Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer's treatment

Shraddha Manish Gupta; Ashok Behera; Neetesh K. Jain; Avanish Tripathi; Dinesh Rishipathak; Siddharth Singh; Nafees Ahemad; Meryem Erol; Devendra Kumar

doi:10.1039/d3ra03224h

Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer's treatment

Shraddha Manish Gupta, Ashok Behera, Neetesh K. Jain, Avanish Tripathi, Dinesh Rishipathak, Siddharth Singh, Nafees Ahemad, Meryem Erol, Devendra Kumar

Malaysia Sch of Pharmacy

Research output: Contribution to journal › Article › Research › peer-review

6 Citations (Scopus)

Abstract

Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Aβ) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Aβ and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC₅₀: 4.16 ± 0.063 μM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Aβ aggregation at 0.5, 10 and 20 μM doses. Approximately, 50% of AChE-induced Aβ aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.

Original language	English
Pages (from-to)	26344-26356
Number of pages	13
Journal	RSC Advances
Volume	13
Issue number	38
DOIs	https://doi.org/10.1039/d3ra03224h
Publication status	Published - 4 Sept 2023

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title = "Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer's treatment",

abstract = "Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Aβ) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Aβ and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC50: 4.16 ± 0.063 μM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Aβ aggregation at 0.5, 10 and 20 μM doses. Approximately, 50\% of AChE-induced Aβ aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.",

author = "Gupta, \{Shraddha Manish\} and Ashok Behera and Jain, \{Neetesh K.\} and Avanish Tripathi and Dinesh Rishipathak and Siddharth Singh and Nafees Ahemad and Meryem Erol and Devendra Kumar",

note = "Funding Information: We gratefully acknowledge UPES, IIT-BHU, Monash University, DIT University, High Performance and Grid Computing Centre (TRUBA) of T{\"U}BİTAK (Scientific and Technological Research Council of Turkey) and ULAKBİM (Turkish Academic Network and Information Centre) for providing the facility to carry out all computational work. Publisher Copyright: {\textcopyright} 2023 The Royal Society of Chemistry.",

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doi = "10.1039/d3ra03224h",

language = "English",

volume = "13",

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TY - JOUR

T1 - Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer's treatment

AU - Gupta, Shraddha Manish

AU - Behera, Ashok

AU - Jain, Neetesh K.

AU - Tripathi, Avanish

AU - Rishipathak, Dinesh

AU - Singh, Siddharth

AU - Ahemad, Nafees

AU - Erol, Meryem

AU - Kumar, Devendra

N1 - Funding Information: We gratefully acknowledge UPES, IIT-BHU, Monash University, DIT University, High Performance and Grid Computing Centre (TRUBA) of TÜBİTAK (Scientific and Technological Research Council of Turkey) and ULAKBİM (Turkish Academic Network and Information Centre) for providing the facility to carry out all computational work. Publisher Copyright: © 2023 The Royal Society of Chemistry.

PY - 2023/9/4

Y1 - 2023/9/4

N2 - Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Aβ) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Aβ and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC50: 4.16 ± 0.063 μM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Aβ aggregation at 0.5, 10 and 20 μM doses. Approximately, 50% of AChE-induced Aβ aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.

AB - Leading pathological markers of Alzheimer's disease (AD) include Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Amyloid beta (Aβ) and reactive oxygen species (ROS). Indole derivatives were identified and optimized to improve the potency against AChE, BuChE, Aβ and ROS. The lead molecule IND-30 was found to be selective for AChE (selectivity ratio: 22.92) in comparison to BuChE and showed maximum inhibition potential for human AChE (IC50: 4.16 ± 0.063 μM). IND-30 was found to be safe on the SH-SY5Y cell line until the dose of 30 mM. Further, molecule IND-30 was evaluated for its ability to inhibit AChE-induced Aβ aggregation at 0.5, 10 and 20 μM doses. Approximately, 50% of AChE-induced Aβ aggregation was inhibited by IND-30. Thus, IND-30 was found to be multitargeting for AD.

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DO - 10.1039/d3ra03224h

M3 - Article

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EP - 26356

JO - RSC Advances

JF - RSC Advances

IS - 38

ER -

Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer's treatment

Abstract

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