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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Diphenyl furans and aza analogs: Effects of structural modification on in vitro activity, DNA binding, and accumulation and distribution in trypanosomes
Antimicrobial Agents and Chemotherapy, Volume 51, No. 8, Year 2007
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Description
Human African trypanosomiasis is a devastating disease with only a few treatment options, including pentamidine. Diamidine compounds such as pentamidine, DB75, and DB820 are potent antitrypanosomal compounds. Previous investigations have shown that diamidines accumulate to high concentrations in trypanosomes. However, the mechanism of action of this class of compounds remains unknown. A long-hypothesized mechanism of action has been binding to DNA and interference with DNA-associated enzymes. The fluorescent diamidines, DB75 and DB820, have been shown to localize not only in the DNA-containing nucleus and kinetoplast of trypanosomes but also to the acidocalcisomes. Here we investigate two series of analogs of DB75 and DB820 with various levels of in vitro antitrypanosomal activity to determine whether any correlation exists between trypanosome accumulation, distribution, and in vitro activity. Despite wide ranges of in vitro antitrypanosomal activity, all of the compounds investigated accumulated to millimolar concentrations in trypanosomes over a period of 8 h. Interestingly, some of the less potent compounds accumulated to concentrations much higher than those of more potent compounds. All of the compounds were localized to the DNA-containing nucleus and/or kinetoplast, and many were also found in the acidocalcisomes. Accumulation in the nucleus and kinetoplast should be important to the mechanism of action of these compounds. The acidocalcisomes may also play a role in the mechanism of action of these compounds. This investigation suggests that the extent of accumulation alone is not responsible for killing trypanosomes and that organelle-specific accumulation may not predict in vitro activity. Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Authors & Co-Authors
Bridges, Arlene S.
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Ismail, Mohamed A.
United States, Atlanta
Georgia State University
Kumar, Arvind
United States, Atlanta
Georgia State University
Tanious, Farial A.
United States, Atlanta
Georgia State University
Wenzler, Tanja
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Wilson, W. David
United States, Atlanta
Georgia State University
Brun, Reto
Switzerland, Allschwil
Swiss Tropical and Public Health Institute Swiss Tph
Boykin, David Withers
United States, Atlanta
Georgia State University
Tidwell, Richard R.
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Hall, James Edwin
United States, Chapel Hill
The University of North Carolina at Chapel Hill
United States, Chapel Hill
Unc Eshelman School of Pharmacy
Statistics
Citations: 70
Authors: 10
Affiliations: 4
Identifiers
Doi:
10.1128/AAC.00005-07
ISSN:
00664804
Research Areas
Genetics And Genomics