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

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