TY - JOUR
T1 - In silico studies, synthesis and pharmacological evaluation to explore multi-targeted approach for imidazole analogues as potential cholinesterase inhibitors with neuroprotective role for Alzheimer's disease
AU - Gurjar, Archana S.
AU - Darekar, Mrunali N.
AU - Yeong, Keng Yoon
AU - Ooi, Luyi
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.
AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.
KW - 2-Substituted-4,5-diphenyl-1H-imidazole
KW - Acetylcholinesterase
KW - In vitro antioxidant assay
KW - In vitro Ellman assay
KW - Molecular docking
UR - http://www.scopus.com/inward/record.url?scp=85041675526&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2018.01.029
DO - 10.1016/j.bmc.2018.01.029
M3 - Article
C2 - 29429576
AN - SCOPUS:85041675526
SN - 0968-0896
VL - 26
SP - 1511
EP - 1522
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
IS - 8
ER -