Background: The increasing incidence of fungal infections, especially caused by Candida
albicans, and their increasing drug resistance has drastically increased in recent years. Therefore,
not only new drugs but also alternative treatment strategies are promptly required.
Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds
with fluconazole for combination antifungal therapy. In this study, we synthesized some
non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination
with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B
(AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated
Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds,
we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates.
Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity
against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations
were either synergistic or additive while as the rest of the combinations were indifferent.
Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted
from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold
reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis
in a concentration-dependent manner, supported by the results from docking studies.
Conclusion: The results of the studies conducted advocate the potential of these compounds as
new antifungal drugs. However, further studies are required to understand the other mechanisms
and in vivo efficacy and toxicity of these compounds.