Design, synthesis and in vitro evaluation of indolotacrine analogues as multi-target-directed ligands for the treatment of Alzheimer’s disease
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In this study, novel indolotacrine analogues have been designed, synthesized and evaluated as potential drugs for the treatment of Alzheimer’s disease. Based on a multi-target-directed ligand approach, novel compounds have been designed to act simultaneously as cholinesterase and monoamine oxidase (MAO) inhibitors. Prepared compounds were also evaluated for their antioxidant, cytotoxic, hepatotoxic and permeability (Blood-Brain Barrier penetration) properties. Indolotacrine 9b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment being a potent inhibitor of acetylcholinesterase (IC50 = 1.5 µM), butyrylcholinesterase (IC50 = 2.4 µM) and monoamine oxidase A (IC50 = 0.49 µM) and a weak inhibitor of monoamine oxidase B (IC50 = 53.9 µM). Although its cytotoxic (IC50 = 5.5 ± 0.4 µM) and hepatotoxic (IC50 = 1.22 ± 0.11 µM) profile is not as good as the standard 7-methoxytacrine (IC50 = 63 ± 4 µM and IC50 = 11.50 ± 0.77 µM respectively), the overall improvement in the inhibitory activities and potential to cross blood-brain barrier make indolotacrine 9b a promising lead compound for further development and investigation.
Benek , O , Soukup , O , Pasdiorova , M , Hroch , L , Sepsova , V , Jost , P , Hrabinova , M , Jun , D , Kuca , K , Zala , D , Ramsay , R R , Marco-Contelles , J & Musilek , K 2016 , ' Design, synthesis and in vitro evaluation of indolotacrine analogues as multi-target-directed ligands for the treatment of Alzheimer’s disease ' , ChemMedChem , vol. 11 , no. 12 , pp. 1264 -1269 . https://doi.org/10.1002/cmdc.201500383
©2016, WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://dx.doi.org/10.1002/cmdc.201500383
DescriptionThis publication was supported by the project Czech National Institute of Mental Health (NIMH – CZ; no. ED2.1.00/03.0078), Ministry of Education, Youth and Sports of the Czech Republic (no. LD14009), MH CZ - DRO (UHHK, 00179906), the University of Defence of the Czech Republic (long term development plan), MINECO (Government of Spain; Grant SAF2012-33304), the School of Biology at the University of St Andrews, and by COST Action CM1103.
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