Design And Synthesis Of Resveratrol Analogues And Biological Evaluation Of Their Anti-AD Activities

Alzheimer’s disease(AD) is incurable, progressive and fatal progressive degenerative disease of the central nervous system. With the deepening of the pathogenesis of AD research, the role of neuroinflammation in AD pathophysiology is of growing concern. Resveratrol(Resveratrol) is a non-flavonoid polyphenol compound, a chemical named 3,5,4- trihydroxy stilbene, widely found in grapes(red wine), Polygonum cuspidatum and other plants. Numerous studies have shown that resveratrol has a variety of biological effects. In recent years, many scholars, at home and abroad, have found that resveratrol has certain anti-neuroinflammatory activity. Structural modification on Resveratral for better activity is one of the hotspots of current research.In our study, a method as the target protein of p38α MAPK using computer-aided drug design(CADD) to design and synthesis of a class of resveratrol analogues through the establishment of pharmacophore and molecular docking, total 32 compounds as the nucleus structure of resveratrol. These compounds have not been reported, the structure had been confirmed by LC-MS, 1H-NMR and 13C-NMR. The method using MTT whether the presence of active compounds cytotoxicity. Simultaneously the method using ELISA tests the target compounds on inflammatory factors NO, IL-1β and TNF-α inhibitory activity in BV-2 cells. The method using Western blot experiment test their ability to inhibit the target protein p38α MAPK. And evaluating their ability through the blood brain barrier in vitro experiments. Eventually by molecular dynamics simulation method describes the mechanism of active small molecules 47 and 67 with target proteins of p38α MAPK.The results showed that the designed compounds in p38α MAPK protein of inflammatory cytokines NO, IL-1β and TNF-α have better inhibitory activity and good through the BBB. Among them, the compounds of 39, 47, 66 and 67 achieved the desired effect of anti-AD, and could be considered as anti-AD lead compounds for further research.