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Antimicrobial Agents and Chemotherapy, November 2004, p. 4209-4216, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4209-4216.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Highly Active Anti-Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Melanie T. Cushion,^1,2* Peter D. Walzer,^1,2 Margaret S. Collins,^1,2 Sandra Rebholz,^1,2 Jean Jacques Vanden Eynde,³ Annie Mayence,³ and Tien L. Huang³

Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati,¹ Medical Research Service, Veterans Affairs Medical Center, Cincinnati, Ohio,² Xavier University of Louisiana, College of Pharmacy, Division of Basic Pharmaceutical Sciences, New Orleans, Louisiana³

Received 28 April 2004/ Returned for modification 18 June 2004/ Accepted 9 July 2004

Trimethoprim-sulfamethoxazole and pentamidine isethionate have been used extensively for the prophylaxis and therapy of pneumonia caused by Pneumocystis jirovecii. Problems associated with toxicity and potential emerging resistance for both therapies necessitate the development of safe and effective analogs or new treatment strategies. In the present study, a library of 36 compounds was synthesized by using the pentamidine molecule as the parent compound modified by a 1,4-piperazinediyl moiety as the central linker to restrict conformation flexibility. The compounds were evaluated for anti-Pneumocystis carinii activity in a bioluminescent ATP-driven assay. Four of the compounds were highly active, with 50% inhibitory concentration (IC₅₀) values of <0.01 µg/ml; four had very marked activity (IC₅₀ < 0.10 µg/ml); ten had marked activity (IC₅₀ < 1.0 µg/ml); nine had moderate activity (IC₅₀ < 10 µg/ml); one had slight activity (IC₅₀ = 34.1 µg/ml); and the remaining eight did not demonstrate activity in this assay system. The high level of activity was specifically associated with an alkyl chain length of five to six carbons attached to one of the nitrogens of the bisamidinium groups. None of the highly active compounds and only one of the very marked compounds exhibited any toxicity when evaluated in three mammalian cell lines. The strategy of substitution of 1,4-piperazine-linked bisbenzamidines produced compounds with the highest level of activity observed in the ATP assay and holds great promise for the development of efficacious anti-P. carinii therapy.

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* Corresponding author. Mailing address: University of Cincinnati College of Medicine, Division of Infectious Diseases, 231 Albert Sabin Way, Cincinnati, OH 45267-0560. Phone: (513) 861-3100, ext. 4417. Fax: (513) 475-6415. E-mail: melanie.cushion{at}uc.edu.

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Antimicrobial Agents and Chemotherapy, November 2004, p. 4209-4216, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4209-4216.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• 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]