|ADAMS, MUNEEBAH - University Of Cape Town|
|STRINGER, TAMERYN - University Of Cape Town|
|DE KOCK, CARMEN - University Of Cape Town|
|SMITH, PETER - University Of Cape Town|
|LAND, KIRKWOOD - Pacific University|
|LIU, NICOLE - Pacific University|
|Cheng, Luisa Wai Wai|
|NJOROGE, MATHEW - University Of Cape Town|
|CHIBALE, KELLY - University Of Cape Town|
|SMITH, GREGORY - University Of Cape Town|
Submitted to: Dalton Transactions
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/14/2016
Publication Date: 11/15/2016
Publication URL: http://handle.nal.usda.gov/10113/5678136
Citation: Adams, M., Stringer, T., De Kock, C., Smith, P.J., Land, K.M., Liu, N., Tam, C.C., Cheng, L.W., Njoroge, M., Chibale, K., Smith, G.S. 2016. Bioisosteric ferrocenyl-containing quinolines with antiplasmodial and antitrichomonal properties. Dalton Transactions. 45(47):19086-19095.
Interpretive Summary: Discovering new drugs against infectious diseases is critical to human and animal health. Here, ARS scientists and collaborating scientists from the University of Cape Town synthesized a new set of iron-based compounds with unique chemical compositions and tested them against two widespread protozoal parasites –malaria and the human STD trichomoniasis. Our results identified several lead compounds against both parasites. Since antibiotics often negatively impact the normal flora of a patient, we also screened the chemical library on several known normal flora bacteria and observed no effect on their growth at the highest concentration used in this study. Taken together, this study shows that several of these compounds are selective for eukaryotic pathogens, and identify possible new leads for drug discovery against malaria and human trichomoniasis.
Technical Abstract: A series of ferrocenyl'containing quinolines and ferrocenylamines were prepared and fully characterized. 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 chloroquine'sensitive (NF54) and CQ'resistant (Dd2) strains of P. falciparum, as well as for their cytotoxicity against a Chinese Hamster Ovarian (CHO) cell'line. The ferrocenyl'containing quinolines displayed activities in the low nanomolar range (6'36 nM), and showed selectivity towards the parasites. ß'haematin inhibition assays reveal that the compounds may in part act via the inhibition of haemozoin formation, and microsomal metabolic stability reveals that the ferrocenyl'containing quinolines metabolise quickly 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 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.