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Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer's disease.

Authors :
Hafez, Donia E.
Dubiel, Mariam
La Spada, Gabriella
Catto, Marco
Reiner-Link, David
Syu, Yu-Ting
Abdel-Halim, Mohammad
Hwang, Tsong-Long
Stark, Holger
Abadi, Ashraf H.
Source :
Journal of Enzyme Inhibition & Medicinal Chemistry; Dec2023, Vol. 38 Issue 1, p1-23, 23p
Publication Year :
2023

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 H<subscript>3</subscript> receptor ligands (H<subscript>3</subscript>R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a K<subscript>i</subscript> value of 0.012 μM. The multitargeting potential of these H<subscript>3</subscript>R 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 K<subscript>i</subscript> value of 0.036 μM at H<subscript>3</subscript>R and IC<subscript>50</subscript> 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
14756366
Volume :
38
Issue :
1
Database :
Complementary Index
Journal :
Journal of Enzyme Inhibition & Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
174161133
Full Text :
https://doi.org/10.1080/14756366.2023.2175821