title: Bioisosteric ferrocenyl-containing quinolines with antiplasmodial and antitrichomonal properties.
abstract: 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 displayed 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 metronidazole-sensitive (G3) strain of the mucosal pathogen T. vaginalis revealed that the quinoline-based compounds 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.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa. Gregory.Smith@uct.ac.za.
authors.forename: Muneebah
authors.initials: M
authors.lastname: Adams
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa. Gregory.Smith@uct.ac.za.
authors.forename: Tameryn
authors.initials: T
authors.lastname: Stringer
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Kirkwood M
authors.initials: KM
authors.lastname: Land
authors.affiliation: Department of Biological Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Liu
authors.affiliation: Foodborne Toxin Detection and Prevention Research Unit. Agricultural Research Service, United States Department of Agriculture, Albany, CA 94710, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Tam
authors.affiliation: Foodborne Toxin Detection and Prevention Research Unit. Agricultural Research Service, United States Department of Agriculture, Albany, CA 94710, USA.
authors.forename: Luisa W
authors.initials: LW
authors.lastname: Cheng
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Mathew
authors.initials: M
authors.lastname: Njoroge
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa. Gregory.Smith@uct.ac.za and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa and South African Medical Research Council Drug Discovery & Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa. Gregory.Smith@uct.ac.za.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Smith
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000994:Antitrichomonal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D015195:Drug Design; D005296:Ferrous Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014246:Trichomonas vaginalis / Q000187:drug effects
chemical_list: D000962:Antimalarials; D000994:Antitrichomonal Agents; D005296:Ferrous Compounds; D011804:Quinolines