Studies On Design And Synthesis Of Combinatorial Library Of Treating Chronic Nephritis Drugs

Chronic nephritis is a serious disease that is dangerous for the life of the patients. The mechanism research of chronic nephritis demonstrates that chronic nephritis is a kind of autoimmunity disease. Immunosuppressive drugs and steroid hormones are often used for treating chronic nephritis in clinic, but have serious side effects in long-term medicining. It is necessary to explore new drugs of treating chronic nephritis. The study of immunology manifests that autoimmunity disease is induced by the disorder of autoimmunity and immunodeficiency. Literatures reported that linomide was a novel immunomodulator, which had potential in the treatment of autoimmune disease such as multiple sclerosis, rheumatoid arthritis and chronic nephritis. Compound FR137316, which is a linomide derivatives, inhibited proteinuria and the production of autoantibodies as effectively as prednissolone in the GVHD mice and autoimmune MRL/1 mice. In order to research the high potent and low side effect drugs of treating chronic nephritis, we chose linomide and FR137316 as the lead compound and the positive control drugs and designed and synthesized a combinatorial library of 4 - hydroxyl - quinoline -3 - carboxamides derivatives. The paper included the several parts of research works illustrated below: 1. Based on comprehensive analysis of the treating chronic nephritis drugs reported by literatures, Linomide and FR137316 were chosen as the lead compound. The combinatorial library of 4 - hydroxyl - quinoline -3 - carboxamides derivatives were designed. Contrasted to the lead compound structure, the scaffolds of 4 -hydroxyl - quinoline -3 - carboxamides are free of 2- oxo group. This structure is beyond the claims of patents of linomide derivatives.2. By experimental studying the synthetic methods of library compounds, we found the synthetic route by which all of library compounds could be prepared easily. The results showed that the synthetic route was effective and convenient for the generation of molecule diversity. The building blocks of 4 - hydroyl - 3 -quinolinecarboxylic ester derivatives and amine derivatives could be bought commercially or prepared easily in my lab. By the synthetic route, a library containing 126 compounds of 4 - hydroxyl - quinoline -3 - carboxamides derivatives was generated for the evaluation. All the library compounds are new compounds out of the literatures, and we have applied for the protection of patent (CN patent Application number 200510063145.7).3. 'HNMR% MS and element analyses were used to identify the structure of the library compounds. 13 compounds were selected randomly and determinded by HPLC, and the results showed that the purity of the Ubrary compounds is above 85%.4. The positive control drugs linpmide and FR137316 were prepared, and their chemical structures of the positive control drugs were identify by 'HNlVfl^ MS and element analysis. The purity of linomide was above 99% by analysis with HPLC.5. The library compounds were initially screened by spleen lymphocyte proliferation and TNF-a production by macrophage. About 50% compounds showed the immunomodulatory activity. This results illustrates that the 2-oxo group of the quinoline ring in linomide and FR13 7316 might be unimportant for their immunomodulatory activities.6. Based on the results of preliminary screens, the structure-activity relationship of 4 - hydroxyl - quinoline -3 - carboxamides derivatives is as follows: 1) When the substituent R4 at the N atom of amide is alkyl group, the immunomodulatory activity is preserved. 2) When the substituents R3 and R4 at the N atom of amide form a cyclic molecule, the immunomodulatory activity decreases remarkably. 3) When the substituent at 6-position of quinoline ring is carboxy group, the immunomodulatory activity is different from those of linomide and FR137316. 4) When the substituents at 6-8 position of quinoline ring are halogen, methyl and methylthio group, the...