| Abstract
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Crude extracts from 40 Iranian and Canadian plants were tested for their antifungal activity against several species of Aspergillus, Candida, and Cryptococcus. The extracts of Diplotaenia damavandica, Heracleum persicum, Sanguisorba minor, and Zataria multiflora exhibited the widest spectrum of activity. Cytotoxicity tests in KB cells were performed on some of the most promising plant extracts. D. damavandica and Bunium persicum were found to exhibit the lowest cytotoxicity among the plants studied. Bioassay guided isolation of D. damavandica active constituents led to identification of four coumarin compounds, angelicin, libanorin, psoralene, and auraptene, which showed antifungal activity. The cytotoxicity evaluation of the fractions demonstrates almost no toxicity. Fraxinus americana has been used traditionally among native Indians of North America for different purposes. Four compounds, verbascoside, 10-hydroxyligstroside, ligstroside, and syringin, were identified in the bark of F. americana. Ligstroside showed weak activity. The presence of phenolic phenylpropanoids can justify the traditional use of the bark of this plant especially for inflammatory conditions. Several derivatives of angelicin were designed and synthesized. The correlation of structure and activity as well as the relevance of the lipophilicity factor, log D{7.0}, to the antifungal activity is discussed. Angelicin and several potent antifungals proved to be non-toxic in human cell line cytotoxicity assay. It was found that angelicin and db-cAMP increased the cellular level of ergosterol in treated C. albicans. This evidence supports the idea that coumarins do not act like azole antifungals. The interaction studies between cAMP derivative and different antifungal drugs suggested the existence of antagonism, which was observed in a similar fashion between the azole drugs and phosphodiesterase inhibitors. This finding suggested a role for cAMP in ergosterol metabolism. Indirect evidence was found in relation to the action of coumarins on the pH controlling system in fungi. The coumarins showed synergism with most of the agents acting on proton pump ATPase. Intracellular pH was reduced in the treated fungi as well. Morphological studies with the electron microscope revealed multiple budding in coumarin treated Candida cells which could be attributed to the phosphodiesterase inhibitory activity of coumarins. The reason for the observed changes in the vacuolar systems of the fungal cells is not quite clear.
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