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

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...

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Main Authors: Lai, Jing Wei, Maah, Mohd Jamil, Tan, Kong Wai, Sarip, Rozie, Lim, Yvonne Ai Lian, Ganguly, Rakesh, Khaw, Loke Tim, Ng, Chew Hee
Format: Article
Published: BioMed Central 2022
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RM Therapeutics. Pharmacology
Online Access:http://eprints.um.edu.my/40240/
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spelling my.um.eprints.402402023-11-21T09:14:58Z http://eprints.um.edu.my/40240/ Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action Lai, Jing Wei Maah, Mohd Jamil Tan, Kong Wai Sarip, Rozie Lim, Yvonne Ai Lian Ganguly, Rakesh Khaw, Loke Tim Ng, Chew Hee RM Therapeutics. Pharmacology 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 & PRIME;-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. BioMed Central 2022-12-17 Article PeerReviewed Lai, Jing Wei and Maah, Mohd Jamil and Tan, Kong Wai and Sarip, Rozie and Lim, Yvonne Ai Lian and Ganguly, Rakesh and Khaw, Loke Tim and Ng, Chew Hee (2022) Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action. Malaria Journal, 21 (1). ISSN 1475-2875, DOI https://doi.org/10.1186/s12936-022-04406-0 <https://doi.org/10.1186/s12936-022-04406-0>. 10.1186/s12936-022-04406-0
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic RM Therapeutics. Pharmacology
spellingShingle RM Therapeutics. Pharmacology
Lai, Jing Wei
Maah, Mohd Jamil
Tan, Kong Wai
Sarip, Rozie
Lim, Yvonne Ai Lian
Ganguly, Rakesh
Khaw, Loke Tim
Ng, Chew Hee
Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action
description 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 & PRIME;-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.
format Article
author Lai, Jing Wei
Maah, Mohd Jamil
Tan, Kong Wai
Sarip, Rozie
Lim, Yvonne Ai Lian
Ganguly, Rakesh
Khaw, Loke Tim
Ng, Chew Hee
author_facet Lai, Jing Wei
Maah, Mohd Jamil
Tan, Kong Wai
Sarip, Rozie
Lim, Yvonne Ai Lian
Ganguly, Rakesh
Khaw, Loke Tim
Ng, Chew Hee
author_sort Lai, Jing Wei
title Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action
title_short Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action
title_full Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action
title_fullStr Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action
title_full_unstemmed Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action
title_sort dinuclear and mononuclear metal(ii) polypyridyl complexes against drug-sensitive and drug-resistant plasmodium falciparum and their mode of action
publisher BioMed Central
publishDate 2022
url http://eprints.um.edu.my/40240/
_version_ 1783876693217247232
score 13.211869

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