| Alzheimer’s disease（AD）is a degenerative neurological disease of the brain,which has a serious impact on the life of patients.Due to the complex pathogenesis of AD,single-target drugs are not effective,and multi-target drugs（MTDs）targeting multiple subpathologies at the same time is a better approach,in terms of innovative drugs.Based on the research strategy of multi-target drugs,I carried out the following two parts of work during my postgraduate study:Part Ⅰ:Our research group has successfully designed and synthesized a batch of compounds with anti-inflammatory activity and cholinesterase inhibitory activity.Compound 1g was screened as a promising compound for the treatment of AD by bioactivity characterization.Although compound 1g showed double inhibitory activity of ACh E/BCh E and anti-inflammatory activity,its cholinesterase inhibitory activity was poor,and its anti-inflammatory activity still needed to be improved.Based on the previous work,this project modified different sites of benzene ring of salicylate and 5sites of tryptamine,designed and synthesized a series of salicyltryptamine carbamate compounds,in order to explore compounds with higher medicinal properties.The structure-activity relationship study showed that the compound H327(eq BCh E IC50=0.057±0.005μM)substituted by phenyl-4 methyl in salicylic acid fragment and chlorine in tryptamine fragment played a key role in improving the inhibitory activity of BCh E.The compound H327 inhibitory activity of BCh E was better than that of rivastigmine(eq BCh E IC50=0.19±0.001μM).H327 showed significant activity in neuroprotective activity,antioxidant activity,anti-inflammatory activity,anti-apoptotic activity,and the corresponding effects were better than compound 1g.In vivo acute toxicity studies proved that the safety of H327 meets the requirements of early AD drug development in the early stage and compound H327 also meets the requirements of AD drugs crossing the blood-brain barrier.Compound H327 was also superior to compound1g in improving scopolamine induced cognitive impairment.Therefore,the modification of compound 1g is successful in this work,providing a efficient and promising pleiotropic compound for the treatment of AD.Part Ⅱ:Salicylic acid,an important phenolic plant hormone,was first found in willow bark.In this part,a series of salicylic acid derivatives containing carbamate were designed and synthesized by using salicylic acid skeleton as support scaffold based on the multi-target design strategy.Compounds 3l and 3t showed strong double inhibitory activity of ACh E/BCh E.At the same time,the in vitro experiments showed that they had good neuroprotective and antiapoptotic activities.Acute toxicity tests confirmed that compounds 3l and 3t had acceptable safety.The discovery of compounds 3l and 3t provides a potential molecular framework for the development of ACh E/BCh E dual inhibitors. |
