Synthesis and evaluation of 1, 2, 3, 4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation. Issue 16 (1st September 2018)

• Record Type: Journal Article
• Authors: Lv, Peng; Xia, Chun-Li; Wang, Ning; Liu, Zhen-Quan; Huang, Zhi-Shu; Huang, Shi-Liang
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 16(2018)
• Page Start: 4693
• Page End: 4705
• Publication Date: 2018-09-01
• Subjects: AD Alzheimer's disease -- Aβ amyloid-β -- BBB blood-brain barrier -- CAs cinnamic acid derivatives -- CD circular dichroism -- DAPI 4′, 6-diamidino-2-phenylindole -- DMED Dulbecco's modified Eagle's medium -- DMSO dimethylsulfoxide -- HRMS high resolution mass spectra -- LMTM leucomethylene blue -- NFT intracellular neurofibrillary tangles -- PBL porcine brain lipid -- SPR surface plasmon resonance -- TEM transmission electron microscope -- ThS Thioflavin S -- ThT Thioflavin T; Alzheimer's disease -- Amyloid β -- Tau protein -- Aggregation inhibitors -- 1, 2, 3, 4-Tetrahydro-1-acridone analogues; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.08.007
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 40 new acridone analogues were synthesized as Aβ and tau aggregation inhibitors. Compounds 25 –30 showed strong inhibitory ability on both Aβ and tau aggregation. Biological activities of 30 in vitro and in cellular were further evaluated. Abstract: Amyloid-β (Aβ) and tau protein are two crucial hallmarks in Alzheimer's disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1, 2, 3, 4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for Aβ and tau aggregation. In vitro studies showed that compounds 25 –30 (20 μM) with N -methylation of the quinolone ring effectively inhibited Aβ1-42 aggregation by 84.7%–99.5% and tau aggregation by 71.2%–101.8%. Their structure-activity relationships are discussed. In particular, 30 could permeate the blood-brain barrier, bind to Aβ1-42 and tau, inhibit Aβ1-42 β-sheets formation, and prevent tau aggregation in living cells.