and artemisinin. Evidence of apoptosis of malaria parasite in red blood cells is also presented.