N-(2-金刚烷基)-N'-(2,3,4-三氟苯基)脲衍生物的合成及其抗结核活性研究

Synthesis and anti-tubercular activity of 1-(2-adamantyl)-3-(2,3,4-trifluorophenyl) urea derivatives

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。

Compound AU1235,1-（2-adamantyl）-3-（2,3,4-trifluorophenyl） urea was reported with a potent anti-tuberculosis activity,which targets the pathway of cell envelope biosynthesis.However,AU1235 suffered from poor in vitro pharmacokinetic profiles.Thus,we would like to modify the structure of AU1235 to deliver the newderivatives with better pharmacological properties while still remain the anti-tuiberculosis potency.We designed and synthesized novel dipeptide and urea analogues as potential anti-tuberculosis agents.All synthetic compounds were screened against Mycobacterium tuberculosis and evaluated the cell cytotoxicity.The structures of the target compounds were identified by HR-M S,1H-NM R and13C-NM R spectra.The results demonstrated that compound Ⅲ i showed the potent anti-tuberculosis activity（M IC =0.060 μg·m L-1） with lowcytotoxicity and lipophilicity.This compound is worthy of attention and further development.