Structure-in vitro activity relationships of pentamidine analogues and dication-substituted bis-benzimidazoles as new antifungal agents.
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 microg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 microg/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.
Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, North Carolina 27710, USA.
M
M
Del Poeta
W A
WA
Schell
C C
CC
Dykstra
S
S
Jones
R R
RR
Tidwell
A
A
Czarny
M
M
Bajic
A
A
Kumar
D
D
Boykin
J R
JR
Perfect
D000935:Antifungal Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010419:Pentamidine / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001562:Benzimidazoles; D010419:Pentamidine