Epimerization of Yahazunol-Related Meroterpenoids for Antifungal Leads

We herein disclose that the epimerization of yahazunol can lead to an antifungal enhancement. Yahazunol-related drimane meroterpenoids and pseudonatural mimics were synthesized based on an improved synthesis of 9-<i>epi</i>-borono-sclareolide and the concomitant Suzuki coupling. Several 9-<i>epi</i>-drimane meroterpenoids presented antifungal activity. The new stereoisomer 9-<i>epi</i>-yahazunol (EC₅₀ = 4.32 μM) and its analog <i>S</i><b>-T5</b> (EC₅₀ = 2.8 μM) showed much better antifungal activity than yahazunol (EC₅₀ >150 μM) against <i>Rhizoctonia solani</i>. Compound <i>S</i><b>-T5</b> possesses a promising in vivo efficacy against <i>R. solani</i>, with preventive efficacies of 87% and 71% at 100 and 50 μM, respectively. It not only induced wizened and wrinkled mycelia but also caused cell membrane damage or disruption in <i>R. solani</i>, as evidenced by a series of biochemical investigations. The biosafety assessment showed that <i>S</i><b>-T5</b> had no adverse effects on seed germination. Configuration inversion may be an alternative strategy for developing new potent antifungal mimics of drimane meroterpenoids.