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Antimicrobial Agents and Chemotherapy, October 2009, p. 4185-4192, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00225-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

New Treatment Option for Second-Stage African Sleeping Sickness: In Vitro and In Vivo Efficacy of Aza Analogs of DB289 {triangledown}

Tanja Wenzler,1* David W. Boykin,2 Mohamed A. Ismail,2 James Edwin Hall,3 Richard R. Tidwell,3 and Reto Brun1

Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland,1 Department of Chemistry, Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia,2 Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina3

Received 18 February 2009/ Returned for modification 14 May 2009/ Accepted 10 July 2009

African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against African trypanosomes. The active parent diamidines showed similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol- and pentamidine-resistant lines, and a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense strain STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated activities superior to that of DB75. The aza prodrugs DB844 and DB868, as well as two metabolites of DB844, were orally more potent in the T. b. brucei strain GVR35 mouse central nervous system (CNS) model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the mouse CNS model by the intraperitoneal route. In conclusion, DB868 with oral and DB829 with parenteral application are potential candidates for further development of a second-stage African sleeping sickness drug.

* Corresponding author. Mailing address: Swiss Tropical Institute, Socinstrasse 57, P.O. Box, CH-4002 Basel, Switzerland. Phone: 41 612848165. Fax: 41 612848101. E-mail: tanja.wenzler{at}unibas.ch

{triangledown} Published ahead of print on 20 July 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4185-4192, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00225-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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