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Antimicrobial Agents and Chemotherapy, August 2007, p. 2801-2810, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00005-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Diphenyl Furans and Aza Analogs: Effects of Structural Modification on In Vitro Activity, DNA Binding, and Accumulation and Distribution in Trypanosomes{triangledown}

Amanda M. Mathis,1 Arlene S. Bridges,1 Mohamed A. Ismail,3 Arvind Kumar,3 Iris Francesconi,3 Mariappan Anbazhagan,3 Qiyue Hu,3 Farial A. Tanious,3 Tanja Wenzler,4 Janelle Saulter,1 W. David Wilson,3 Reto Brun,4 David W. Boykin,3 Richard R. Tidwell,2 and James Edwin Hall1,2*

Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina Chapel Hill, Chapel Hill, North Carolina,1 Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina, Chapel Hill, North Carolina,2 Department of Chemistry, Georgia State University, Atlanta, Georgia,3 Swiss Tropical Institute, Basel, Switzerland4

Received 2 January 2007/ Returned for modification 28 January 2007/ Accepted 3 April 2007

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.

* Corresponding author. Mailing address: Molecular Pharmaceutics, UNC School of Pharmacy, 3312 Kerr Hall, CB#7360, Chapel Hill, NC 27599. Phone: (919) 966-6297. Fax: (919) 966-0197. E-mail: je_hall{at}unc.edu

{triangledown} Published ahead of print on 21 May 2007.

Antimicrobial Agents and Chemotherapy, August 2007, p. 2801-2810, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00005-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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