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Antimicrobial Agents and Chemotherapy, October 1998, p. 2495-2502, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents

Maurizio Del Poeta,1,2 Wiley A. Schell,1 Christine C. Dykstra,3 Susan Jones,4 Richard R. Tidwell,4 Agnieszka Czarny,5 Miroslav Bajic,5 Marina Bajic,5 Arvind Kumar,5 David Boykin,5 and John R. Perfect1,*

Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, North Carolina 277101; Department of Pathobiology, Auburn University, Auburn, Alabama 368493; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275994; Department of Chemistry, Georgia State University, Atlanta, Georgia 303035; and Institute of Infectious Diseases and Public Health, University of Ancona, Ospedale Umberto I°, 60121 Ancona, Italy2

Received 13 February 1998/Returned for modification 1 April 1998/Accepted 10 July 1998

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of <= 0.09 µg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 µg/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential.

* Corresponding author. Mailing address: Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, P.O. Box 3353, Durham, NC 27710. Phone: (919) 684-2660. Fax: (919) 684-8902. E-mail: perfe001{at}mc.duke.edu.

Antimicrobial Agents and Chemotherapy, October 1998, p. 2495-2502, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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