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      Design and Synthesis of Novel Hybrid 8-Hydroxy Quinoline-Indole Derivatives as Inhibitors of Aβ Self-Aggregation and Metal Chelation-Induced Aβ Aggregation

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          Abstract

          A series of novel hybrid 8-hydroxyquinoline-indole derivatives ( 7a–7e, 12a–12b and 18a–18h) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced Aβ 1–42 aggregation as potential treatments for Alzheimer’s disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ 1–42 aggregation as 18c, 18d and 18f (EC 50 = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol ( 1, EC 50 = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by Aβ 1–42 aggregation in the presence of Cu 2+ or Zn 2+ ions was also dramatically decreased by treatment with 18c, 18d and 18f. The most potent hybrid compound 18f afforded 82.3% and 88.3% inhibition, respectively, against Cu 2+- induced and Zn 2+- induced Aβ 1–42 aggregation. Compounds 18c, 18d and 18f were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APP Sw cells. Molecular docking studies with the most active compounds performed against Aβ 1–42 peptide indicated that the potent inhibitory activity of 18d and 18f were predicted to be due to hydrogen bonding interactions, π–π stacking interactions and π–cation interactions with Aβ 1–42, which may inhibit both self-aggregation as well as metal ion binding to Aβ 1–42 to favor the inhibition of Aβ 1–42 aggregation.

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          Most cited references28

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          Metals in Alzheimer's and Parkinson's diseases.

          There has been steadily growing interest in the participation of metal ions (especially, zinc, copper, and iron) in neurobiological processes, such as the regulation of synaptic transmission. Recent descriptions of the release of zinc and copper in the cortical glutamatergic synapse, and influencing the response of the NMDA receptor underscore the relevance of understanding the inorganic milieu of the synapse to neuroscience. Additionally, major neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, are characterized by elevated tissue iron, and miscompartmentalization of copper and zinc (e.g. accumulation in amyloid). Increasingly sophisticated medicinal chemistry approaches, which correct these metal abnormalities without causing systemic disturbance of these essential minerals, are being tested. These small molecules show promise of being disease-modifying.
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            Bioinorganic chemistry of Alzheimer's disease.

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              Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta.

              As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                08 August 2020
                August 2020
                : 25
                : 16
                : 3610
                Affiliations
                [1 ]Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; skbowroju@ 123456uams.edu (S.K.B.); NRPenthala@ 123456uams.edu (N.R.P.)
                [2 ]Bioinformatics Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; nmainali@ 123456ualr.edu (N.M.); SKAKRABA@ 123456uams.edu (S.K.)
                [3 ]Central Arkansas Veterans Healthcare Service, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; sesha@ 123456uams.edu (S.K.); AyyadevaraSrinivas@ 123456uams.edu (S.A.)
                [4 ]Department of Geriatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; ReisRobertJ@ 123456uams.edu
                Author notes
                [* ]Correspondence: PACrooks@ 123456uams.edu
                Author information
                https://orcid.org/0000-0001-9679-1174
                https://orcid.org/0000-0001-6978-5588
                https://orcid.org/0000-0002-6362-5126
                Article
                molecules-25-03610
                10.3390/molecules25163610
                7463714
                32784464
                451b8b22-4645-4402-94a6-d551f536f912
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 July 2020
                : 07 August 2020
                Categories
                Article

                alzheimer’s disease,clioquinol analogues,hybrid 8-hydroxyquinoline-indole analogs,aβ-aggregation,metal chelating agents

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