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

Donia E. Hafez; Mariam Dubiel; Gabriella La Spada; Marco Catto; David Reiner-Link; Yu Ting Syu; Mohammad Abdel-Halim; Tsong Long Hwang; Holger Stark; Ashraf H. Abadi

doi:10.1080/14756366.2023.2175821

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

Donia E. Hafez
, Mariam Dubiel
, Gabriella La Spada
, Marco Catto
, David Reiner-Link
, Yu Ting Syu
, Mohammad Abdel-Halim^*
, Tsong Long Hwang^*
, Holger Stark
, Ashraf H. Abadi^*

^*Corresponding author for this work

School of Traditional Chinese Medicine

Research output: Contribution to journal › Journal Article › peer-review

37 Scopus citations

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 K_i 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 K_i 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.

Original language	English
Article number	2175821
Pages (from-to)	2175821
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	38
Issue number	1
DOIs	https://doi.org/10.1080/14756366.2023.2175821
State	Published - 12 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

Alzheimer’s disease
Multitarget-directed ligands
benzothiazole derivatives
cholinesterase inhibitors
histamine H receptor ligands
monoamine oxidase inhibitors
Acetylcholinesterase/metabolism
Benzothiazoles/pharmacology
Humans
Structure-Activity Relationship
Cholinesterase Inhibitors/pharmacology
Monoamine Oxidase Inhibitors/pharmacology
Alzheimer Disease/drug therapy
Monoamine Oxidase/metabolism
Ligands

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1080/14756366.2023.2175821

Cite this

Hafez, D. E., Dubiel, M., La Spada, G., Catto, M., Reiner-Link, D., Syu, Y. T., Abdel-Halim, M., Hwang, T. L., Stark, H., & Abadi, A. H. (2023). Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease. Journal of Enzyme Inhibition and Medicinal Chemistry, 38(1), 2175821. Article 2175821. https://doi.org/10.1080/14756366.2023.2175821

@article{97ad1dcbca344b97bd655012e413d9df,

title = "Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer{\textquoteright}s disease",

abstract = "Neurodegenerative diseases such as Alzheimer{\textquoteright}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.",

keywords = "Alzheimer{\textquoteright}s disease, Multitarget-directed ligands, benzothiazole derivatives, cholinesterase inhibitors, histamine H receptor ligands, monoamine oxidase inhibitors, Acetylcholinesterase/metabolism, Benzothiazoles/pharmacology, Humans, Structure-Activity Relationship, Cholinesterase Inhibitors/pharmacology, Monoamine Oxidase Inhibitors/pharmacology, Alzheimer Disease/drug therapy, Monoamine Oxidase/metabolism, Ligands",

author = "Hafez, \{Donia E.\} and Mariam Dubiel and \{La Spada\}, Gabriella and Marco Catto and David Reiner-Link and Syu, \{Yu Ting\} and Mohammad Abdel-Halim and Hwang, \{Tsong Long\} and Holger Stark and Abadi, \{Ashraf H.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Informa UK Limited, trading as Taylor \& Francis Group.",

year = "2023",

month = dec,

doi = "10.1080/14756366.2023.2175821",

language = "英语",

volume = "38",

pages = "2175821",

journal = "Journal of Enzyme Inhibition and Medicinal Chemistry",

issn = "1475-6366",

publisher = "Taylor and Francis Ltd.",

number = "1",

}

Hafez, DE, Dubiel, M, La Spada, G, Catto, M, Reiner-Link, D, Syu, YT, Abdel-Halim, M, Hwang, TL, Stark, H & Abadi, AH 2023, 'Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease', Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 38, no. 1, 2175821, pp. 2175821. https://doi.org/10.1080/14756366.2023.2175821

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.

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 -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this