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Hybridization‐based design of novel anticholinesterase indanone–carbamates for Alzheimer's disease: Synthesis, biological evaluation, and docking studies
Author(s) -
ShahrivarGargari Mohammad,
HamzehMivehroud Maryam,
Hemmati Salar,
Mojarrad Javid S.,
Tüylü Küçükkılınç Tuba,
Ayazgök Beyza,
Dastmalchi Siavoush
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000453
Subject(s) - butyrylcholinesterase , chemistry , acetylcholinesterase , pharmacophore , allosteric regulation , carbamate , stereochemistry , docking (animal) , enzyme , ic50 , lead compound , rational design , cholinesterase , donepezil , organophosphate , aché , combinatorial chemistry , biochemistry , pharmacology , in vitro , nanotechnology , medicine , dementia , materials science , nursing , disease , pathology , pesticide , agronomy , biology
Inspired by the structures of donepezil and rivastigmine, a novel series of indanone–carbamate hybrids was synthesized using the pharmacophore hybridization‐based design strategy, and their biological activities toward acetylcholinesterase (AChE) and butyrylcholinesterase were evaluated. Among the synthesized compounds, 4d and 4b showed the highest AChE inhibitory activities with IC 50 values in the micromolar range (compound 4d : IC 50 = 3.04 μM; compound 4b : IC 50 = 4.64 μM). Moreover, the results of the Aβ 1–40 aggregation assay revealed that compound 4b is a potent Aβ 1–40 aggregation inhibitor. The kinetics of AChE enzymatic activity in the presence of 4b was investigated, and the results were indicative of a reversible partial noncompetitive type of inhibition. A molecular docking study was conducted to determine the possible allosteric binding mode of 4b with the enzyme. The allosteric nature of AChE inhibition by these compounds provides the opportunity for the design of subtype‐selective enzyme inhibitors. The presented indanone–carbamate scaffold can be structurally modified and optimized through medicinal chemistry‐based approaches for designing novel multitargeted anti‐Alzheimer agents.