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Antimicrobial Agents and Chemotherapy, July 1999, p. 1783-1787, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Anti-Toxoplasma gondii Activities and Structure-Activity Relationships of Novel Fluoroquinolones Related to Trovafloxacin

Anis A. Khan,^1,2 Fausto G. Araujo,¹ Katherine E. Brighty,³ Thomas D. Gootz,³ and Jack S. Remington^1,2,*

Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, California 94301¹; Central Research Division, Pfizer, Inc., Groton, Connecticut 06340³; and Division of Infectious Disease and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305²

Received 14 January 1999/Returned for modification 11 February 1999/Accepted 12 April 1999

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 µM; the IC₅₀ of the 11 analogs ranged from 0.53 to 14.09 µM. 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.

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^* Corresponding author. Mailing address: Department of Immunology and Infectious Diseases, Research Institute, Palo Alto Medical Foundation, 860 Bryant St., Palo Alto, CA 94301. Phone: (650) 853-6061. Fax: (650) 329-9853.

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Antimicrobial Agents and Chemotherapy, July 1999, p. 1783-1787, Vol. 43, No. 7
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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