Development of multi-targetable chalcone derivatives bearing N-aryl piperazine moiety for the treatment of Alzheimer's disease.

Autor: Bajad NG; Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India., Singh RB; Institute of Pharmacy, Harish Chandra PG College, Varanasi, India., T A G; Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India., Gutti G; Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India., Kumar A; Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India., Krishnamurthy S; Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India., Singh SK; Pharmaceutical Chemistry Research Laboratory I, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi - 221005, India. Electronic address: sksingh.phe@iitbhu.ac.in.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Feb; Vol. 143, pp. 107082. Date of Electronic Publication: 2024 Jan 02.
DOI: 10.1016/j.bioorg.2023.107082
Abstrakt: The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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