含异噁唑片段的3-Methylcarbazole衍生物的设计、合成与抗菌活性

Design, Synthesis and Antibacterial Activities of 3-Methylcarbazole Derivatives Containing Isoxzole

摘要

为了获取抗菌候选化合物, 以天然产物3-methylcarbazole为起始化合物, 对其结构进行修饰及优化, 设计合成了系列含异噁唑片段的3-methylcarbazole衍生物; 利用核磁共振氢谱(¹H NMR)、碳谱(¹³C NMR)和元素分析确定了其结构. 抗菌活性测试结果表明, 该类化合物对金黄色葡萄球菌(S. aureus)、表皮葡萄球菌(S. epidermidis)和耐甲氧西林金黄色葡萄球菌(MRSA)具有较好的抑制作用, 大部分衍生物的抗菌活性优于3-methylcarbazole; 尤其以化合物3q最为突出, 对三者的最小抑菌浓度(MIC)分别为0.5, 1和2 µg/mL, 抗S. aureus和S. epidermidis活性与对照药相当,抗MRSA活性远优于对照药. 时间-杀菌曲线显示, 化合物3q在4×MIC时, 对S. aureus整个生长周期具有快速杀菌作用; 分子对接结果表明, 化合物3q与靶蛋白GyrB有较好的结合作用; 同时, 化合物3q对小鼠单核巨噬细胞无明显毒性. 综上, 异噁唑片段的引入能够提高3-methylcarbazole的抗菌活性.

Abstract

In order to obtain antibacterial candidate compounds, natural product 3-methylcarbazole was used as a hit compound for structural modification and optimization. A series of 3-methylcarbazole derivatives containing isoxazole moieties was designed and synthesized in this study, and their structures were confirmed by means of¹H NMR,¹³C NMR and elemental analysis. Antibacterial activity tests showed that these compounds exhibited significant activity against S. aureus, S. epidermidis and methicillin-resistant S. aureus (MRSA), with most derivatives demonstrating superior antibacterial activity compared to 3-methylcarbazole. Among them, compound 3q was the most prominent, with minimum inhibitory concentration (MIC) values of 0.5, 1 and 2 µg/mL against the three strains, respectively. Its anti-S. aureus and anti-S. epidermidis activities were comparable to those of the control drugs, while its anti-MRSA effect was significantly superior to that of the control drugs. The time-kill curve showed that compound 3q exerted rapid bactericidal activity against S. aureus throughout its entire growth cycle at 4×MIC. Molecular docking results revealed that compound 3q exhibited favorable binding interactions with the target protein GyrB. Additionally, compound 3q showed no toxicity toward mouse mononuclear macrophages. The introduction of the isoxazole moiety can enhance the antibacterial activity of 3-methylcarbazole.

关键词

3-Methylcarbazole衍生物 / 结构修饰 / 异噁唑 / 抗菌活性

Key words

3-Methylcarbazole derivative / Structural modification / Isoxzole / Antibacterial activity

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基金资助

贵州省科技计划项目(黔科合基础-ZK[2024]265)

国家级大学生创新创业训练计划项目(202510661273)