The Design And Synthesis Of Nitrogen Containng Biheterocyclic Amide Compounds And The Preliminary Researches On The Immunosuppressive Activity

Immunosuppressants are a class of substances which reduce damaged tissuethrough inhibiting cellular and humoral immune response. It can inhibit abnormalimmune response and primarily used for the treatment of rejection in organtransplantation and autoimmune diseases. Although, a lot of new immunity inhibitorsconstantly come out in recent years, most of them do not have high selectivity and canreduce the body’s normal immune response even can induced infections and tumors orother issues.The study found that PI3K/Akt/mTOR pathway was actived in a number oftumor and immune diseases. Although immunity inhibitors towards single proteinkinase have developed respectively however, these inhibitors still have somedrawbacks in the treatment of immune diseases. We carried out the task in order tofind new immunosuppressants which have the quality of high selectivity, act quickly,obvious effect, less adverse reaction. This task was based on the computer-aided drugdesign (CADD), using PI3K protein kinase and mTOR protein as receptors to screenlead compounds. The optimal experimental route was determined using inversesynthetic method, then I synthesized a series of Nitrogen Containng BiheterocyclicAmide Compounds which have immunosuppressive activity. The task providesexperimental bases for the study of new PI3K/mTOR dual inhibitors.The main contents of the research are as follows:1）Determination of lead compoundsThis study screened nearly2million small compounds (download from ZINCand PubMed database) using Sybyl2.0, with PI3K and mTOR as receptorsrespectively.3-(2,6-dichlorophenyl)-5-methyl-N-(6-(methylsulfonyl)benzo[d]thiazol-2-yl)isoxazole-4-carboxamide was selected as the lead compound through the biological activity test.2）Synthesis and purification of Nitrogen Containng Biheterocyclic AmideCompoundsRetrosynthesis Analysis was used to choose the best synthetic route.Then wesynthesis a series of derivatives of lead compound. All the structures were verifiedthrough LC-MS and NMR technology.3）The biological activity test of Nitrogen Containng Biheterocyclic AmideCompounds towards Jurkat cellAll the compounds were used to test the biological activity of Jurkat (T cell line)based on CCK8technology.Through the research above, we got results as follows:1）3-(2,6-dichlorophenyl)-5-methyl-N-(6-(methylsulfonyl)benzo[d]thiazol-2-yl)isoxazole-4-carboxamide was selected as the lead compound.12compounds,including the lead compound were synthesized successfully after6-step reaction. Allof them have the high purity through LC-MS and NMR test.2） A set of valid and reliable data came from CCK8test which confirmed theinhibition of Nitrogen Diheterocyclic amide Compounds towards Jurkat T cells.3） The task confirmed that Nitrogen Diheterocyclic amide Compounds havegood immunosuppressive action. Which provide a good experimental foundation forfurther research on PI3K/mTOR dual inhibitors.