TY - JOUR
T1 - Half-sandwich cyclopentadienylruthenium(II) complexes
T2 - a new antimalarial chemotype
AU - Milheiro, Sofia A.
AU - Gonçalves, Joana
AU - Lopes, Ricardo M. R. M.
AU - Madureira, Margarida
AU - Lobo, Lis
AU - Lopes, Andreia
AU - Nogueira, Fátima
AU - Fontinha, Diana
AU - Prudêncio, Miguel
AU - Piedade, M. Fátima M.
AU - Pinto, Sandra N.
AU - Florindo, Pedro R.
AU - Moreira, Rui
N1 - Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/8/24
Y1 - 2020/8/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85090481236&partnerID=8YFLogxK
U2 - 10.1021/acs.inorgchem.0c01795
DO - 10.1021/acs.inorgchem.0c01795
M3 - Article
C2 - 32838513
AN - SCOPUS:85090481236
SN - 0020-1669
VL - 59
SP - 12722
EP - 12732
JO - Inorganic Chemistry
JF - Inorganic Chemistry
IS - 17
ER -
