title: In vitro antimalarial activity of a series of cationic 2,2'-bipyridyl- and 1,10-phenanthrolineplatinum(II) benzoylthiourea complexes.
abstract: 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 beta-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.
authors.affiliation: Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa. tegan@science.uct.ac.za
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Koch
authors.forename: Paul L
authors.initials: PL
authors.lastname: Swan
authors.forename: Cailean
authors.initials: C
authors.lastname: Clarkson
authors.forename: Donelly A
authors.initials: DA
authors.lastname: Van Schalkwyk
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
mesh_terms: D015082:2,2'-Dipyridyl / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D006427:Hemin / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C487372:(N-benzoyl-N',N'-di(2-hydroxyethyl)thioureato-S,O)(4,4'-di-tert-butyl-2,2'-bipyridyl)platinum(II); D000962:Antimalarials; D009944:Organoplatinum Compounds; D010618:Phenanthrolines; D015082:2,2'-Dipyridyl; D006427:Hemin; D013890:Thiourea; C025205:1,10-phenanthroline