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

Abstract

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.

Regiospecific and Enantiospecific Effects of the β-Benzyl-α-benzylidene-γ-butyrolactone Structure on Phytotoxic Fungi

“…The synthetic methods of (8 R ,8′ R )- 13 and (8 S ,8′ R )- 13 are shown in Supporting Information. Since butane and tetrahydrofuran type lignans have been effective against the A. alternata Japanese pear pathotype and C.…”

“…It was assumed that some size of the hydrophobic group at the 4′-position on the benzylic aromatic ring and the hydrophobic group at the 6-position on the benzylidene aromatic ring would accelerate the activity. We developed outstanding antifungal lignans of β-benzyl-α-benzylidene-γ-butyrolactones without the phenolic group that were more potent than previously synthesized tetrahydrofuran-type lignans with phenolic and electron-withdrawing groups . The more selective toxicity against A.…”

“…18 The synthetic methods of (8R,8′R)-13 and (8S,8′R)-13 are shown in Supporting Information. Since butane 19 and tetrahydrofuran 16 type lignans have been effective against the A. alternata Japanese pear pathotype and C. lagenarium, which have been isolated in Japanese fields, in the previous experiment, these fungi were employed for the antifungal tests. In the tests against the A. alternata Japanese pear pathotype, both coumarin compounds 7 (EC 50 = 370 μM) and ent-7 (EC 50 = 285 μM) showed low activities, whereas the enantiospecific and regiospecific activities were provided in benzylidene compounds.…”

“…In our previous work, tetrasubstituted tetrahydrofuran lignan, which is a fixed conformation of butane-type lignan, showed higher antifungal activity than butane-type lignan. 16 As a next step, the effects of substituents at the aromatic rings on the activity were examined by employing the synthesized derivatives 6 to develop the novel compounds providing higher activity. This is a first report on the anti-phytotoxic fungal β-benzyl-α-benzylidene-γ-butyrolactone with the 9,9′-lactone lignan structure.…”

“…The activities of α,β-dibenzyl-γ-butyrolactone 5 , whose rotation between the 7- and 8-positions is possible, were also examined to search the effect of the conformation or α,β-unsaturated double bond. In our previous work, tetrasubstituted tetrahydrofuran lignan, which is a fixed conformation of butane-type lignan, showed higher antifungal activity than butane-type lignan . As a next step, the effects of substituents at the aromatic rings on the activity were examined by employing the synthesized derivatives 6 to develop the novel compounds providing higher activity.…”