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目的以AU1235为先导化合物,设计合成含金刚烷基和三氟苯基的二肽类衍生物以及用其他基团替代金刚烷基的脲类衍生物,并对这两类化合物进行抗结核活性评价和哺乳动物细胞毒评价。方法以α-氨基酸为起始原料,经过缩合、脱保护基、再缩合等步骤合成二肽类化合物;以2,3,4-三氟苯胺为起始原料,经过异氰酸酯化、偶联反应等步骤合成脲类化合物。采用Microplate Alamar Blue Assay(MABA)法及四氮唑盐(MTT)还原法测试化合物的抗结核活性(MIC值)和细胞毒性(IC50值)。结果与结论合成了24个未见文献报道的目标化合物,其结构经过1H-NMR、13C-NMR、HR-MS谱确证。生物活性评价表明,脲类化合物Ⅲi不仅具有很好的抗结核活性(MIC=0.060μg·m L-1),还具有较低的细胞毒性和脂水分配系数,值得进一步研究。
OBJECTIVE To design and synthesize dipeptide derivatives containing adamantyl and trifluorophenyl groups and urea derivatives with other groups to replace adamantyl groups using AU1235 as the lead compound and to evaluate the anti-TB activity of these two compounds And mammalian cytotoxicity assessment. Methods The α-amino acids were used as the starting materials to synthesize the dipeptides through condensation, deprotection and further condensation. The 2,3,4-trifluoroaniline was used as the starting material to undergo isocyanation, coupling reaction, etc. Step Synthesis of urea compounds. Compounds were tested for anti-TB activity (MIC value) and cytotoxicity (IC50 values) using the Microplate Alamar Blue Assay (MABA) method and the tetrazolium salt (MTT) reduction method. RESULTS AND CONCLUSION Twenty-four target compounds were synthesized and their structures were confirmed by 1H-NMR, 13C-NMR and HR-MS. The bioactivity evaluation showed that urea Ⅲi not only had good antituberculous activity (MIC = 0.060μg · m L-1), but also had lower cytotoxicity and lipid-water partition coefficient, which deserved further study.