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Bioisosteric ferrocenyl-containing quinolines with antiplasmodial and antitrichomonal properties

Muneebah Adams, Tameryn Stringer, Carmen De Kock, Peter J. Smith, Kirkwood M. Land, Nicole Liu, Christina Tam, Luisa W. Cheng, Mathew Njoroge, Kelly Chibale, Gregory S. Smith
Dalton Trans 2016 v.45 no.47 pp. 19086-19095
Chinese hamsters, Escherichia coli, Lactobacillus, Plasmodium falciparum, Trichomonas vaginalis, X-ray diffraction, animal ovaries, antimalarials, antiparasitic properties, carbon, cells, chemical structure, cytotoxicity, growth retardation, humans, liver microsomes, microbiome, parasites, pathogens, quinolines, screening, strains
Bioisosteric ferrocenyl-containing quinolines and ferrocenylamines containing organosilanes and their carbon analogues, were prepared and fully characterised. The molecular structures of two ferrocenyl- containing quinolines, determined using single-crystal X-ray diffraction, revealed that the compounds crystallise in a folded conformation. The compounds were screened for their antiplasmodial activity against the chloroquine-sensitive (NF54) and CQ-resistant (Dd2) strains of P. falciparum, as well as for their cytotoxicity against Chinese Hamster Ovarian (CHO) cells. The ferrocenyl-containing quinolines dis- played activities in the low nanomolar range (6–36 nM), and showed selectivity towards parasites. β-Haematin inhibition assays suggest that the compounds may in part act via the inhibition of haemozoin formation, while microsomal metabolic stability studies reveal that the ferrocenyl-containing quinolines are rapidly metabolised in liver microsomes. Further, antitrichomonal screening against the metronida- zole-sensitive (G3) strain of the mucosal pathogen T. vaginalis revealed that the quinoline-based com- pounds displayed superior parasite growth inhibition when compared to the ferrocenylamines. The library was also tested E. coli and on Lactobacilli spp. found as part of the normal flora of the human microbiome and no effect on growth in vitro was observed, supporting the observation that these compounds are specific for eukaryotic pathogens.