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-epi-borono-sclareolide and the concomitant Suzuki
coupling. Several 9-epi-drimane meroterpenoids presented
antifungal activity. The new stereoisomer 9-epi-yahazunol
(EC50 = 4.32 μM) and its analog S-T5 (EC50 = 2.8 μM) showed much better
antifungal activity than yahazunol (EC50 >150 μM)
against Rhizoctonia solani. Compound S-T5 possesses a promising in vivo efficacy
against R. solani, 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 R. solani, as evidenced by a series of biochemical investigations. The biosafety
assessment showed that S-T5 had no adverse
effects on seed germination. Configuration inversion may be an alternative
strategy for developing new potent antifungal mimics of drimane meroterpenoids.