Design, Synthesis And Biological Evaluation Of Some Nitrogen-containing Heterocyclic Compounds

This thesis focuses on the design and synthesis of nitrogen-containingheterocyclic compounds as VEGFR-2inhibitors/glucose kinase activators.Chapter1covers the design，synthesis and biological evaluation of naphthamidederivatives as VEGFR-2Inhibitors.Vascular endothelial growth factor plays an important role in tumor angiogenesis.Neovascularization of tumors is mainly driven by VEGFR-2through VEGF signalingpathway.The previous result in our lab revealed that some naphthamide derivativesexhibited good inhibitory activity against VEGFR-2. Among these derivatives,pyrimidinyloxy naphthamides DW10051, DW10111and indazolyl naphthamideDW10066displayed excellent potency (IC50less than2nM). In this thesis, we chosethese compopunds as our lead molecules in an effort to discover more potentcompounds. Thirty-one compounds were synthesized, most of which exhibited potentinhibitory activity against VEGFR-2with IC50less than10nM, and compounds1-B-3and1-C-1are the most potent compounds with IC50less than1nM.Chapter2presents the design, synthesis and biological evaluation of7-azaindolederivatives as glucokinase activators.As a key enzyme during glucose metabolism, glucokinase promotes glucosemetabolism and insulin secretion. Given its important role in controlling glucosehomeostasis, glucokinase has already become one of the most promising targets forthe treatment of type2diabetes. GK activators that enhance the activity of GK viabinding to an allosteric site on the enzyme hold promise as a novel and effectivetreatment for type2diabetes.According to the crystal structure of GK-GKAs complex reported and thestructure of GKAs disclosed, most of GKAs contain a common pharmacophore,which consists of a core structure and three moieties. The hydrophobic side chain embedded into the hydrophobic cavity of the allosteric site, the aromatic groupoccupied the lipophilic pocket in the allosteric site, and the nitrogen-containingheterocycles made dual hydrogen bonds with Arg63, which played a critical role inmantaining good potency for GK activation. Based on these findings, we designedand synthesized a series of GKAs that contain a central pyridine ring and a7-azaindole fragment. The result showed that eleven of sixteen compounds showedactive in glucose kinase activation assay, compound2-A-1,2-A-4,2-A-5and2-B-1exhibited good GK activation potency with EC50less than1μM.