Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl-derived complexes

Authors: STRINGER, TAMERYN - University Of Cape Town; SELDON, RONNETT - University Of Cape Town; LIU, NICOLE - University Of Cape Town; WARNER, DIGBY - University Of Cape Town; Tam, Christina; Cheng, Luisa; LAND, KIRKWOOD - University Of The Pacific; SMITH, PETER - 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: 7/4/2017
Publication Date: 7/17/2017
Citation: Stringer, T., Seldon, R., Liu, N., Warner, D.F., Tam, C.C., Cheng, L.W., Land, K.M., Smith, P.J., Chibale, K., Smith, G.S. 2017. Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl-derived complexes. Dalton Transactions. 46:9875-9885. https://doi.org/10.1039/c7dt01952a.
DOI: https://doi.org/10.1039/c7dt01952a

Interpretive Summary: Complexes containing ferrocene moieties conjugated to antimycobacterial pharmacophores, isoniazid and pyrazinamide, were prepared by a Schiff base condensation reaction using hydrazides and ferrocenyl aldehydes. Three heterobimetallic complexes were synthesized from the Schiff base isonicotinyl ferrocene complex using various platinum group metal dimers based on ruthenium, rhodium and iridium. Against H37Rv Mycobacterium tuberculosis, the platinum group metal complexes showed glycerol-dependent antimycobacterial activity in vitro. The antiplasmodial activities against the NF54 chloroquine-sensitive strain of Plasmodium falciparum of some compounds were moderate, while some complexes also showed promising activity against Trichomonas vaginalis, in vitro. Incorporation of the ferrocenyl-salicylaldimine moiety results in enhanced antimicrobial activity compared to the non-ferrocenyl compound in some cases. The bimetallic iridium-ferrocene isonicotinyl complex exhibited promising antitrichomonal activity, enhanced compared to its organic counterpart, isoniazid. Screening all of these compounds on several normal flora bacteria showed no effect on microbial growth, emphasizing the selection of these compounds for pathogens. The promising antimicrobial activities of the complexes thus supports incorporation of ferrocene as part of existing antimicrobial therapies in order to favorably alter their biological properties.

Technical Abstract: The discovery of new drugs against microbial diseases is imperative to human and animal health. In this study, we synthesized a novel set of iron-based compounds and tested them against three widespread microbial diseases –tuberculosis, malaria, and trichomoniasis. Our results identified several lead compounds against all three pathogens. We also tested these compounds against normal human cells had there were no observable effects. Given that new antibiotics often impact normal flora of the patient, we also screened the entire set of new compounds on several known normal flora bacteria and observed no impact on growth at the highest concentration tested. Taken together, this work shows that several of these compounds are selective for three different human pathogens; and demonstrate potential new leads for drug discovery against tuberculosis, malaria and trichomoniasis.