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

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 proteasome inhibition, loss of mitochondrial membrane potential and morphological features indicative of apoptosis. Conclusion The dinuclear [Cu(phen)-4,4′-bipy-Cu(phen)](NO3)4 is highly potent and can overcome the total drug-resistance of Pf5202 towards chloroquine and artemisinin. The other three copper(II) and zinc(II) complexes were only effective towards the drug-sensitive Pf3D7, with the latter causing no haemolysis of RBC. Their mode of action involves multiple targets. Graphical Abstract

Transition Metal Complexes as Antimalarial Agents: A Review

“…reported in vitro anti‐malarial potency of mononuclear and dinuclear Cu(II) ( 80 , 81 ) and Zn(II) ( 82 , 83 ) complexes on blood‐stage drug‐sensitive Plasmodium falciparum strain 3D7 (Pf3D7) and artemisinin‐resistant Plasmodium falciparum strain IPC5202 (Pf5202) (Figure 19). [149] 82 and 83 did not cause any significant hemolysis of RBC while 80 and 81 significantly induced concentration‐dependent increased hemolysis. The PNDA and DCFH‐DA assay clearly indicate ROS generation by all the complexes.…”

“…Among 80-83, complex 81 was most active against both the strains 3D7 (Pf3D7) (IC 50 = 0.90 μM) and IPC5202 (Pf5202) (IC 50 = 2.21 μM). [149] The Proteasome inhibition study of 80-83 was evaluated on 20S proteasome at three different proteolytic sites e. g., chymotrypsin-like (CTÀ L) site, trypsin-like (TÀ L) site and caspase-like (CÀ L) site of P. falciparum 20S proteasome. 82 and 83 (IC 50 > 25 μM for both) poorly inhibited all three proteolytic sites of the proteasome while 80 and 81 selectively inhibited the TÀ L site (IC 50 = ca.…”

“…Furthermore, the mechanistic studies of 80 and 81 on both Pf3D7 and Pf5202 strains showed ROS generation, MMP loss, and ultimately apoptosis. [149,150] Recently, Chellan and co-workers investigated the in vitro antiplasmodial activity of ferrocene complexes (84-85) linking ART (L10) and ARS (L11) scaffold respectively, using triazole or alkyl-amide linkers (Figure 20). [151] The antiplasmodial activity of 84-85 along with L10-L11 was determined against two different Pf strains, i. e., 3D7 and Dd2.…”

“…[158] The release of CO upon light exposure was established by IR spectroscopy and myoglobin assay. [158] Both 86 and 87 were active in dark [149] conditions with IC 50 equal to 4.22 μM and 1.16 μM respectively against the MDR (K1) strain of P. falciparum. Interestingly 86 displayed ca.…”

“…The PNDA and DCFH‐DA assay clearly indicate ROS generation by all the complexes. Among 80 – 83 , complex 81 was most active against both the strains 3D7 (Pf3D7) (IC 50 =0.90 μM) and IPC5202 (Pf5202) (IC 50 =2.21 μM) [149] . The Proteasome inhibition study of 80 – 83 was evaluated on 20S proteasome at three different proteolytic sites e. g., chymotrypsin‐like (CT−L) site, trypsin‐like (T−L) site and caspase‐like (C−L) site of P. falciparum 20S proteasome.…”