Premium
Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget‐Directed Ligands for the Treatment of Alzheimer's Disease
Author(s) -
Benek Ondrej,
Soukup Ondrej,
Pasdiorova Marketa,
Hroch Lukas,
Sepsova Vendula,
Jost Petr,
Hrabinova Martina,
Jun Daniel,
Kuca Kamil,
Zala Dominykas,
Ramsay Rona R.,
MarcoContelles José,
Musilek Kamil
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500383
Subject(s) - butyrylcholinesterase , ic50 , acetylcholinesterase , chemistry , cholinesterase , pharmacology , monoamine oxidase , in vitro , aché , blood–brain barrier , stereochemistry , biochemistry , enzyme , medicine , central nervous system
Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget‐directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood–brain barrier (BBB) permeability properties. Indolotacrine 9 b (9‐methoxy‐2,3,4,6‐tetrahydro‐1 H ‐indolo[2,3‐ b ]quinolin‐11‐amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC 50 : 1.5 μ m ), butyrylcholinesterase (BChE IC 50 : 2.4 μ m ) and MAO A (IC 50 : 0.49 μ m ), and it is also a weak inhibitor of MAO B (IC 50 : 53.9 μ m ). Although its cytotoxic (IC 50 : 5.5±0.4 μ m ) and hepatotoxic (IC 50 : 1.22±0.11 μ m ) profiles are not as good as those of the standard 7‐methoxytacrine (IC 50 : 63±4 and 11.50±0.77 μ m , respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.