Natural Sesquiterpene Lactone as Source of Discovery of Novel Fungicidal Candidates: Structural Modification and Antifungal Activity Evaluation of Xanthatin Derived from Xanthium strumarium L

Abstract

As part of our ongoing efforts to discover novel agricultural fungicidal candidates from natural sesquiterpene lactones, in the present work, sixty-three xanthatin-based derivatives containing a arylpyrazole, arylimine, thio-acylamino, oxime, oxime ether, or oxime ester moiety were synthesized. Their structures were well characterized by 1 H and 13 C nuclear magnetic resonance and high-resolution mass spectrometry, while the absolute configurations of compounds 5′ and 6a were further determined by singlecrystal X-ray diffraction. Meanwhile, the antifungal activities of the prepared compounds against several phytopathogenic fungi were investigated using the spore germination method and the mycelium growth rate method in vitro. The bioassay results illustrated that compounds 5, 5′, and 15 exhibited excellent inhibitory activity against the tested fungal spores and displayed remarkable inhibitory effects on fungal mycelia. Compounds 5 and 5′ exhibited more potent inhibitory activity (IC 50 = 1.1 and 24.8 μg/mL, respectively) against the spore of Botrytis cinerea than their precursor xanthatin (IC 50 = 37.6 μg/mL), wherein the antifungal activity of compound 5 was 34-fold higher than that of xanthatin and 71-fold higher than that of the positive control, difenoconazole (IC 50 = 78.5 μg/mL). Notably, compound 6′a also demonstrated broad-spectrum inhibitory activity against the four tested fungal spores. Meanwhile, compounds 2, 5, 8, and 15 showed prominent inhibitory activity against the mycelia of Cytospora mandshurica with the EC 50 values of 2.3, 11.7, 11.1, and 3.0 μg/mL, respectively, whereas the EC 50 value of xanthatin was 14.8 μg/mL. Additionally, compounds 5′ and 15 exhibited good in vivo therapeutic and protective effects against B. cinerea with values of 55.4 and 62.8%, respectively. The preliminary structure−activity relationship analysis revealed that the introduction of oxime, oxime ether, or oxime ester structural fragment at the C-4 position of xanthatin or the introduction of a chlorine atom at the C-3 position of xanthatin might be significantly beneficial to antifungal activity. In conclusion, the comprehensive investigation indicated that partial xanthatin-based derivatives from this study could be considered for further exploration as potential lead structures toward developing novel fungicidal candidates for crop protection.