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Development of the "hidden" multifunctional agents for Alzheimer's disease
Wenhai Huang1, Meihao Liang2, Qin Li2
1Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, 310013, PR China; State Key Laboratory of Medicinal Chemical Biology, NanKai University, Tianjin, PR China.
Abstract:
Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-β (Aβ) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the "hidden" agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Aβ aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models.
Insights
Researchers developed a novel drug delivery system for Alzheimer's disease (AD) that conceals a metal chelator within an acetylcholinesterase (AChE) inhibitor. This multi-target approach effectively crosses the blood-brain barrier to treat AD pathology.
Area of Science:
- Neuroscience
- Medicinal Chemistry
- Pharmacology
Background:
- Alzheimer's disease (AD) involves complex pathologies including cholinergic dysfunction, metal dyshomeostasis, and amyloid-beta (Aβ) aggregation.
- Single-target agents are often insufficient for treating AD; thus, multi-target-directed ligands (MTDLs) are a promising therapeutic strategy.
- Developing MTDLs requires innovative design to address multiple AD pathological hallmarks simultaneously.
Purpose of the Study:
- To design and synthesize novel quinoline derivatives as multi-target agents for Alzheimer's disease.
- To develop an innovative drug delivery method by concealing a metal chelator within an acetylcholinesterase (AChE) inhibitor.
- To evaluate the efficacy of these compounds in vitro and in vivo for AD treatment.
Main Methods:
- Synthesis of 14 quinoline derivatives.
- Evaluation of compounds for blood-brain barrier (BBB) penetration.
- In vitro assessment of AChE inhibitory activity and metal ion chelating function.
- In vitro and in vivo studies on Aβ aggregation inhibition.
- In vivo efficacy testing in zebrafish and mouse models of AD.
Main Results:
- Compound 9b demonstrated efficient BBB crossing and released its metabolite, 8a, in the brain.
- Compound 9b exhibited potent AChE inhibition, while its metabolite 8a showed significant metal ion chelating properties.
- The combined action of 9b and 8a effectively inhibited Aβ aggregation.
- Compound 9b showed therapeutic efficacy in AD models.
Conclusions:
- The developed MTDL approach, where an AChE inhibitor acts as a carrier for a metal chelator, is a viable strategy for AD drug discovery.
- Compound 9b represents a promising multifunctional agent for Alzheimer's disease treatment.
- This innovative design enhances drug delivery and targets multiple AD pathologies.