title: In vitro effects of three new 1,2,4-trioxanes (pentatroxane, thiahexatroxane, and hexatroxanone) on Toxoplasma gondii.
abstract: The in vitro effects of three synthetic, cis-fused, bicyclic 1,2,4-trioxanes (pentatroxane, thiahexatroxane, and hexatroxanone) against intracellular Toxoplasma gondii were studied. Unactivated peritoneal macrophages were infected with the virulent RH strain of T. gondii and exposed to the 1,2,4-trioxanes at different concentrations. The antitoxoplasmic activity of the drugs was first assessed with [3H]uracil, which is incorporated by the parasite but not the host cell. Pentatroxane and thiahexatroxane were the most active, exhibiting 90% inhibitory concentrations of 6.8 and 5.3 micrograms/ml, respectively. Furthermore, microscopic examination of the infected macrophages after treatment with pentatroxane, thiahexatroxane, and hexatroxanone at their respective 90% inhibitory concentrations confirmed the inhibition of intracellular growth of T. gondii. Their activities were comparable to those of pyrimethamine (1 micrograms/ml) and pyrimethamine (0.1 micrograms/ml) in combination with sulfadiazine (25 micrograms/ml). Pentatroxane and thiahexatroxane were also able to inhibit intracellular growth of T. gondii within nonprofessional phagocytes (HeLa cells), suggesting that the antitoxoplasmic activity was not caused by a macrophage-specific mechanism, such as macrophage activation. However, the 1,2,4-trioxanes were not active against extracellular T. gondii. Pentatroxane and thiahexatroxane are new, promising compounds that deserve further study to assess their usefulness for treating toxoplasmosis.
authors.affiliation: Department of Microbiology, School of Medicine, Centre Médical Universitaire, Geneva, Switzerland.
authors.forename: H R
authors.initials: HR
authors.lastname: Chang
authors.forename: C W
authors.initials: CW
authors.lastname: Jefford
authors.forename: J C
authors.initials: JC
authors.lastname: Pechère
mesh_terms: D000818:Animals; D005260:Female; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D014122:Toxoplasma / Q000187:drug effects*; D014124:Toxoplasmosis, Animal / Q000188:drug therapy / Q000469:parasitology; D014498:Uracil / Q000378:metabolism
chemical_list: D006571:Heterocyclic Compounds; C061891:thiahexatroxane; C061889:pentatroxane; C061890:hexatroxanone; D014498:Uracil