含膦酸酯结构的异噁唑酰胺衍生物的设计、合成及抗菌活性

doi:10.6023/cjoc202512004

摘要/Abstract

为了获取抗菌候选化合物, 运用分子杂合策略, 将甲基异噁唑和膦酸酯结构通过酰胺键组合, 设计合成了18个含膦酸酯结构的异噁唑酰胺衍生物, 经¹H NMR, ¹³C NMR和元素分析确证其结构. 抗菌活性测试结果表明, 该类衍生物对所测细菌均有不同程度的抑制作用, 尤其是对革兰氏阴性菌活性较显著, 以二乙基((3-(2-氯-6-氟苯基)-5-甲基异噁唑-4-甲酰胺基)(对羟苯基)甲基)膦酸酯(Ⅲl)的活性最为突出, 对大肠杆菌(E. coli)和耐氟喹诺酮大肠杆菌(FREC)的最小抑菌浓度(MIC)均为2 μg/mL, 优于对照药庆大霉素, 且不易产生耐药; 时间-杀菌曲线显示, 化合物Ⅲl在浓度≥1 MIC时, 对E. coli整个生长周期均有杀菌作用, 尤其是在4 MIC, 效果最为明显; 胞内杀菌实验表明, 化合物Ⅲl对感染巨噬细胞E. coli具有胞内杀菌活性; 同时, 化合物Ⅲl对小鼠单核巨噬细胞无毒性, 可作为抗菌先导化合物深入研究.

关键词: 膦酸酯, 异噁唑, 酰胺衍生物, 合成, 抗菌活性

In order to obtain antibacterial candidate compounds, eighteen isoxazoleamide derivatives containing phosphonate fragment were designed and synthesized by combining methylisoxazole and phosphonate via amide bonds based on molecular hybridization strategy. Their structures were confirmed by ¹H NMR, ¹³C NMR and elemental analysis. Antibacterial activity tests revealed that these derivatives exhibited varying degrees of inhibition against the tested bacteria, with particularly significant activity against Gram-negative bacteria. Diethyl ((3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxamido) (4-hydroxyphenyl)methyl)phosphonate (Ⅲl) stood out as the most potent, showing minimum inhibitory concentrations (MIC) of 2 μg/mL against both E. coli and fluoroquinolone-resistant E. coli (FREC), outperforming the control drug gentamicin. Additionally, compound Ⅲl demonstrated a low tendency to induce resistance. Time-kill curve analysis indicated that at concentrations≥1 MIC, compound Ⅲl exhibited bactericidal effects throughout the growth cycle of E. coli, with the most pronounced effect observed at 4 MIC. Intracellular bactericidal assays confirmed that compound Ⅲl possesses intracellular antibacterial activity against E. coli-infected macrophages. Furthermore, compound Ⅲl showed no toxicity toward murine mononuclear macrophages, suggesting its potential as a promising lead compound for further antibacterial development.

Key words: phosphonateptide, isoxazole, amide derivatives, synthesis, antibacterial activities

引用此文

佘慧娴, 汪晴, 查琴, 杨家强. 含膦酸酯结构的异噁唑酰胺衍生物的设计、合成及抗菌活性[J]. 有机化学, 2026, 46(5): 2059-2066.

Huixian She, Qing Wang, Qin Zha, Jiaqiang Yang. Design, Synthesis and Antibacterial Activities of Isoxzoleamide Derivatives Containing Phosphonate Fragment[J]. Chinese Journal of Organic Chemistry, 2026, 46(5): 2059-2066.

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