Discovery of Natural Sesquiterpene Lactone 1--Acetylbritannilactone Analogues Bearing Oxadiazole, Triazole, or Imidazole Scaffolds for the Development of New Fungicidal Candidates.

In recent decades, natural products have been considered important resources for developing of new agrochemicals because of their novel architectures and multibioactivities. Consequently, herein, 1--acetylbritannilactone (ABL), a natural sesquiterpene lactone from L., was used as a lead for further modification to discover fungicidal candidates. Six series of ABL-based derivatives containing an oxadiazole, triazole, or imidazole moiety were designed and synthesized, and their antifungal activities were also evaluated and . Bioassay results revealed that compounds , , and (EC = 61.4, 30.9, and 12.4 μg/mL, respectively) exhibited more pronounced inhibitory activity against than their precursor ABL (EC > 500 μg/mL) and positive control hymexazol (EC = 77.2 μg/mL). Derivatives and (EC = 19.6 and 41.5 μg/mL, respectively) exhibited more potent antifungal activity toward than ABL (EC = 68.3 μg/mL). Compound exhibited excellent and broad-spectrum antifungal activity against seven phytopathogenic fungal mycelia. Particularly, the inhibitory activity of compound against the mycelium of was more than 10.8- and 2.3-fold those of ABL and hymexazol, respectively. Meanwhile, derivative (IC = 47.7 μg/mL) displayed more pronounced inhibitory activity against the spore of than ABL (IC > 500 μg/mL) and difenoconazole (IC = 80.8 μg/mL). Additionally, the control efficacy of compound against was further studied using infected tomatoes (protective effect = 58.4%; therapeutic effect = 48.7%). The preliminary structure-activity relationship analysis suggested that the introduction of the 1,3,4-oxadiazole moiety (especially the 1,3,4-oxadiazole heterocycle containing the 4-chlorophenyl, 2-furyl, or 2-pyridinyl group) on the skeleton of ABL was more likely to produce potential antifungal compounds. These findings pave the way for further design and development of ABL-based derivatives as potential antifungal agents.