Design,Synthesis And Biological Activity Of 1-azabenzanthrone-1,2,3,4-tetrahydroisoquinoline Hybrids

Finding novel anti-Alzheimer's disease(AD)drugs from natural active ingredients and their derivatives is a hot research field for the development of medicinal chemistry.The structural modification of natural active ingredients is an important way to find new anti-Alzheimer's disease drugs.In this paper,Based on the "Multi-target therapy strategy",two series hybrids derivatives had been designed and synthesized from 1-azabenzanthrone and 1,2,3,4-tetrahydroisoquinoline.The activities of 1-azabenzanthrone-1,2,3,4-tetrahydroisoquinoline hybrids were tested through the modle of acetylcholinesterase(AchE)?butyrylcholinesterase(BuChE)??-amyloid(A?)?BV-2 cells and RAW264.7 cells we had established in vitro.The main works are shown as follows.1)Most hybrids derivatives exhibit their high AChE,BuChE and A? inhibitory activity and their inhibitory potency with IC50 values in the micromolar range,Fortunately,Compounds 8a and 8b show their very strong AChE inhibitory potency with IC50 values 0.031and 0.067?mol·L-1.2)The anti-inflammatory activity of our compounds show that these drugs can strongly inhibit inflammatory factors(NO and TNF-?)of cells BV-2 and RAW264.7 stimulated by LPS.Derivatives show high inhibition ratio for inflammatory factors in the range of 70-90%,with the concentration of compounds increase to 15?mol·L-1.3)Western-blotting was used to detect the expression level of iNOS.The results showed that derivatives 8a and 8b exhibit their strongly inhibiting activities.The rsearch would could be beneficent for further structural modification with higher anti-AD potency.