Design,Synthesis And Pharmacological Screening Of MyD88 Inhibitor As Anti-AD Agent

Alzheimer’s disease（AD）is a common neurodegenerative disease.Neuroinflammation mediated by the innate immune system plays an important role in the pathogenesis of AD and can interact with other factors to affect the disease process.TLRs/My D88 signaling pathway plays a key role in the regulation of inflammation.It may be an effective way to improve AD by inhibiting the dimerization of My D88,regulating the TLRs/My D88 signaling pathway in the innate immune system,regulating the release of inflammatory factors,and reducing inflammation.In this paper,we modified the structure of My D88 inhibitor TJ-M2010-5（as the lead compound）with the aid of computer-aided drug design（CADD）software for the purpose of improving activity,solubility and stability,and then 15 compounds（A1-F2）were designed.Based on the biult pharmacophore model,the activity of the designed compounds were predicted.The interaction between the designed compounds and My D88 were predicted by the molecular docking function of the software Cerius2.According to the structure of the compounds,the target compounds were prepared through different synthetic routes.The compounds were characterized by IR,UV,TG-DTA,¹H-NMR,¹³C-NMR,MS,optical rotation determination and other analytical methods.HPLC analysis confirmed that the purity of the compounds were all>95%.In pharmacological screening,the effect of the target compounds on AD was evaluated by studying the inhibitory activity of the target compounds on Aβaggregation,and the protective effect on SH-SY5Y cell damage caused by oxidative stress and hypoxia.The experimental results show that the designed compounds can effectively inhibit the aggregation of Aβ,and had significant protective effect on SH-SY5Y cell damage caused by oxidative stress and hypoxia at low compounds concentrations（8n M,40n M）.The innovation of this paper is that we regulate the innate immunity of the central nervous system based on the importance of neuroinflammation in the AD etiological network by designing new My D88 inhibitors using CADD,inhibiting My D88 dimerization,regulating TLRs/My D88 signaling pathway to provide a possible method for the prevention and treatment of AD.