Design, Synthesis And Research Of Quantitative Structure Activity Relationships For Quinazoline-dervied VEGFR2 Inhibitors And Schiff-base-dervied FabH Inhibitors With Dioxygenated Rings

This thesis has mainly carried on the discussion of two parts:Part ? is design, synthesis and structure-activity relationship studies of quinazoline-dervied VEGFR2 inhibitors; Part ? is the design, synthesis and the activity of novel Schiff-base-dervied FabH inhibitors with dioxygenated rings as antibiotic agents.Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays an important role in the process of tumor growth and metastasis. Many factors are involved in tumor angiogenesis, one of which the vascular endothelial growth factors (VEGFs) play a major role, especially VEGFR2, which is a receptor tyrosine kinase that comprises blood vessels. Vascular endothelial growth factor (VEGF) signaling through VEGFR2 has been proved that it plays a major role in the regulation of tumor angiogenesis. As VEGFR2 signaling is important in tumor angiogenesis, blocking VEGFR2 signaling pathway has become an attractive approach for the treatment of cancers. Therefore, the development of novel small molecule VEGRF2 inhibitors has become a hot issue in the field of medicinal chemistry. In this thesis, we designed, synthetized many novel VEGFR2 tyrosine kinase inhibitors based on the 4-ol-quinazoline core by the principle of rational drug design and virtual screening program.47 compounds (two series of novel VEGFR2 tyrosine kinase inhibitors) have been synthesized. All the structures of these compounds were charactered by 'H-NMR, MS-ESI and elemental analysis, some of them were charactered by 13C-NMR. To test the anticancer activity of the first serie of compounds, the target compounds were evaluated by in vitro anti-proliferation assays. The results revealed that most of the synthetic compounds exhibited significant antiproliferative activities, and the compounds (3a-3p) containing the piperazine structure performed better than others, showing relatively good antiproliferative activities. What's more, compounds (3a-3m) with phenylpiperazine have better antiproliferative activity than compounds (3n-3p) with alkylpiperazine. Of the three cell lines tested, the inhibitory effect of MCF-7 was the best. To validate whether the above anti-proliferative effect was produced by interaction of VEGFR2 protein and the synthesized compounds, the synthesized compounds were evaluated for their abilities to inhibit the activity of four protein kinases relevant to cancer:VEGFR2, EGFR, bFGF, and PDGFR. The results showed that all of the compounds not only had significant VEGFR2 inhibitory activity, but also had good selectivity. Out of the given compounds, it was observed that compound 3h showed the most potent antiproliferative activity (IC50= 0.25 ?M for MCF-7 and ICso=2.89nM for VEGFR-2) with low cytotoxicity (CC50= 299.73 ?M). All of the above results indicated that compound 3h could be a potent VEGFR2 and anti-tumor agent. To test the anticancer activity of the first serie of compounds, the target compounds were evaluated by in vitro anti-proliferation assays. The results showed that With a few exceptions, the active analogs show a remarkable potent antitumor activity. Compound 6t showed the best biological activity (IC50= 0.22 ?g/ml for Hela, IC50= 0.15 ?g/ml for A549 and IC50= 0.34 p.g/ml for MCF-7). The disubstituted compounds (6r?6y) showed more potent anticancer activity than those with one substituent group(6a?6q), While electron-donating groups substituent improved the VEGFR2 inhibitory activity compared to electron-withdrawing groups substituent. The results suggested that stronger electro negativity groups in the 4-position and 3-position and weaker groups in the 2-position afford better inhibitory activity. The synthesized compounds were evaluated for their abilities to inhibit the activity of four protein kinases relevant to cancer The results showed that they not only have significant kinase inhibitory activities, but also have good selectivities. In addition, the synthesized compounds can inhibit the function of VEGFR2 and the anti-proliferative effect is produced partly by the interaction between VEGFR2 protein and the molecule inhibitors.FabH small molecule inhibitors have been a hot spot in the research of new antimicrobial agents, and further studies on the quantitative structure activity relationships have been carried out for many years. On this basis, two series of novel Schiff bases (51 compounds) derived from YKAs3003 that maintain the structure of the cyclohexylamine moiety were designed via molecular docking. The minimum inhibitory concentrations (MIC) of fisrt series compouds against these bacteria were tested. Within our research, most compounds (except 9q, 9f,9g) showed potent anti-Gram-negative bacteria activities. Compound 9e showed the most potent antibacterial activity with MIC values of 1.56-3.13 mg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 2.1 HM. Preliminary structure activity relationships and molecular modeling study provided further insight into interactions between the enzyme and its ligands. This study showed that 9e was a novel compound that can be potent antimicrobial inhibitor of FabH and provides valuable information for the design of E. coli FabH inhibitors as antibacterial agents. Moreover, the development of similar novel compounds based on the structure of compound 9e will be investigated in future studies. We have synthetized the second series 36 compounds, and The minimum inhibitory concentrations (MIC) of sceond series compouds are now under way.