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Half- Sandwich cyclopentadienylruthenium(II) Complexes: A New Antimalarial Chemotype

preprint
submitted on 20.04.2020, 11:00 and posted on 21.04.2020, 13:30 by Sofia Alexandra Milheiro, Joana Gonçalves, Ricardo Lopes, Margarida Madureira, Lis Lobo, Andreia Lopes, Fatima Nogueira, Diana Fontinha, Miguel Prudêncio, Fátima Piedade, Sandra Pinto, Pedro Florindo, Rui Moreira

A small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of general formula [(η5-C5R5)Ru(PPh3)(N-N)][PF6], a scaffold hitherto unfeatured in 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 P. berghei. The best performing compounds displayed dual-stage activity, with single-digit nM IC50 values against blood stage malaria parasites, nM activity against liver stage parasites, and residual cytotoxicity against mammalian cells (HepG2, Huh7). 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 P. falciparum 3D7 strain. These results point to cyclopentadienylruthenium(II) complexes as a highly promising chemotype for the development of dual-stage antiplasmodials.

Funding

PTDC/MED-QUI/31468/2017

PTDC/MED-QUI/30021/2017

UIDB/04565/2020

SAICTPAC/0019/2015

PPBI-POCI-01-0145-FEDER-022122

Global Health and Tropical Medicine

Fundação para a Ciência e Tecnologia

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PTDC/SAU-INF/29550/2017

History

Email Address of Submitting Author

pedrorrflorindo@ff.ulisboa.pt

Institution

Instituto de Investigação do Medicamento, iMed.ULisboa

Country

Portugal

ORCID For Submitting Author

0000-0002-8582-7036

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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