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Molecules 2017, 22(6), 1006; doi:10.3390/molecules22061006

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

1
Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
2
National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic
3
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
*
Author to whom correspondence should be addressed.
Received: 12 May 2017 / Revised: 9 June 2017 / Accepted: 12 June 2017 / Published: 16 June 2017
(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)
View Full-Text   |   Download PDF [1976 KB, uploaded 16 June 2017]   |  

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 (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 ≥ 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. View Full-Text
Keywords: Alzheimer’s disease; 6-chlorotacrine; scutellarin; enzyme inhibitor; acetylcholinesterase; butyrylcholinesterase Alzheimer’s disease; 6-chlorotacrine; scutellarin; enzyme inhibitor; acetylcholinesterase; butyrylcholinesterase
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Spilovska, K.; Korabecny, J.; Sepsova, V.; Jun, D.; Hrabinova, M.; Jost, P.; Muckova, L.; Soukup, O.; Janockova, J.; Kucera, T.; Dolezal, R.; Mezeiova, E.; Kaping, D.; Kuca, K. Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation. Molecules 2017, 22, 1006.

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