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Review
. 2022 May 29;23(11):6085.
doi: 10.3390/ijms23116085.

Effects of Linkers and Substitutions on Multitarget Directed Ligands for Alzheimer's Diseases: Emerging Paradigms and Strategies

Narayanaperumal Pravin  1 , Krzysztof Jozwiak  1
Affiliations
Review

Effects of Linkers and Substitutions on Multitarget Directed Ligands for Alzheimer's Diseases: Emerging Paradigms and Strategies

Narayanaperumal Pravin et al. Int J Mol Sci. .

Abstract

Alzheimer's disease (AD) is multifactorial, progressive and the most predominant cause of cognitive impairment and dementia worldwide. The current "one-drug, one-target" approach provides only symptomatic relief to the condition but is unable to cure the disease completely. The conventional single-target therapeutic approach might not always induce the desired effect due to the multifactorial nature of AD. Hence, multitarget strategies have been proposed to simultaneously knock out multiple targets involved in the development of AD. Herein, we provide an overview of the various strategies, followed by the multitarget-directed ligand (MTDL) development, rationale designs and efficient examples. Furthermore, the effects of the linkers and substitutional functional groups on MTDLs against various targets of AD and their modes of action are also discussed.

Keywords: Alzheimer’s disease; amyloid-β-fibrils; cholinesterase; monoamine oxidase B; multitarget directed ligands.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Current cholinesterase inhibitors and Aβ inhibitors are in clinical use (with trade names in parentheses), together with the years in which they received approval by the FDA.
Figure 2
Figure 2
The major molecular targets in AD for MTDLs.
Figure 3
Figure 3
A schematic representation of the linked, fused and merged strategies in the MTDL designs.
Figure 4
Figure 4
(A) and (B) Representative structure of linked pharmacophores.
Figure 5
Figure 5
(A–C) Representative structure of fused pharmacophores.
Figure 6
Figure 6
(A) and (B) Representative structure of merged pharmacophores.
Figure 7
Figure 7
Examples of MTDLs for diverse AD targets.
Figure 8
Figure 8
(A) and (B) Chemical structures of pyrazolopyrimidinone-derived MTDLs.
Figure 9
Figure 9
(A–D) Chemical structures of donepezil-derived MTDLs for AD.
Figure 10
Figure 10
(A–C) Chemical structures of tacrine-derived MTDLs for AD.
Figure 11
Figure 11
(A) and (B) Chemical structures of rivastigmine-derived MTDLs for AD.
Figure 12
Figure 12
(A) and (B) Chemical structures of coumarin-derived MTDLs for AD.
Figure 13
Figure 13
(A–D) MTDLs are designed using computational approaches.
See this image and copyright information in PMC

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