Research On The Multicomponent Synthesis And Bioactivities Of Aza-heterocyclic Compounds

Multi-component reaction (MCRs) is an ideal reaction mode which is consistent with the concept of green chemistry. In theory, a four-component reaction with one hundred kinds of reactants for each of component can produce 108 products with different structures. Therefore, MCRs can be used to build large-scale of structural diversity and complexity of compound libraries to meet the requirements of new drug discovery process. In view of the wide range of biological activities and the uses of aza-heterocyclic compounds, on the one hand we dedicated to the development of new practical MCRs for the synthesis of aza-heterocyclic compounds, on the other hand we made great efforts to synthesize large-scale structural diversity and complexity of aza-heterocyclic compounds for their bioactivity research to discover drug candidates as lead compounds. The content of this thesis is divided into three parts.The first part consists of chapter one, two and three. The progress in MCRs and their application in the synthesis of aza-heterocyclic compounds, the advances in the synthesis of pyrimidine and pyrrole derivatives, the content and significance of our research are firstly introduced in the chapter one. Then the synthesis of tetrahydropyrimidine derivatives via MCRs and their reaction mechanism are described in chapter two. In chapter two, an energy-saving and practical MCR for the synthesis of tetrahydropyrimidines has been developed, the hydroamination stereoselectivity in the MCR is found to be controlled by using proton and nonproton solvents, and a reasonable reaction mechanism is proposed according to the molecular energy of intermediates and related experimental results. Two novel and practical MCRs for the synthesis of tetra- and penta-substituted dihydropyrroles respectively and the corresponding reaction mechanisms are described in the third chapter. The MCRs with ready reactants, wide substrate scope, and high yields can be used to build structural diversity of small-molecule compound libraries for biological activity screening.The advances in cysteinyl aspartate-specific protease 3 (caspase-3) and its inhibitors, the purpose and contents of our research in this section are first explained in the second part (Chapter 4). And then the synthesis, design and activity of dihydropyrrole derivatives as potent caspase-3 inhibitors are described in detail. Excessive apoptosis-related diseases such as Alzheimer's and Parkinson's disease, have seriously affected the health and life of the people. Numerous studies made over the last decade have shown that caspase-3 is a key executive enzyme in apoptosis process, and that the activity inhibition of caspase-3 can significantly prevent apoptosis in vitro and in vivo. Therefore, caspase-3 has been deemed to be a new target molecule for the treatment of apoptosis-related diseases. Under the concentration of 20μg/mL, most of dihydropyrroles that we synthesized have more than 90% of the inhibitory activity on caspase-3. Of 39 dihydropyrroles that we designed and synthesized, 14 compounds inhibit the activity of caspase-3 with IC50 values of 5 to 20μM. The relations between activity and structure of compounds showed that all substituents on the dihydropyrrol-one ring could inhibit the activity of caspase-3 significantly. The MCR conditions are established for the synthesis of tetra-substituted dihydropyrroles with Carboxyl group.The discovery and development of non-steroidal anti-inflammatory drugs (NSAIDs), the development of Cyclooxygenase-2 (COX-2) inhibitors (new generation of NSAIDs), and the purpose and content of our research are first described in the third part (chapter 5). The design, synthesis and activity of tetrahydropyrimidine and dihydropyrrole derivatives as COX-2 inhibitors are then presented in detail. COX-2 inhibitors can be not only used for the treatment of various acute and chronic inflammation, they can also be used for many types of cancer and neurodegenerative diseases. In this chapter we established the MCR reaction conditions for the synthesis of tetrahydropyrimidines with COX-2 inhibitor pharmacophore aminosulfonyl, synthesized 34 tetrahydropyrimidine and dihydropyrrole derivatives with aminosulfonyl. Under the concentration of 10μg/mL, four compounds have more than 50% inhibition on the COX-2 activity, of which two compounds with IC50 values of 4.65μM and 8.49μM.