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...
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Malaria Journal |
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| Online Access: | https://doi.org/10.1186/s12936-022-04406-0 |
| _version_ | 1811199422556536832 |
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| author | Jing Wei Lai Mohd Jamil Maah Kong Wai Tan Rozie Sarip Yvonne Ai Lian Lim Rakesh Ganguly Loke Tim Khaw Chew Hee Ng |
| author_facet | Jing Wei Lai Mohd Jamil Maah Kong Wai Tan Rozie Sarip Yvonne Ai Lian Lim Rakesh Ganguly Loke Tim Khaw Chew Hee Ng |
| author_sort | Jing Wei Lai |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-04-12T01:47:51Z |
| format | Article |
| id | doaj.art-15f984ed79ea451c8ecea3740d4ba80a |
| institution | Directory Open Access Journal |
| issn | 1475-2875 |
| language | English |
| last_indexed | 2024-04-12T01:47:51Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Malaria Journal |
| spelling | doaj.art-15f984ed79ea451c8ecea3740d4ba80a2022-12-22T03:53:01ZengBMCMalaria Journal1475-28752022-12-0121112110.1186/s12936-022-04406-0Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of actionJing Wei Lai0Mohd Jamil Maah1Kong Wai Tan2Rozie Sarip3Yvonne Ai Lian Lim4Rakesh Ganguly5Loke Tim Khaw6Chew Hee Ng7Department of Chemistry, Faculty of Science, Universiti MalayaDepartment of Chemistry, Faculty of Science, Universiti MalayaDepartment of Chemistry, Faculty of Science, Universiti MalayaDepartment of Chemistry, Faculty of Science, Universiti MalayaDepartment of Parasitology, Faculty of Medicine, University of MalayaShiv Nadar UniversityDepartment of Microbiology and Immunology, School of Medicine, International Medical UniversityDepartment of Pharmaceutical Chemistry, School of Pharmacy, International Medical UniversityAbstract 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 Abstracthttps://doi.org/10.1186/s12936-022-04406-0Copper complexZinc complexAntimalarialPlasmodium falciparumReactive oxygen speciesDepolarization of mitochondrial membrane potential |
| spellingShingle | Jing Wei Lai Mohd Jamil Maah Kong Wai Tan Rozie Sarip Yvonne Ai Lian Lim Rakesh Ganguly Loke Tim Khaw Chew Hee Ng Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action Malaria Journal Copper complex Zinc complex Antimalarial Plasmodium falciparum Reactive oxygen species Depolarization of mitochondrial membrane potential |
| title | 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_short | 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 |
| topic | Copper complex Zinc complex Antimalarial Plasmodium falciparum Reactive oxygen species Depolarization of mitochondrial membrane potential |
| url | https://doi.org/10.1186/s12936-022-04406-0 |
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