|CHELLAN, PRINESSA - University Of Warwick|
|AVERY, VICKY - Griffiths University|
|DUFFY, SANDRA - Griffiths University|
|TRICCAS, JAMES - University Of Sydney|
|NAGALINGAM, GAYATHRI - University Of Sydney|
|Cheng, Luisa Wai Wai|
|LIU, JENNY - University Of The Pacific|
|LAND, KIRKWOOD - University Of The Pacific|
|CLARKSON, GUY - University Of Warwick|
|ROMERO, ISOLDA - University Of Birmingham|
|SADLER, PETER - University Of Warwick|
Submitted to: Chemistry - A European Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/6/2018
Publication Date: 4/13/2018
Citation: Chellan, P., Avery, V., Duffy, S., Triccas, J.A., Nagalingam, G., Tam, C.C., Cheng, L.W., Liu, J., Land, K.M., Clarkson, G.J., Romero, I., Sadler, P.J. 2018. Organometallic conjugates of the drug sulfadoxine for combatting antimicrobial resistance. Chemistry - A European Journal. 24(40):10078-10090. https://doi.org/10.1002/chem.201801090.
Interpretive Summary: Microbial diseases are still responsible for significant human and animal morbidity and mortality. In this study, we synthesized a novel set of sulfadoxine-based compounds and tested them against three widespread infectious diseases–tuberculosis, malaria, and trichomoniasis. Our results identified several lead compounds in this set that have activity against all three pathogens. We also tested these compounds against normal human cells had there were no observable effects. Furthermore, given that new antibiotics can often impact normal flora of the patient, we tested the entire set of compounds on several known normal flora bacteria and observed no effect on growth, even at the highest concentration tested. Taken together, this work shows that several of these compounds are selective for three different human pathogens; and demonstrate promising and potential new leads for drug discovery against tuberculosis, malaria and trichomoniasis.
Technical Abstract: Fourteen new RuII, RhIII and IrIII complexes conjugated to the antimalarial drug sulfadoxine functionalised with either a pyridylimino- or quinolylimino- group to allow N,N’-chelation ligands have been synthesized and characterized. The effect of the arene/Cpx, planarity of imino group on sulfadoxine ligands with and metal on biological activity was investigated. The x-ray crystal structures of[('5-Cp*)Rh(N,N’-2-pyridyliminosulfadoxine)Cl]PF6(2),[('5-CpxPh)Rh(N,N’-2-quinolyliminosulfadoxine)Cl]PF6,.1.5C3H6O(10.1.5C3H6O), and [('5-CpxPh)IrCl(N,N’-2-quinolyliminosulfadoxine)]PF6·1.5C3H6O(13·1.5C3H6O)confirm the piano-stool structures of the complexes and the presence of sulfadoxine conjugation. The complexes were screened for anti-infective activity against strains of Plasmodium falciparum (Pf), Trichomonas vaginalis (Tv) and Mycobacterium tuberculosis (Mtb). The rhodium and iridium complexes exhibited good antiplasmodial activity with IC50 values between 0.10 – 2.0 µM in all three Pf assays (3D7 chloroquine sensitive, Dd2 chloroquine sensitive and LSGNF54) but were only moderately active in the Tv assay. It was also observed that the rhodium and iridium sulfadoxinyl complexes were active in the late stage gametocyte assay, LSGNF54, while the clinical parent drug, sulfadoxine, was not. This observation demonstrates that conjugation of organometallic groups to the sulfadoxine drug can alter its biological target. Against Mtb, five complexes were moderately active with IC50 values less than 6 'M; sulfadoxine shows no antitubercular activity. Experimental studies of the rate of aquation and relative hydrophobicity of the Rh and Ir complexes revealed that with an increase in the size of both the Cpx ligand and the aromatic imino group, there is an increase in hydrophobicity which appears to lead to an increase in antiplasmodial activity in the order of Cp*biph > Cp*ph > Cp* and quinolylimino-group > pyridylimino-group. No structure-activity trend could be discerned for the complexes as anti-TB agents. Also, given that T. vagnalis exists in a mucosal microbiome, we also screened all of these complexes against common normal flora bacteria, and no detectable effects on flora bacteria was observed.