Organometallic Conjugates of the Drug Sulfadoxine for Combatting Antimicrobial Resistance

Prinessa Chellan; Vicky M Avery; Sandra Duffy; James A Triccas; Gayathri Nagalingam; Christina Tam; Luisa W Cheng; Jenny Liu; Kirkwood M Land; Guy J Clarkson; Isolda Romero-Canelón; Peter J Sadler

doi:10.1002/chem.201801090

Organometallic Conjugates of the Drug Sulfadoxine for Combatting Antimicrobial Resistance

Chemistry. 2018 Jul 17;24(40):10078-10090. doi: 10.1002/chem.201801090. Epub 2018 Jun 13.

Authors

Prinessa Chellan^{1

2}, Vicky M Avery³, Sandra Duffy³, James A Triccas⁴, Gayathri Nagalingam⁴, Christina Tam⁵, Luisa W Cheng⁵, Jenny Liu⁶, Kirkwood M Land⁶, Guy J Clarkson¹, Isolda Romero-Canelón^{1

7}, Peter J Sadler¹

Affiliations

¹ Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
² Current address: Stellenbosch University, Matieland, Western Cape, South Africa.
³ Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, 4111, Australia.
⁴ Microbial Immunity and Pathogenesis Group, Department of, Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia.
⁵ Foodborne Toxin Detection and Prevention Research Unit, Agricultural Research Service, United States Department of Agriculture, Albany, CA, 94710, USA.
⁶ Department of Biological Sciences, University of the Pacific, Stockton, CA, 95211, USA.
⁷ School of Pharmacy, University of Birmingham, Birmingham, B15 2TT, UK.

PMID: 29653033
DOI: 10.1002/chem.201801090

Abstract

Fourteen novel arene Ru^II , and cyclopentadienyl (Cp^x ) Rh^III and Ir^III complexes containing an N,N'-chelated pyridylimino- or quinolylimino ligand functionalized with the antimalarial drug sulfadoxine have been synthesized and characterized, including three by X-ray crystallography. The rhodium and iridium complexes exhibited potent antiplasmodial activity with IC₅₀ values of 0.10-2.0 μm in either all, or one of the three Plasmodium falciparum assays (3D7 chloroquine sensitive, Dd2 chloroquine resistant and NF54 sexual late stage gametocytes) but were only moderately active towards Trichomonas vaginalis. They were active in both the asexual blood stage and the sexual late stage gametocyte assays, whereas the clinical parent drug, sulfadoxine, was inactive. Five complexes were moderately active against Mycobacterium tuberculosis (IC₅₀ <6.3 μm), while sulfadoxine showed no antitubercular activity. An increase in the size of both the Cp^x ligand and the aromatic imino substituent increased hydrophobicity, which resulted in an increase in antiplasmodial activity.

Keywords: antiparasitic; antitubercular; organometallic; sulfonamides; transition metals.

Abstract

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