Mono- and multimeric ferrocene congeners of quinoline-based polyamines as potential antiparasitics

Authors: STRINGER, TAMERYN - University Of Cape Town; DE KOCK, CARMEN - University Of Cape Town; GUZGAY, HAJIRA - University Of Cape Town; OKOMBO, JOHN - University Of Cape Town; LIU, JENNY - University Of The Pacific; KANETAKE, SIERRA - University Of The Pacific; KIM, JIHWAN - University Of The Pacific; Tam, Christina; Cheng, Luisa; SMITH, PETER - University Of Cape Town; HENDRICKS, DENVER - University Of Cape Town; LAND, KIRKWOOD - University Of The Pacific; EGAN, TIMOTHY - University Of Cape Town; SMITH, GREGORY - University Of Cape Town

Submitted to: Dalton Transactions
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/26/2016
Publication Date: 8/3/2016
Publication URL: http://handle.nal.usda.gov/10113/63169
Citation: Stringer, T., De Kock, C., Guzgay, H., Okombo, J., Liu, J., Kanetake, S., Kim, J., Tam, C.C., Cheng, L.W., Smith, P.J., Hendricks, D.T., Land, K.M., Egan, T.J., Smith, G.S. 2016. Mono- and multimeric ferrocene congeners of quinoline-based polyamines as potential antiparasitics. Dalton Transactions. 45:13415-13426 doi: 10.1039/c6dt02685k.

Interpretive Summary: Drug discovery against microbial diseases is imperative to human and animal health. In this study, we synthesized a novel 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. We also tested these compounds against esophageal cancer cells and several compounds had potent effects. Given that new antibiotics often impact normal flora of the patient, we screened the compound set on several known normal flora bacteria and observed no impact on growth at the highest concentration tested. This set also had no impact on two known bacterial pathogens. Collectively, this work shows that several of these compounds are selective for eukaryotic pathogens and cancer; and demonstrate potential new leads for drug discovery against malaria and trichomoniasis.

Technical Abstract: A series of mono- and multimeric polyamine-containing ferrocenyl complexes bearing a quinoline motif were prepared. The complexes were characterised by standard techniques. The molecular structure of the monomeric salicylaldimine derivative was elucidated using single crystal X-ray diffraction and was consistent with the proposed structure. The antiplasmodial activity of the compounds were evaluated in vitro against both the NF54 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains of Plasmodium falciparum. The polyamine derivatives exhibit good RI values suggesting that these systems are beneficial in overcoming the resistance experienced by chloroquine. Mechanistic studies suggest that haemozoin may be the target of these quinoline complexes in the parasite. Some of the complexes exhibit moderate to high cytotoxicity against WHCO1 oesophageal cancer cells in vitro. The monomeric ferrocenyl-amine complexes exhibit potent activity against this particular cell-line. The complexes were also screened against the G3 strain of Trichomonas vaginalis and only the salicylaldimine complexes demonstrated promising activity at the tested concentration. All of these compounds show no inhibitory effect on several common normal flora bacteria, indicative of their selectivity for eukaryotic pathogens and cancer.