Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action

• Published in: Malaria Journal
• Main Authors: Jing Wei Lai, Mohd Jamil Maah, Kong Wai Tan, Rozie Sarip, Yvonne Ai Lian Lim, Rakesh Ganguly, Loke Tim Khaw, Chew Hee Ng
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMC 2022
• Subjects: Copper complex; Zinc complex; Antimalarial; Plasmodium falciparum; Reactive oxygen species; Depolarization of mitochondrial membrane potential; Arctic medicine. Tropical medicine; RC955-962; Infectious and parasitic diseases; RC109-216; Arctic
• Online Access: https://doi.org/10.1186/s12936-022-04406-0; https://doaj.org/article/15f984ed79ea451c8ecea3740d4ba80a

Abstract Background Malaria remains one of the most virulent and deadliest parasitic disease in the world, particularly in Africa and Southeast Asia. Widespread occurrence of artemisinin-resistant Plasmodium falciparum strains from the Greater Mekong Subregion is alarming. This hinders the national economies, as well as being a major drawback in the effective control and elimination of malaria worldwide. Clearly, an effective anti-malarial drug is urgently needed. Methods The dinuclear and mononuclear copper(II) and zinc(II) complexes were synthesized in ethanolic solution and characterized by various physical measurements (FTIR, CHN elemental analysis, solubility, ESI-MS, UV-Visible, conductivity and magnetic moment, and NMR). X-ray crystal structure of the dicopper(II) complex was determined. The in vitro haemolytic activities of these metal complexes were evaluated spectroscopically on B+ blood while the anti-malarial potency was performed in vitro on blood stage drug-sensitive Plasmodium falciparum 3D7 (Pf3D7) and artemisinin-resistant Plasmodium falciparum IPC5202 (Pf5202) with fluorescence dye. Mode of action of metal complexes were conducted to determine the formation of reactive oxygen species using PNDA and DCFH-DA dyes, JC-1 depolarization of mitochondrial membrane potential, malarial 20S proteasome inhibition with parasite lysate, and morphological studies using Giemsa and Hoechst stains. Results Copper(II) complexes showed anti-malarial potency against both Pf3D7 and Pf5202 in sub-micromolar to micromolar range. The zinc(II) complexes were effective against Pf3D7 with excellent therapeutic index but encountered total resistance against Pf5202. Among the four, the dinuclear copper(II) complex was the most potent against both strains. The zinc(II) complexes caused no haemolysis of RBC while copper(II) complexes induced increased haemolysis with increasing concentration. Further mechanistic studies of both copper(II) complexes on both Pf3D7 and Pf5202 strains showed induction of ROS, 20S malarial ...