Synthesis and biological evaluation of burnettiene A derivatives enabling discovery of novel fungicide candidates.

An antifungal polyene-decalin polyketide natural product, burnettiene A (1) has been re-discovered from the culture broth of Lecanicillium primulinum (current name: Flavocillium primulinum) FKI-6715 strain utilizing our original multidrug-sensitive yeast system. This polyene-decalin polyketide natural product was originally isolated from Aspergillus burnettii. The antifungal activity of 1 against Candida albicans has been reported. However, only one fungal species for the antifungal activity of 1 has been revealed, and details of the antifungal activity against other pathogenic fungus remain unknown. After extensive screening for antifungal activity, we found that 1 exhibits broad antifungal activity against pathogenic plant fungi, including Colletotrichum gloeosporioides, Botrytis cinerea, Pyricularia oryzae, Leptosphaeria maculans, and Rhizoctonia solani. Furthermore, we synthesized 12 derivatives from 1 and evaluated their antifungal activity to reveal the detailed structure-activity relationship. The methyl ester derivative showed antifungal activity against Saccharomyces cerevisiae 12geneΔ0HSR-iERG6 100-fold more potent than that of 1. Our research indicates that 1 would be a promising natural product as a new fungicidal candidate and the methyl ester derivative especially has great potential.