Dataset Information

New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors.

ABSTRACT: A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC₅₀ values ranged 0.88 to 1.28 µM. The AChE enzyme kinetic study of 3-(4-phenylbutoxy)-9H-xanthen-9-one (23) and ethyl 2-((9-oxo-9H-xanthen-3-yl)oxy)acetate (28) showed a mixed inhibition mechanism. Molecular docking study showed that 23 binds to the active site of AChE and interacts via extensive π-π stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and π-π interaction with the phenol side chain of Y72. This study revealed that 3-O-alkoxyl substituted xanthone derivatives are potential lead structures, especially 23 and 28 which can be further developed into potent AChE inhibitors.

SUBMITTER: Loh ZH

PROVIDER: S-EPMC8759733 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors.

Loh Zi Han ZH Kwong Huey Chong HC Lam Kok Wai KW Teh Soek Sin SS Ee Gwendoline Cheng Lian GCL Quah Ching Kheng CK Ho Anthony Siong Hock ASH Mah Siau Hui SH

Journal of enzyme inhibition and medicinal chemistry 20211201 1

A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC50 values ranged 0.88 to 1.28 µM. The ACh ...[more]

PMID: 33557647

Similar Datasets

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.

Dataset Information

New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors.

Publications

New 3-<i>O</i>-substituted xanthone derivatives as promising acetylcholinesterase inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets