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Antimicrobial Agents and Chemotherapy, July 2009, p. 2824-2833, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01568-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity {triangledown} ,{dagger}

Georgina A. Holloway,1 William N. Charman,2 Alan H. Fairlamb,3 Reto Brun,4 Marcel Kaiser,4 Edmund Kostewicz,2 Patrizia M. Novello,1 John P. Parisot,1 John Richardson,2 Ian P. Street,1 Keith G. Watson,1 and Jonathan B. Baell1*

The Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde,1 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, VIC-3052, Australia,2 Division of Biological Chemistry and Drug Discovery, School of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Dundee, Scotland, United Kingdom,3 Swiss Tropical Institute, Medical Parasitology and Infection Biology, Socinstrasse 57, CH-4051 Basel, Switzerland4

Received 24 November 2008/ Returned for modification 7 January 2009/ Accepted 25 March 2009

High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.

* Corresponding author. Mailing address: The Walter and Eliza Hall Institute of Medical Research Biotechnology Centre, Structural Biology-Medicinal Chemistry Group, 4 Research Ave., LaTrobe Research & Development Park, Bundoora, Australia 3086. Phone: (061 3) 9345 2108. Fax: (061 3) 9345 2211. E-mail: jbaell{at}wehi.edu.au

{triangledown} Published ahead of print on 13 April 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2824-2833, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01568-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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