Synthesis and molecular modeling studies of 1-benzyl-2-indolinones as selective AChE inhibitors
Possible bioisosteres can be developed by replacing the 1-indanone ring (one of three pharmacophore groups) of donepezil with an indoline ring. As H S donors, thioamide, thiocarbamate and thiourea groups are also critically important. The 1-benzyl-2-indolinones were designed using molecular modeling...
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Published in | Future medicinal chemistry Vol. 14; no. 23; pp. 1705 - 1723 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
England
Newlands Press Ltd
01.12.2022
|
Subjects | |
Online Access | Get full text |
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Summary: | Possible bioisosteres can be developed by replacing the 1-indanone ring (one of three pharmacophore groups) of donepezil with an indoline ring. As H
S donors, thioamide, thiocarbamate and thiourea groups are also critically important.
The 1-benzyl-2-indolinones
were designed using molecular modeling and synthesized, and their acetylcholinesterase and butyrylcholinesterase inhibitory effects were then investigated.
The compounds
(inhibition constant [
] = 0.22 μM; selectivity index [SI] = 26.22),
(
= 0.24 μM; SI = 25.83),
(
= 0.22 μM; SI = 28.31) and
(
= 0.21 μM; SI = 27.14) were approximately twofold more effective against and >12-fold more selective for acetylcholinesterase compared with donepezil (
= 0.41 μM; SI = 2.12). Analysis of molecular dynamics simulations with compounds
and
indicated that the preferred binding might be at allosteric binding pocket 4 of the enzyme.
Benzyl substitution at the 1-position of the indole ring significantly increased potency and selectivity. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1756-8919 1756-8927 |
DOI: | 10.4155/fmc-2022-0139 |