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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
New treatment option for second-stage African sleeping sickness: In vitro and in vivo efficacy of aza analogs of DB289
Antimicrobial Agents and Chemotherapy, Volume 53, No. 10, Year 2009
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Description
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. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Authors & Co-Authors
Wenzler, Tanja
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Boykin, David Withers
United States, Atlanta
Georgia State University
Ismail, Mohamed A.
United States, Atlanta
Georgia State University
Hall, James Edwin
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Tidwell, Richard R.
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Brun, Reto
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Statistics
Citations: 132
Authors: 6
Affiliations: 3
Identifiers
Doi:
10.1128/AAC.00225-09
ISSN:
10986596
Research Areas
Environmental
Health System And Policy