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

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∼C hydrocarbon chain are recommended for exploration of antifungal agents, while substituents with C∼C 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 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.