Half-Sandwich Cyclopentadienylruthenium(II) Complexes: A New Antimalarial Chemotype
| Autor: | Margarida Madureira, J. R. P. Goncalves, Sandra N. Pinto, Fátima Nogueira, Lis Lobo, Rui Moreira, M. Fátima M. Piedade, Diana Fontinha, Miguel Prudêncio, Ricardo M R M Lopes, Pedro Florindo, Sofia A. Milheiro, Andreia A. S. Lopes |
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| Rok vydání: | 2020 |
| Předmět: |
Erythrocytes
Plasmodium berghei Plasmodium falciparum Drug Resistance Cyclopentanes Ruthenium Inorganic Chemistry Antimalarials chemistry.chemical_compound Coordination Complexes parasitic diseases Fluorescence microscope Humans Parasite hosting Physical and Theoretical Chemistry Cytotoxicity Oxadiazoles Chemotype Strain (chemistry) biology Chemistry Hep G2 Cells biology.organism_classification Biochemistry Lead compound |
| Zdroj: | Inorganic Chemistry. 59:12722-12732 |
| ISSN: | 1520-510X 0020-1669 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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