摘要/Abstract

使用自制的3-溴甲基喹喔啉-2-甲酸乙酯为反应物，经一锅连续的Arbuzov反应/Horner-Wadsworth-Emmons（HWE）反应/酯基水解反应，简便有效地合成了一系列结构新型的3-芳乙烯基喹喔啉-2-羧酸类化合物，并对其进行了初步的结核杆菌亮氨酰-tRNA合成酶（Mtb LeuRS）抑制活性实验.结果表明（E）-3-（3-硝基苯乙烯基）喹喔啉-2-羧酸（5j）的抑制活性最好，其IC₅₀值为14.7 μmol·L^-1，高于参考药物AN2679，具有很好的Mtb LeuRS抑制剂开发潜力.利用Discovery Studio分子模拟软件CDOCKER程序进行分子模拟分析，结果表明该化合物能够与Mtb LeuRS的活性点很好的结合.而且，体外抗耻垢分枝杆菌Mycobacterium smegmatis（M.smegmatis）活性实验也发现，化合物5j的抗结核杆菌的活性最佳，其最小抑菌浓度（MIC）为15.6 μg/mL与参考药物rifampicin相当.
关键词: 喹喔啉, 溴化反应, 三步一锅法, 结核杆菌, 亮氨酰-tRNA合成酶
In the present work, a simple and facile synthesis of a new series of 3-arylvinylquinoxaline-2-carboxylic acids has been achieved using the newly-synthesized ethyl 3-bromomethylquinoxaline-2-carboxylate as substrate through one-pot sequential Arbuzov/Horner-Wadsworth-Emmons (HWE)/ester hydrolysis reaction procedure. A primary in vitro evaluation for their inhibitory activity against Mycobacterium smegmatis (M. smegmatis) Leucyl-tRNA synthetase (Mtb LeuRS) revealed that (E)-3-(3-nitrostyryl)quinoxaline-2-carboxylic acid (5j) represented the most active compound in this round of effort with the IC₅₀ value of 14.7 μmol·L^-1, which was much superior to the reference drug AN2679, indicating the potential medicinal value for the exploration of novel Mtb LeuRS inhibitor. The results of molecular docking analyses using CDOCKER module of Discovery Studio (DS) software suggested that it could bind well to the active site of Mtb LeuRS. Moreover, the antitubercular assay against M. smegmatis also revealed that the nitro-substituted 5j has the best anti-tubercular activity with the minimum inhibitory concentration (MIC) value 15.6 μg/mL, being comparable with the reference rifampicin.
Key words: quinoxaline, bromination reaction, one-pot three-step, M. smegmatis, Leucyl-tRNA synthetase


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