TY - JOUR
T1 - Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease
AU - Hafez, Donia E.
AU - Dubiel, Mariam
AU - La Spada, Gabriella
AU - Catto, Marco
AU - Reiner-Link, David
AU - Syu, Yu Ting
AU - Abdel-Halim, Mohammad
AU - Hwang, Tsong Long
AU - Stark, Holger
AU - Abadi, Ashraf H.
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - Multitarget-directed ligands
KW - benzothiazole derivatives
KW - cholinesterase inhibitors
KW - histamine H receptor ligands
KW - monoamine oxidase inhibitors
KW - Acetylcholinesterase/metabolism
KW - Benzothiazoles/pharmacology
KW - Humans
KW - Structure-Activity Relationship
KW - Cholinesterase Inhibitors/pharmacology
KW - Monoamine Oxidase Inhibitors/pharmacology
KW - Alzheimer Disease/drug therapy
KW - Monoamine Oxidase/metabolism
KW - Ligands
UR - https://www.scopus.com/pages/publications/85148112640
U2 - 10.1080/14756366.2023.2175821
DO - 10.1080/14756366.2023.2175821
M3 - 文章
C2 - 36789662
AN - SCOPUS:85148112640
SN - 1475-6366
VL - 38
SP - 2175821
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
IS - 1
M1 - 2175821
ER -