Half-Sandwich Cyclopentadienylruthenium(II) Complexes: A New Antimalarial Chemotype
A small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of the general formula [(η5-C5R5)Ru(PPh3)(N-N)][PF6], a scaffold hitherto absent from the toolbox of antiplasmodials, was screened for activity against the blood stage of CQ-sensitive 3D7-GFP, CQ-resistant Dd2, and artem...
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| Veröffentlicht in: | Inorganic chemistry 2020-09, Vol.59 (17), p.12722-12732 |
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| creator | Milheiro, Sofia A Gonçalves, Joana Lopes, Ricardo M. R. M Madureira, Margarida Lobo, Lis Lopes, Andreia Nogueira, Fátima Fontinha, Diana Prudêncio, Miguel M. Piedade, M. Fátima Pinto, Sandra N Florindo, Pedro R Moreira, Rui |
| description | A small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of the general formula [(η5-C5R5)Ru(PPh3)(N-N)][PF6], a scaffold hitherto absent from the toolbox of antiplasmodials, was screened for activity against the blood stage of CQ-sensitive 3D7-GFP, CQ-resistant Dd2, and artemisinin-resistant IPC5202 Plasmodium falciparum strains and the liver stage of Plasmodium berghei. The best-performing compounds displayed dual-stage activity, with single-digit nanomolar IC50 values against blood-stage malaria parasites, nanomolar activity against liver-stage parasites, and residual cytotoxicity against HepG2 and Huh7 mammalian cells. The parasitic absorption/distribution of 7-nitrobenzoxadiazole-appended fluorescent compounds Ru4 and Ru5 was investigated by confocal fluorescence microscopy, revealing parasite-selective absorption in infected erythrocytes and nuclear accumulation of both compounds. The lead compound Ru2 impaired asexual parasite differentiation, exhibiting fast parasiticidal activity against both ring and trophozoite stages of a synchronized culture of the P. falciparum 3D7 strain. These results point to cyclopentadienylruthenium(II) complexes as a highly promising chemotype for the development of dual-stage antiplasmodials. |
| doi_str_mv | 10.1021/acs.inorgchem.0c01795 |
| format | Article |
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R. M ; Madureira, Margarida ; Lobo, Lis ; Lopes, Andreia ; Nogueira, Fátima ; Fontinha, Diana ; Prudêncio, Miguel ; M. Piedade, M. Fátima ; Pinto, Sandra N ; Florindo, Pedro R ; Moreira, Rui</creator><creatorcontrib>Milheiro, Sofia A ; Gonçalves, Joana ; Lopes, Ricardo M. R. M ; Madureira, Margarida ; Lobo, Lis ; Lopes, Andreia ; Nogueira, Fátima ; Fontinha, Diana ; Prudêncio, Miguel ; M. Piedade, M. Fátima ; Pinto, Sandra N ; Florindo, Pedro R ; Moreira, Rui</creatorcontrib><description>A small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of the general formula [(η5-C5R5)Ru(PPh3)(N-N)][PF6], a scaffold hitherto absent from the toolbox of antiplasmodials, was screened for activity against the blood stage of CQ-sensitive 3D7-GFP, CQ-resistant Dd2, and artemisinin-resistant IPC5202 Plasmodium falciparum strains and the liver stage of Plasmodium berghei. The best-performing compounds displayed dual-stage activity, with single-digit nanomolar IC50 values against blood-stage malaria parasites, nanomolar activity against liver-stage parasites, and residual cytotoxicity against HepG2 and Huh7 mammalian cells. The parasitic absorption/distribution of 7-nitrobenzoxadiazole-appended fluorescent compounds Ru4 and Ru5 was investigated by confocal fluorescence microscopy, revealing parasite-selective absorption in infected erythrocytes and nuclear accumulation of both compounds. The lead compound Ru2 impaired asexual parasite differentiation, exhibiting fast parasiticidal activity against both ring and trophozoite stages of a synchronized culture of the P. falciparum 3D7 strain. 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The lead compound Ru2 impaired asexual parasite differentiation, exhibiting fast parasiticidal activity against both ring and trophozoite stages of a synchronized culture of the P. falciparum 3D7 strain. These results point to cyclopentadienylruthenium(II) complexes as a highly promising chemotype for the development of dual-stage antiplasmodials.</description><subject>Antimalarials - chemistry</subject><subject>Antimalarials - pharmacology</subject><subject>Coordination Complexes - chemistry</subject><subject>Coordination Complexes - pharmacology</subject><subject>Cyclopentanes - chemistry</subject><subject>Drug Resistance - drug effects</subject><subject>Erythrocytes - drug effects</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Oxadiazoles - chemistry</subject><subject>Plasmodium berghei - drug effects</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Ruthenium - chemistry</subject><issn>0020-1669</issn><issn>1520-510X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1OwzAQhC0EoqXwCKAcyyHFP7ETc6sioJUqOBQkbpbrOjSV4wQ7Ucnb46qlV067h5nZ2Q-AWwQnCGL0IJWflLZ2X2qjqwlUEKWcnoEhohjGFMHPczCEMOyIMT4AV95vIYScJOwSDAjOSEYRGYLlTJoiXkq73pVqE-W9MnWjbSvXpba9cV270bbsqvF8fh_lddUY_aP9YzSNXvUumtq2rKSRrpQmykORuu0bfQ0uCmm8vjnOEfh4fnrPZ_Hi7WWeTxexJDxr4xQTVmDOQ3cupaJhcExUlrEswSrhMmMsITApaLFWKUIZYlRJDJM0XRFCFBmB8SG3cfV3p30rqtIrbYy0uu68wAlJEaaI0yClB6lytfdOF6JxobnrBYJiz1MEnuLEUxx5Bt_d8US3qvT65PoDGAToINj7t3XnbPj4n9BfJnuE0w</recordid><startdate>20200908</startdate><enddate>20200908</enddate><creator>Milheiro, Sofia A</creator><creator>Gonçalves, Joana</creator><creator>Lopes, Ricardo M. 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M ; Madureira, Margarida ; Lobo, Lis ; Lopes, Andreia ; Nogueira, Fátima ; Fontinha, Diana ; Prudêncio, Miguel ; M. Piedade, M. 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| subjects | Antimalarials - chemistry Antimalarials - pharmacology Coordination Complexes - chemistry Coordination Complexes - pharmacology Cyclopentanes - chemistry Drug Resistance - drug effects Erythrocytes - drug effects Hep G2 Cells Humans Oxadiazoles - chemistry Plasmodium berghei - drug effects Plasmodium falciparum - drug effects Ruthenium - chemistry |
| title | Half-Sandwich Cyclopentadienylruthenium(II) Complexes: A New Antimalarial Chemotype |
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