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Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

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      Abstract

      A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase ( hAChE) and human butyrylcholinesterase ( hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC 50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC 50 ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.

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      Most cited references 88

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      UCSF Chimera--a visualization system for exploratory research and analysis.

      The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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        Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays

        A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
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          AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.

           Oleg Trott,  Jay Olson (2010)
          AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user. Copyright 2009 Wiley Periodicals, Inc.
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            Author and article information

            Affiliations
            [1 ]Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; k.spilovska@ 123456gmail.com (K.S.); korabecny.jan@ 123456gmail.com (J.K.); vsepsova@ 123456gmail.com (V.S.); daniel.jun@ 123456unob.cz (D.J.); martina.hrabinova@ 123456unob.cz (M.H.); petr.jost@ 123456unob.cz (P.J.); lubica.muckova@ 123456unob.cz (L.M.); Tomas.kucera2@ 123456unob.cz (T.K.)
            [2 ]National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic; ondrej.soukup@ 123456fnhk.cz (O.S.); eva.mezeiova@ 123456gmail.com (E.M.); Daniel.Kaping@ 123456nudz.cz (D.K.)
            [3 ]Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; jana.janockova@ 123456gmail.com (J.J.); rafael.dolezal@ 123456centrum.cz (R.D.)
            Author notes
            [* ]Correspondence: kamil.kuca@ 123456fnhk.cz ; Tel.: +420-495-833-447
            Journal
            Molecules
            Molecules
            molecules
            Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
            MDPI
            1420-3049
            16 June 2017
            June 2017
            : 22
            : 6
            28621747
            6152717
            10.3390/molecules22061006
            molecules-22-01006
            © 2017 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/).

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