In Vitro Antimalarial Activity of a Series of Cationic 2,2‘-Bipyridyl- and 1,10-Phenanthrolineplatinum(II) Benzoylthiourea Complexes

• Published in: Journal of medicinal chemistry 2004-05, Vol.47 (11), p.2926-2934
• Main Authors: Egan, Timothy J, Koch, Klaus R, Swan, Paul L, Clarkson, Cailean, Van Schalkwyk, Donelly A, Smith, Peter J
• Format: Article
• Language: English
• Subjects: 2,2'-Dipyridyl - chemical synthesis; 2,2'-Dipyridyl - chemistry; 2,2'-Dipyridyl - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; CHO Cells; Cricetinae; Hemin - chemistry; Medical sciences; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Pharmacology. Drug treatments; Phenanthrolines - chemical synthesis; Phenanthrolines - chemistry; Phenanthrolines - pharmacology; Plasmodium falciparum - drug effects; Structure-Activity Relationship; Thiourea - analogs & derivatives; Thiourea - chemical synthesis; Thiourea - chemistry; Thiourea - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm031132g

We have synthesized a series of novel 2,2‘-bipyridyl and 1,10-phenanthroline benzoylthiourea complexes of platinum(II) with various substituents on the bipyridyl and phenanthroline ligands. All of these square-planar mixed-ligand cationic complexes were found to form moderately strong complexes with ferriprotoporphyrin IX in 40% aqueous DMSO (log K ranging from 4.81 to 6.24). The complexes also all inhibit β-hematin (synthetic hemozoin or malaria pigment) formation in acetate solution. Four of the compounds were found to exhibit in vitro antimalarial activity, with (N-benzoyl-N ‘ ,N ‘ -di(2-hydroxyethyl)thioureato)(4,4‘-di-tert-butyl-2,2‘-bipyridyl)platinum(II) chloride being particularly active. These active complexes exhibited equally strong activity against both the D10 chloroquine sensitive and K1 chloroquine resistant strains of malaria parasite. Cytotoxicity testing of the four most active compounds shows that they exhibit selective activity against malaria parasites with selectivity indices greater than 85. These compounds represent a new family of potential antimalarials.