<p><a>A
small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of
general formula [(</a>η<sup>5</sup>-C<sub>5</sub>R<sub>5</sub>)Ru(PPh<sub>3</sub>)(N-N)][PF<sub>6</sub>], 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 <i>Plasmodium falciparum</i>
strains, and the liver stage of <i>P. berghei</i>. The best performing compounds displayed
dual-stage activity, with single-digit nM IC<sub>50</sub> 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 <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 <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.</p>
A new coupling reaction for the synthesis of ruthenium half-sandwich complexes with sterically demanding cyclopentadienyl ligands
