| Nowadays, malignant tumor is one of the main diseases that have deep impact on human health and threat to human life. Drugs play an important role in the treatment of malignant tumor. With the rapid progress of science and technology, molecular biology and cell biology have been developing rapidly. This allows the development of antitumor drugs shifting from the traditional cytotoxic drugs to the molecule targeted drug which takes the tumor-associated signaling pathway as a target. Nitrogen-containing heterocyclic compounds, an important class of compounds which pervasively exist in nature, has drawn attention of many scientists due to its wide range of biological activity. Pyridine is an important class of nitrogen-containing heterocyclic compounds and display a very wide range of biological activity. Therefore, pyridine has a very important application value in pesticide, medicine, life science and other fields. Naphthyridine, as a kind of pyridine fused heterocyclic derivatives, is also an important nitrogen-containing heterocyclic compound. As its novel chemical structure, naphthyridine also has important potential applications in the field of pesticides and medicine. Therefore, it has important scientific significance and potential applications to design and synthesize pyridine and naphthyridine derivatives with biological activity. Firstly, on the basis of the diversity-oriented synthesis strategy, this thesis has designed and synthesized 30 heterocyclic derivatives each of which contains 8-amino-2,7-naphthyridine. By biological screening, we found a number of new antitumor lead compounds that show good inhibitory activity against c-Kit or VEGFR-2 kinase. Moreover, on the basis of bioisosterism and principle of combination of bioactive sub-structures, we have carried out a preliminary structure optimization to a class of 4-amino-3-acyl pyridine derivatives which acquired by random activity screening and have got 11 new compounds. At last, we have found several fungicides lead compounds with good antifungal activity. The details are as follows:1. The research progress of tyrosine kinase inhibitors, two representative tyrosine kinase:c-Kit and VEGFR-2 and its inhibitors are simply introduced in the paper; the research progress of types, synthetic methods and biological activity of naphthyridine heterocyclic derivatives and the types and listed varieties’design thinking of pyridine fungicides are summarized.2. In prior period of the research, our group have successfully developed a new type of c-Met inhibitor by using 2,7-naphthyridine framework. On the basis of this work, we have successfully applied 2,7-naphthyridine framework to the discovery of novel inhibitors of c-Kit and VEGFR-2 kinase. On the basis of the strategies of diversity-oriented synthesis,30 diversitified 8-amino-2,7-naphthyridine derivatives have been designed and synthesized. We successfully found three potent lead compounds (2-3a11,2-3d11 and 2-3e11) by screening of kinase inhibitory activity. In these three compounds, the inhibitory activity of compound 2-3a11 (ICso:8.5 nM) to c-Kit kinase is significantly better than the positive reference drug Motesinib (IC50:46.3nM) and OSI-930 (IC50:130.8 nM); the inhibitory activity of compound 2-3d11 (IC50:56.5 nM) and 2-3ell (IC50:31.7 nM) to VEGFR-2 kinase is comparable to or slightly better than OSI-930 (IC50:42.2 nM).3. On the basis of bioisosterism and combination of bioactive sub-structures, we have carried out a preliminary structure optimization to the class of 4-amino-3-acyl pyridine derivatives which acquired by random activity screening in prophase. We found more than one potent leadi compounds by antifungal activity screening in vitro. Among of them, the inhibitory activity of compound 3-T3,3-T5,3-T6 to mango stem end rot is comparable to chlorothalonil’s and better than azoxystrobin’s; the inhibitory activity of compound 3-T5 to banana anthracnose is comparable to chlorothalonil’s, the inhibitory activity of compound 3-T10,3-T3,3-T6 to banana anthracnose slightly better than azoxystrobin’s; the inhibitory activity of compound 3-T10,3-T3,3-T5,3-T6 to Banana wilt is comparable to chlorothalonil’s and azoxystrobin’s; the inhibitory activity of compound 3-T5,3-T6 to wheat scab is comparable to azoxystrobin’s. |
