Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer's disease. (31st December 2023)

• Record Type: Journal Article
• 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.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 38:Number 1(2023)
• Publication Date: 2023-12-31
• Subjects: Multitarget-directed ligands -- Alzheimer's disease -- cholinesterase inhibitors -- histamine H3 receptor ligands -- monoamine oxidase inhibitors -- benzothiazole derivatives; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2023.2175821
• Languages: English
• ISSNs: 1475-6366

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 (H3 R). 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 H3 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 Ki value of 0.036 μM at H3 R 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. Graphical abstract: UF0001