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Widespread occurrence of artemisinin-resistant <jats:italic>Plasmodium falciparum<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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 <jats:italic>Plasmodium falciparum<\/jats:italic> 3D7 (<jats:italic>Pf3D7<\/jats:italic>) and artemisinin-resistant <jats:italic>Plasmodium falciparum<\/jats:italic> IPC5202 (<jats:italic>Pf5202<\/jats:italic>) 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Copper(II) complexes showed anti-malarial potency against both <jats:italic>Pf3D7<\/jats:italic> and <jats:italic>Pf5202<\/jats:italic> in sub-micromolar to micromolar range. The zinc(II) complexes were effective against <jats:italic>Pf3D7<\/jats:italic> with excellent therapeutic index but encountered total resistance against <jats:italic>Pf5202<\/jats:italic>. 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 <jats:italic>Pf3D7<\/jats:italic> and <jats:italic>Pf5202<\/jats:italic> strains showed induction of ROS, 20S malarial proteasome inhibition, loss of mitochondrial membrane potential and morphological features indicative of apoptosis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The dinuclear [Cu(phen)-4,4\u2032-bipy-Cu(phen)](NO<jats:sub>3<\/jats:sub>)<jats:sub>4<\/jats:sub> is highly potent and can overcome the total drug-resistance of <jats:italic>Pf5202<\/jats:italic> towards chloroquine and artemisinin. The other three copper(II) and zinc(II) complexes were only effective towards the drug-sensitive <jats:italic>Pf3D7<\/jats:italic>, with the latter causing no haemolysis of RBC. Their mode of action involves multiple targets.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1186\/s12936-022-04406-0","type":"journal-article","created":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T05:02:51Z","timestamp":1671253371000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Dinuclear and mononuclear metal(II) polypyridyl complexes against drug-sensitive and drug-resistant Plasmodium falciparum and their mode of action"],"prefix":"10.1186","volume":"21","author":[{"given":"Jing Wei","family":"Lai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohd Jamil","family":"Maah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kong Wai","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rozie","family":"Sarip","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvonne Ai Lian","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rakesh","family":"Ganguly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loke Tim","family":"Khaw","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chew Hee","family":"Ng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,12,17]]},"reference":[{"key":"4406_CR1","volume-title":"World malaria report 2021","author":"WHO","year":"2021","unstructured":"WHO. 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