Di- and Trinuclear Ruthenium-, Rhodium-, and Iridium-Functionalized Pyridyl Aromatic Ethers: A New Class of Antiparasitic Agents

Two new di- and tripyridyl aromatic ether ligands ( 1 and 2 ) have been synthesized using the Williamson ether method. Functionalization of these ligands with either dichlorido( p -cymene)ruthenium(II), dichlorido(pentamethylcyclopentadienyl)rhodium(III), or dichlorido(pentamethylcyclopentadienyl)iridium(III) fragments yielded three di- and three trinuclear organometallic complexes ( 1a – c and 2a – c ). Both ligands act as monodentate donors to each metal center via the pyridyl nitrogen atoms, and this coordination mode of the polyaryl ether ligands has been confirmed upon elucidation of the molecular structure of the dinuclear iridium complex 1c . All of the synthesized compounds were evaluated for inhibitory effects on the Plasmodium falciparum strain NF54 (chloroquine-sensitive) and found to have moderate to high antiplasmodial activities, with the trinuclear complexes displaying activities in the nanomolar range. The most active compounds were studied for their ability to inhibit formation of synthetic hemozoin in a cell-free medium. Against the Trichomonas vaginalis strain G3, these aryl ether compounds were only moderately active.