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

preprint
submitted on 20.04.2020 and posted on 21.04.2020 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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