Half-sandwich Cyclopentadienylruthenium(II) complexes: a new antimalarial chemotype

Sofia A. Milheiro, Joana Gonçalves, Ricardo M.R.M. Lopes, Margarida Madureira, Lis Lobo, Andreia Lopes, Fátima Nogueira, Diana Fontinha, Miguel Prudêncio, M. Fátima M. Piedade, Sandra N. Pinto, Pedro R. Florindo, Rui Moreira

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)12722-12732
Number of pages11
JournalInorganic Chemistry
Volume59
Issue number17
DOIs
Publication statusPublished - 8 Sep 2020

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