Abstract

Abstract

Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional “one-target, one-molecule” approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 μM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 μM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.

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Graphical Abstract

Details

Title
Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease
Author
Hafez, Donia E 1 ; Dubiel, Mariam 2 ; Gabriella La Spada 3 ; Catto, Marco 3 ; Reiner-Link, David 2 ; Yu-Ting Syu 4 ; Abdel-Halim, Mohammad 1 ; Tsong-Long, Hwang 5 ; Stark, Holger 2 ; Abadi, Ashraf H 1 

1  Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo , Cairo , Egypt 
2  Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf , Duesseldorf , Germany 
3  Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro , Bari , Italy 
4  Graduate Institute of Natural Products, College of Medicine, Chang Gung University , Taoyuan , Taiwan 
5  Graduate Institute of Natural Products, College of Medicine, Chang Gung University , Taoyuan , Taiwan, Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology , Taoyuan , Taiwan, Department of Anesthesiology, Chang Gung Memorial Hospital , Taoyuan , Taiwan, Department of Chemical Engineering, Ming Chi University of Technology , New Taipei City , Taiwan 
Publication year
2023
Publication date
Dec 2023
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1080/14756366.2023.2175821
ProQuest document ID
2917549005
Copyright
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.. This work is licensed under the Creative Commons  Attribution – Non-Commercial License http://creativecommons.org/licenses/by-nc/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.