This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hall, J. E. Articles by Tidwell, R. R. Search for Related Content PubMed PubMed Citation Articles by Hall, J. E. Articles by Tidwell, R. R.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, March 1998, p. 666-674, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Anti-Pneumocystis Activities of Aromatic Diamidoxime Prodrugs

James Edwin Hall,^1,2 John E. Kerrigan,^2, Kishore Ramachandran,² Brendan C. Bender,² Jason P. Stanko,² Susan K. Jones,² Donald A. Patrick,² and Richard R. Tidwell^2,3,*

Departments of Epidemiology,¹ Pathology,² and Medicinal Chemistry,³ University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Received 29 May 1997/Returned for modification 19 September 1997/Accepted 22 December 1997

Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

---

^* Corresponding author. Mailing address: Department of Pathology, CB #7525, 807 Brinkhous-Bullitt, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525. Phone: (919) 966-4294. Fax: (919) 966-6718. E-mail: Tidwell{at}Med.UNC.edu.

Present address: Department of Chemistry, University of South Alabama, Mobile, AL 36688-0002.

---

Antimicrobial Agents and Chemotherapy, March 1998, p. 666-674, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

This article has been cited by other articles:

• Mdachi, R. E., Thuita, J. K., Kagira, J. M., Ngotho, J. M., Murilla, G. A., Ndung'u, J. M., Tidwell, R. R., Hall, J. E., Brun, R. (2009). Efficacy of the Novel Diamidine Compound 2,5-Bis(4-Amidinophenyl)- Furan-Bis-O-Methlylamidoxime (Pafuramidine, DB289) against Trypanosoma brucei rhodesiense Infection in Vervet Monkeys after Oral Administration. Antimicrob. Agents Chemother. 53: 953-957 [Abstract] [Full Text]  
• Wang, M. Z., Saulter, J. Y., Usuki, E., Cheung, Y.-L., Hall, M., Bridges, A. S., Loewen, G., Parkinson, O. T., Stephens, C. E., Allen, J. L., Zeldin, D. C., Boykin, D. W., Tidwell, R. R., Parkinson, A., Paine, M. F., Hall, J. E. (2006). CYP4F Enzymes Are the Major Enzymes in Human Liver Microsomes That Catalyze the O-Demethylation of the Antiparasitic Prodrug DB289 [2,5-Bis(4-amidinophenyl)furan-bis-O-methylamidoxime]. Drug Metab. Dispos. 34: 1985-1994 [Abstract] [Full Text]  
• Cushion, M. T., Walzer, P. D., Ashbaugh, A., Rebholz, S., Brubaker, R., Vanden Eynde, J. J., Mayence, A., Huang, T. L. (2006). In Vitro Selection and In Vivo Efficacy of Piperazine- and Alkanediamide-Linked Bisbenzamidines against Pneumocystis Pneumonia in Mice.. Antimicrob. Agents Chemother. 50: 2337-2343 [Abstract] [Full Text]  
• Kurian, J. R., Bajad, S. U., Miller, J. L., Chin, N. A., Trepanier, L. A. (2004). NADH Cytochrome b5 Reductase and Cytochrome b5 Catalyze the Microsomal Reduction of Xenobiotic Hydroxylamines and Amidoximes in Humans. J. Pharmacol. Exp. Ther. 311: 1171-1178 [Abstract] [Full Text]  
• Cushion, M. T., Walzer, P. D., Collins, M. S., Rebholz, S., Vanden Eynde, J. J., Mayence, A., Huang, T. L. (2004). Highly Active Anti-Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds. Antimicrob. Agents Chemother. 48: 4209-4216 [Abstract] [Full Text]  
• Del Poeta, M., Schell, W. A., Dykstra, C. C., Jones, S., Tidwell, R. R., Czarny, A., Bajic, M., Bajic, M., Kumar, A., Boykin, D., Perfect, J. R. (1998). Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents. Antimicrob. Agents Chemother. 42: 2495-2502 [Abstract] [Full Text]  
• Del Poeta, M., Schell, W. A., Dykstra, C. C., Jones, S. K., Tidwell, R. R., Kumar, A., Boykin, D. W., Perfect, J. R. (1998). In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles, Furans, and Benzimidazoles. Antimicrob. Agents Chemother. 42: 2503-2510 [Abstract] [Full Text]