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Antimicrobial Agents and Chemotherapy, March 2002, p. 797-807, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.797-807.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antileishmanial Activities of Several Classes of Aromatic Dications

Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910,¹ Department of Chemistry, Georgia State University, Atlanta, Georgia 30303,² Pathology Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,³ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210⁴

Received 19 July 2001/ Returned for modification 8 October 2001/ Accepted 20 November 2001

Aromatic dicationic molecules possess impressive activity against a broad spectrum of microbial pathogens, including Pneumocystis carinii, Cryptosporidium parvum, and Candida albicans. In this work, 58 aromatic cations were examined for inhibitory activity against axenic amastigote-like Leishmania donovani parasites. In general, the most potent of the compounds were substituted diphenyl furan and thiophene dications. 2,5-Bis-(4-amidinophenyl)thiophene was the most active compound. This agent displayed a 50% inhibitory concentration (IC₅₀) of 0.42 ± 0.08 µM against L. donovani and an in vitro antileishmanial potency 6.2-fold greater than that of the clinical antileishmanial dication pentamidine and was 155-fold more toxic to the parasites than to a mouse macrophage cell line. 2,4-Bis-(4-amidinopheny)furan was twice as active as pentamidine (IC₅₀, 1.30 ± 0.21 µM), while 2,5-bis-(4-amidinopheny)furan and pentamidine were essentially equipotent in our in vitro antileishmanial assay. Carbazoles, dibenzofurans, dibenzothiophenes, and benzimidazoles containing amidine or substituted amidine groups were generally less active than the diphenyl furans and thiophenes. In all cases, aromatic dications possessing strong antileishmanial activity were severalfold more toxic to the parasites than to a cultured mouse macrophage cell line. These structure-activity relationships demonstrate the potent antileishmanial activity of several aromatic dications and provide valuable information for the future design and synthesis of more potent antiparasitic agents.

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