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.
Del Poeta
M
M
Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, North Carolina 27710, USA.
Schell
W A
WA
Dykstra
C C
CC
Jones
S
S
Tidwell
R R
RR
Czarny
A
A
Bajic
M
M
Kumar
A
A
Boykin
D
D
Perfect
J R
JR
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