A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced Aβ aggregation (IC = 3.05 μM) and Cu-induced Aβ aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu-induced Aβ aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD.
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Electrostatic interactions between middle domain motif-1 and the AAA1 module of the bacterial ClpB chaperone are essential for protein disaggregation.
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Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, U.S.A.
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Center for Molecular Biology of the Heidelberg University, German Cancer Research Center Heidelberg, Germany.
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