Searching for the Stereoisomer of 7,7′-Epoxylignan Showing the Most Potent Antifungal Activity and Finding the 3-(Trifluoromethyl)-4-hydroxy-3′-fluoro Derivative to Have the Highest Activity

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The effect of the stereochemistry of 9,9′-epoxylignan, 7,9′-epoxylignan, and 7,7′-epoxylignan bearing the 4-hydroxy-3-methoxyphenyl group on their antifungal activity was estimated by employing stereoisomers of these compounds. The results suggest that the (7S,7′R,8R,8′R)-stereoisomers of 7,7′-epoxylignan are the most potent. (−)-Verrucosin (16) had an EC50 value of 89 μM against the Alternaria alternata Japanese pear pathotype, whereas the most effective derivative against the A. alternata Japanese pear pathotype was (7S,7′R,8R,8′R)-3-(trifluoromethyl)-4-hydroxy-3′-fluoro-7,7′-epoxylignan derivative 38, which was found to be ∼124 times more potent (EC50 = 0.72 μM) than natural (−)-verrucosin (16). The presence of both hydroxy and electron-withdrawing groups on the 7-aromatic ring enhanced the activity. Compared with that of butane type structure 42, the activity of 7,7′-epoxylignan structure 38, which is fixed between positions 7 and 7′, was 38 times higher.