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

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 <i>Plasmodium falciparum</i> strains and the liver stage of <i>Plasmodium berghei</i>. 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 <b>Ru4</b> and <b>Ru5</b> was investigated by confocal fluorescence microscopy, revealing parasite-selective absorption in infected erythrocytes and nuclear accumulation of both compounds. The lead compound <b>Ru2</b> impaired asexual parasite differentiation, exhibiting fast parasiticidal activity against both ring and trophozoite stages of a synchronized culture of the <i>P. falciparum</i> 3D7 strain. These results point to cyclopentadienylruthenium(II) complexes as a highly promising chemotype for the development of dual-stage antiplasmodials.