吡噁唑菌酮类似物的合成及杀菌活性

Synthesis and Fungicidal Activity of Pyramoxadone Analogues

摘要

基于吡噁唑菌酮(噁唑菌酮的5-位吡啶类似物)的结构, 设计合成了一系列新型噁唑烷二酮衍生物(化合物2-2～2-30). 目标化合物的结构通过核磁共振氢谱(¹H NMR), 核磁共振碳谱(¹³C NMR)和高分辨质谱仪(HRMS)进行了表征. 采用菌丝生长速率法, 以噁唑菌酮为阳性对照, 评价了所有化合物对9种植物病原真菌的体外抑制活性. 初步筛选结果显示, 50 mg/L浓度下大多数化合物表现出中等至优异的抑制活性, 尤其对立枯丝核菌(Rhizoctonia solani)、核盘菌(Sclerotinia sclerotiorum)、灰葡萄孢(Botrytis cinerea)和稻瘟病菌(Pyricularia grisea)的抑制效果显著. 构效关系(SARs)分析结果表明, 叔丁基、环己基等大位阻基团对活性提升不利, 含氟化合物的抗真菌活性普遍增强. 化合物2-16(EC₅₀=3.78 mg/L)和2-26(EC₅₀=1.61 mg/L)对立枯丝核菌的抑制活性优于对照药剂噁唑菌酮(EC₅₀=4.38 mg/L)和先导化合物吡噁唑菌酮(EC₅₀=9.67 mg/L). 体内保护活性实验结果表明, 200 mg/L浓度下化合物2-13, 2-16和2-18对棉花立枯病的防治效果分别达到88.3%, 89.5%和81.7%, 显著优于阳性对照药. 分子对接与静电表面图分析表明, 该类化合物的构效关系遵循疏水骨架决定结合取向、静电互补决定结合强度及取代基微调决定活性高低的规律.

Abstract

A series of novel oxazolidinedione derivatives(2-2-2-30) was designed and synthesized based on the structure of pyramoxadone, a 5-position pyridine analogue of famoxadone. The target compounds were characterized by means of ¹H NMR, ¹³C NMR and high-resolution mass spectrometry(HRMS). Their in vitro antifungal activities were evaluated against nine plant pathogenic fungi using the mycelial growth rate method, with famoxadone as a positive control. Preliminary screening at 50 mg/L revealed that most compounds exhibited moderate to excellent inhibitory activity, particularly againstRhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Pyricularia grisea. Structure-activity relationship(SAR) analysis indicated that bulky groups such as tert-butyl and cyclohexyl are detrimental to the enhancement of antifungal activity, while fluorine-containing compounds generally exhibited enhanced antifungal activity. Compounds 2-16(EC₅₀=3.78 mg/L) and 2-26(EC₅₀=1.61 mg/L) exhibited superior activity against R. solani compared to famoxadone(EC₅₀=4.38 mg/L) and pyramoxadone(EC₅₀=9.67 mg/L). In vivo protective efficacy assays demonstrated that compounds 2-13, 2-16 and 2-18 provided 88.3%, 89.5% and 81.7% control against cotton damping-off at 200 mg/L, respectively, significantly outperforming the positive control. Molecular docking and electrostatic surface map analysis revealed that the SAR of this class of compounds follows a pattern where the hydrophobic skeleton determines the binding orientation, electrostatic complementarity determines the binding strength, and substituent fine-tuning determines the activity level.

关键词

噁唑菌酮 / 噁唑烷二酮 / 抑菌活性 / 构效关系 / 分子对接

Key words

Famoxadone / Oxazolidinedione / Antifungal activity / Structure-activity relationship (SAR) / Molecular docking

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基金资助

国家自然科学基金(21877125)