Design And Synthesis Of Novel Sulfonamide HNE Inhibitors

As an important member of the superfamily of the serine protease,Human Neutrophil Elastase(HNE)can hydrolyze the amide bonds of the protein or peptides,which can degrade a variety of proteins.It was confirmed that the elevated HNE closely related to a number of diseases,such as acute lung injury,acute respiratory syndrome,chronic lung disease and cystic fibrosis.In addition,HNE also plays a vital role in the occurrence of the inflammation and the proliferation of the cancer cell.So it is of great importance to inhibit the excessive HNE.The research on the inhibitors of HNE started almost 30 years ago,although in this process many candidates were found in clinical research,only the Sivelestat sodium was commercialized in Japan and Korea.At the same time,the number of patients related to HNE is increasing rapidly,so it's urgent to design and synthesize novel HNE inhibitors.Based on the computer-aided drug design and the combination of the active substructure,a series of novel sulfonamide HNE inhibitor was designed and synthesized and the biological activity was also tested.1.The structure and function of HNE were introduced in detail,as well as the recent progress of HNE inhibitor and its mode of action.2.Two series of 48 novel sulfonamide target molecules were synthesized.All of the target molecules were characterized by 1H NMR,GC-MS and Elemental analysis.Some compounds were even confirmed by 13C NMR.3.The biological activity showed that part of the target molecules showed good activity against HNE at the concentration of 100 ?M.Some of these compounds display the potential to be further investigated.4.The cell based experiments were carried out for those compounds whose Ki are at micromolar levels against HNE.Some of them displayed potent activity against lung cells,and no obvious toxicity against normal cell line HEK293.5.The structure-activity relationship was summarized and it will be helpful for the research on the HNE inhibitor further.