Organometallic Conjugates of the Drug Sulfadoxine for Combatting Antimicrobial Resistance

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.