title: Anti-Toxoplasma gondii activities and structure-activity relationships of novel fluoroquinolones related to trovafloxacin.
abstract: Eleven novel fluoroquinolones closely related to trovafloxacin were evaluated for their in vitro activity against Toxoplasma gondii, and their structure-activity relationships were examined. The 50% inhibitory concentration (IC50) of trovafloxacin against T. gondii was 2.93 microM; the IC50 of the 11 analogs ranged from 0.53 to 14. 09 microM. Six analogs had IC50s lower than that of trovafloxacin. Examination of the structure-activity relationships of the compounds revealed that addition of a -CH3 at C-5 of the 1,8-naphthyridone ring, at C-2 of the azabicyclohexane ring, or on the -NH2 at the 6 position of the azabicyclohexane ring resulted in a four- to sixfold increase in activity. Moreover, replacement of 2,4-difluorophenyl by cyclopropyl at N-1 of the 1,8-naphthyridone ring increased activity twofold, and moving the -NH2 one atom further away from the azabicyclohexane ring decreased activity. There was no difference between the naphthyridone and quinolone analogs. These results indicate that structure-activity studies of compounds related to drugs active against T. gondii may be useful in producing compounds with more potent activities against the parasite.
authors.affiliation: Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, California 94301, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Khan
authors.forename: F G
authors.initials: FG
authors.lastname: Araujo
authors.forename: K E
authors.initials: KE
authors.lastname: Brighty
authors.forename: T D
authors.initials: TD
authors.lastname: Gootz
authors.forename: J S
authors.initials: JS
authors.lastname: Remington
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D024841:Fluoroquinolones; D009287:Naphthyridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects*; D014498:Uracil / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D014498:Uracil; C080163:trovafloxacin