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Antimicrobial Agents and Chemotherapy, August 2002, p. 2393-2399, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2393-2399.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification of Small-Molecule Inhibitors of Nucleoside Triphosphate Hydrolase in Toxoplasma gondii

Takashi Asai,1 Tsutomu Takeuchi,1 Jeff Diffenderfer,2 and L. David Sibley2*

Department of Tropical Medicine and Parasitology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan,1 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 631102

Received 11 February 2002/ Returned for modification 18 March 2002/ Accepted 22 April 2002

Approximately 150,000 small-molecule compounds were tested by a robotic screening assay for their ability to inhibit nucleoside triphosphate hydrolase (NTPase), a novel enzyme of the tachyzoite form of Toxoplasma gondii. Five unrelated species of compounds were found to inhibit the activities of both NTPase isoforms (NTPase isoform I [NTPase-I] and NTPase-II). The 50% inhibitory concentrations (IC50s) ranged from 0.1 to 20 µM, and in general, the IC50s were similar for both NTPase isoforms. However, the activity of NTPase-I was 20 times more sensitive than the activity of NTPase-II to one of the inhibitors: 9-hydroxy-10-(pentachlorophenoxy)stearic acid. The five compounds identified also prevented tachyzoite replication in vitro, with IC50s ranging from ~7 to >=50 µM. The most effective of these initial compounds, 2-phenylthio-indole, was used to identify six additional, structurally related compounds, which were tested for their inhibitory effects on enzyme activities and tachyzoite replication. Surprisingly, these compounds were competitive inhibitors of NTPase-I but noncompetitive inhibitors of NTPase-II. Modifications to the indole and phenol rings resulted in alterations of activity, thus providing insight into the structural features that are important for inhibition of T. gondii NTPases.

* Corresponding author. Mailing address: Department of Molecular Microbiology, Washington University School of Medicine, Campus Box 8230, 660 South Euclid Ave., St. Louis, MO 63110-1093. Phone: (314) 362-7059. Fax: (314) 362-1232. E-mail: Sibley{at}borcim.wustl.edu.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2393-2399, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2393-2399.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.





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