All chemicals were used as purchased, without further purification. Thin-layer chromatography (TLC) was conducted on silica gel 60 F254 plates (Merck KGaA). Melting points were determined on an XT-5A digital melting point apparatus and are uncorrected. IR spectra were obtained using KBr pellets on a Bruker VERTEX 70 spectrometer. 1 H NMR spectra were recorded on a Bruker Avance 400 (400 MHz) spectrometer in CDCl 3 or Acetone-d6, with tetramethylsilane (TMS) as an internal standard.

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... on mass spectra were obtained on a VG 70SE mass spectrometer (Manchester, UK), which was operated in electron impact or electrospray ionization modes. Preparation of the receptor and ligands using GAUSSVIEW The three-dimensional structures of ligands were constructed using standard bond lengths and angles using GAUSSVIEW 3.09 software. Geometry optimizations were carried out with the semi-empirical AM1 method, and output files were minimized by using the density functional (DFT) method, applying the B3LYP (Becke, Lee, Yang and Parr) correlation function in the second optimization. Gasteiger partial charges were assigned using AutoDock Tools. The crystal structure of the TTR receptor in a complex with T4 was retrieved from the Protein Data Bank (PDB entry code 1ICT). After removing the inhibitor from the complex, polar hydrogen atoms and Kollman-united charges were added to the macromolecule. Docking of ligands using AutoDock 4.0 27 Docking was carried out using one of several search methods. The most efficient method is a Lamarckian genetic algorithm (LGA), which is a hybrid of a genetic algorithm and a local search algorithm. This algorithm first builds a population of individuals, each 'gene' being a different random conformation of the docked compound. The local search algorithm then performs energy minimizations on a user-specified proportion of the population of individuals. If the energy of the new individual is lower than that of the old individual, the new one is automatically accepted as the next step in docking. However, traditional genetic algorithms and simulated annealing are also available. For typical systems, AutoDock is run several times to produce several docked Electronic Supplementary Material (ESI) AutoDockTools includes a number of methods for analysing the results of docking simulations, including tools for clustering results by conformational similarity, visualizing conformations, and visualizing interactions between ligands and proteins. In this study, model analyses were performed using ACCELRYS DS VISUALIZER 3.1 software. Fibril formation assay Each compound was dried and then dissolved at 7.2 mM in spectroscopic grade DMSO as a primary stock solution. For assays in which the final inhibitor concentration was 7.2 μM and 3.6 μM, the initial 7.2mM inhibitor stock solution was diluted to 1.4mM and 720 μM solutions respectively with DMSO. A typical sample for the measurement of fibril inhibition was prepared by micropipetting 5 µL of inhibitor solution into an Eppendorf tube and adding 500 µL of TTR at 0.4 mg/mL in 10 mM sodium phosphate, 100 mM KCl and 1 mM EDTA (pH 7.6). The inhibitor-TTR solutions were vortexing and incubated for 30 min at 37℃ to allow plenty of time for potential inhibitors to bind to TTR. Then, the solutions were rendered acidic and amyloidogenic by the addition of 495uL of 200mM acetate buffer, 100mM KCl, 1mM EDTA (pH 4.2), which was added to each solution to yield a final pH of 4.4. These solutions were incubated for 72h to evaluate inhibitor efficacy. The Eppendorf tube was then vortexed again to ensure a uniform suspension, and the turbidity of the suspension at 400 nm was measured. All compounds were soluble and none absorbed appreciably at 400nm, ensuring that turbidity was the result of TTR amyloid formation. All samples were done in triplicate. The ratio of the turbidities of the sample of interest to that of a sample prepared in the same way but lacking any inhibitor multiplied by 100% gave the percent fibril formation. In this study, inhibiting ratio is one hundred Electronic Supplementary Material (ESI)