title: Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of Toxoplasma gondii.
abstract: We have prepared 23 new dehydroartemisinin (DART) trioxane derivatives (11 thiazoles, 2 oxadiazoles, and 10 carboxamides) and have screened them for in vitro activity in the Toxoplasma lytic cycle. Fifteen (65%) of the derivatives were noncytotoxic to host cells (TD(50) > or = 320 microM). Eight thiazole derivatives and two carboxamide derivatives displayed effective inhibition of Toxoplasma growth (IC(50) = 0.25-0.42 microM), comparable in potency to artemether (IC(50) = 0.31 microM) and >100 times more inhibitory than the currently employed front-line drug trimethoprim (IC(50) = 46 microM). The thiazoles as a group were more effective than the other derivatives at inhibiting growth of extracellular as well as intracellular parasites. Unexpectedly, two thiazole trioxanes (5 and 6) were parasiticidal; both inhibited parasite replication irreversibly after parasite exposure to 10 microM of drug for 24 h, whereas the standard trioxane drugs artemisinin and artemether were not parasiticidal. Some of the new derivatives of artemisinin described here represent effective anti-Toxoplasma trioxanes as well as molecular probes for elucidating the mechanism of action of the DART class of artemisinin derivatives.
authors.affiliation: Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA. chencke2@jhu.edu
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hencken
authors.forename: Lorraine
authors.initials: L
authors.lastname: Jones-Brando
authors.forename: Claudia
authors.initials: C
authors.lastname: Bordón
authors.forename: Remo
authors.initials: R
authors.lastname: Stohler
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Mott
authors.forename: Robert
authors.initials: R
authors.lastname: Yolken
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Woodard
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000977:Antiparasitic Agents; D000981:Antiprotozoal Agents / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000577:Amides; D000977:Antiparasitic Agents; D000981:Antiprotozoal Agents; D037621:Artemisinins; D010069:Oxadiazoles; D013844:Thiazoles