Synthesis and bio-inspired optimization of drimenal: Discovery of chiral drimane fused oxazinones as promising antifungal and antibacterial candidates

摘要

Abstract The synthesis of antifungal natural product drimenal was accomplished. Bio-inspired optimization protruded chiral 8-( R )-drimane fused oxazinone D as a lead, considering favorable physicochemical profiles for novel pesticides. The improved scalable synthesis of scaffold D was implemented by Hofmann rearrangment under mild conditions. Detailed structural optimization was discussed for both antifungal and antibacterial exploration. Substituted groups (SGs) with C 3 ～C 5 hydrocarbon chain are recommended for exploration of antifungal agents, while substituents with C 4 ～C 6 carbon length are preferred for antibacterial ingredients. The chiral drimane fused oxazinone D8 was selected as a promising antifungal candidate against Botrytis cirerea , with an EC 50 value of 1.18?mg/L, with the enhancement of up to >25 folds and >80 folds than the mother compound D , and acyclic counterpart AB5 , respectively. The in vivo bioassay confirmed much better preservative effect of D8 than that of Carbendazim. The chiral oxazinone variant D10 possessed prominent antibacterial activity, with MIC values of 8?mg/L against both Bacillus subtilis and Ralstonia solanacearum , showing advantages over the positive control streptomycin sulfate. Graphical abstract Display Omitted Highlights ? Synthesis and bioassay of natural products drimenal and drimenol was accomplished from sclareol. ? Bio-inspired optimization protruded 8-( R )-drimane fused oxazinone D as a lead for novel agrochemicals. ? Practical synthesis and divergent optimization of scaffold D were implemented. ? Both antifungal and antibacterial candidates with prominent activities were achieved.