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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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          Multi-target-directed ligands to combat neurodegenerative diseases.

          Andrea Cavalli, Maria Bolognesi, Anna Minarini … (2008)
          Article 0 comments Cited 234 times – based on 0 reviews     Review now
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            Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase.

            Florian Nachon, Eugénie Carletti, Cyril Ronco … (2013)
            The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget-directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesterase) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, π-π/cation-π interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. Huprine W forms additional interactions with hAChE, which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine residue and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE that is able to accommodate the chlorine substituent.
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              The Public Health Impact of Alzheimer's Disease, 2000–2050: Potential Implication of Treatment Advances

              Philip Sloane, Sheryl Zimmerman, Chirayath Suchindran … (2002)
              Recent developments in basic research suggest that therapeutic breakthroughs may occur in Alzheimer's disease treatment over the coming decades. To model the potential magnitude and nature of the effect of these advances, historical data from congestive heart failure and Parkinson's disease were used. Projections indicate that therapies which delay disease onset will markedly reduce overall disease prevalence, whereas therapies to treat existing disease will alter the proportion of cases that are mild as opposed to moderate/severe. The public health impact of such changes would likely involve both the amount and type of health services needed. Particularly likely to arise are new forms of outpatient services, such as disease-specific clinics and centers. None of our models predicts less than a threefold rise in the total number of persons with Alzheimer's disease between 2000 and 2050. Therefore, Alzheimer's care is likely to remain a major public health problem during the coming decades.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 16 June 2017
                Publication date Collection: June 2017
                Volume: 22
                Issue: 6
                Electronic Location Identifier: 1006
                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
                Article
                Publisher ID: molecules-22-01006
                DOI: 10.3390/molecules22061006
                PMC ID: 6152717
                PubMed ID: 28621747
                SO-VID: 9d557dd7-10bd-4f7f-80fa-fd5aacd3e1f8
                Copyright © © 2017 by the authors.
                License:

                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
                Date received : 12 May 2017
                Date accepted : 12 June 2017
                Categories
                Subject: Article

                Keywords: alzheimer’s disease,6-chlorotacrine,scutellarin,enzyme inhibitor,acetylcholinesterase,butyrylcholinesterase
                Data availability:
                Keywords: alzheimer’s disease, 6-chlorotacrine, scutellarin, enzyme inhibitor, acetylcholinesterase, butyrylcholinesterase

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