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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.

SUBMITTER: Gupta SM

PROVIDER: S-EPMC10476022 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Gupta Shraddha Manish SM Behera Ashok A Jain Neetesh K NK Tripathi Avanish A Rishipathak Dinesh D Singh Siddharth S Ahemad Nafees N Erol Meryem M Kumar Devendra D

RSC advances 20230904 38

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 (IC<sub>50</sub>: 4.16 ± 0.063 μM). IND-30 was found ...[more]

PMID: 37671344

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Project description:Methylxanthines and their derivatives are of great interest due to their diverse biological activities. In this work, a new series of twenty-eight semisynthetic theobromine and theophylline derived compounds were designed and synthesized by applying a simple and efficient strategy. First, the corresponding methylxanthine was reacted with a dibromoalkane (n = 3, 5-8) and subsequently, the brominated intermediate was reacted with an amine, including pyrrolidine, piperidine, diethylamine, methylpiperazine, 1-(2-aminoethyl)pyrrolidine, 1-(2-aminoethyl)piperidine, 2-(1-methylpyrrolidin-2-yl)ethanamine, 1-benzylpiperidin-4-amine, 1-benzylpiperidin-4-yl-methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine. The two synthetic steps were carried out in very short times using a microwave reactor. The biological activity of the new compounds was evaluated on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases (MAO-A, MAO-B) and beta-secretase (BACE-1). The majority of the new derivatives showed potent and selective in vitro AChE inhibition. Compounds 21, 28 and 30 exhibited the strongest effect on both electric eel and human AChE enzyme, with IC50 values on the low nanomolar scale. The kinetic study of compound 28 in hAChE displayed a mixed inhibition mechanism, suggesting a simultaneous interaction with both the CAS and PAS of the enzyme. This experimental binding mode is consistent with the results of docking and molecular dynamics modelling studies, where it was observed that the piperidinium fragment of 16, 21, 28 and 32 was located at the CAS, whereas the xanthine fragment of each inhibitor interacted with Trp286 in the PAS. These results indicate that these novel xanthine analogues act as selective and potent AChE inhibitors that could also prevent the precipitation of the aberrant Aβ peptide. These properties, in conjunction with their in silico good pharmacokinetic profiles, make these molecules promising lead compounds for the development of new effective drugs against several forms of dementia.

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

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

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