New Insights into the Development of Donepezil-Based Hybrid and Natural Molecules as Multi-Target Drug Agents for Alzheimer's Disease Treatment – PubMed Black Hawk Supplements

BLACK HAWK: Best lions mane supplement for memory

Published article

Alzheimer’s disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease’s progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In…
Black Hawk Supplements, best supplements in the UK

New Insights into the Development of Donepezil-Based Hybrid and Natural Molecules as Multi-Target Drug Agents for Alzheimer's Disease Treatment - PubMed

Review

New Insights into the Development of Donepezil-Based Hybrid and Natural Molecules as Multi-Target Drug Agents for Alzheimer’s Disease Treatment

Violina T Angelova et al. Molecules. .

Abstract

Alzheimer’s disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease’s progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer’s disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer’s disease treatment.

Keywords: Alzheimer’s disease; antioxidation; benzylpiperidine hybrids; beta-amyloid; cholinergic; donepezil analogs; melatonin; multi-target drugs; natural molecules; neuroinflammation; tau hyperphosphorylation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1

Current treatment options for Alzheimer’s disease.

Figure 2
Figure 2

Current anti-AD drugs approved by FDA/China. Aducanumab, lecanemab, and donanemab are monoclonal antibodies that target amyloid-beta plaques.

Figure 3
Figure 3

Hybrid multi-target therapeutic compounds addressing the multifaceted nature of Alzheimer’s disease (AD).

Figure 4
Figure 4

Donepezil possesses a chemical structure characterized by a bicyclic system that includes an indanone (or indole-like) ring connected to the N-benzylpiperidine ring, playing a crucial role in its pharmacological activity.

Figure 5
Figure 5

Natural compounds in clinical trials for AD treatment, 2008–2023 [115].

Figure 6
Figure 6

Melatonin (N-acetyl-5-methoxytryptamine), a tryptophan metabolite synthesized mainly in the pineal gland.

Figure 7
Figure 7

Structure of CBD. This compound mainly contains a cyclohexene ring, a phenolic ring, and a pentyl side chain in the structure.

Figure 8
Figure 8

Dronabinol, the synthetic form of delta-9-tetrahydrocannabinol (THC), is a psychoactive compound and primary active component found in cannabis.

Figure 9
Figure 9

The structure of curcumin with the chemical name of diferuloylmethane.

Figure 10
Figure 10

Structure of resveratrol, a natural polyphenolic compound.

Figure 11
Figure 11

Chemical structure of quercetin (3,3′,4′,5,7-pentahydroxyflavone). Quercetin has a polyphenolic structure characterized by two benzene rings (A and B) connected by a three-carbon chain that includes a ketone group.

Figure 12
Figure 12

Licochalcone A is a flavonoid compound derived from the roots of Glycyrrhiza uralensis (licorice) and has a unique chalcone structure, which differentiates it from other flavonoids.

Figure 13
Figure 13

Pinitol, a naturally occurring sugar alcohol, is a derivative of inositol, specifically known as 3-O-methyl-D-chiro-inositol.

References

    1. Peng Y., Jin H., Xue Y.-H., Chen Q., Yao S.-Y., Du M.-Q., Liu S. Current and future therapeutic strategies for Alzheimer’s disease: An overview of drug development bottlenecks. Front. Aging Neurosci. 2023;15:1206572. doi: 10.3389/fnagi.2023.1206572. – DOI – PMC – PubMed
    1. Better M.A. Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19:1598–1695. – PubMed
    1. Noorda K., Noorda K., Sabbagh M.N., Bertelson J., Singer J., Decourt B. Amyloid-Directed Antibodies: Past, Present, and Future. J. Alzheimer’s Dis. 2024;101:S3–S22. doi: 10.3233/JAD-240189. – DOI – PubMed
    1. Jin Y., Du Q., Song M., Kang R., Zhou J., Zhang H., Ding Y. Amyloid-β-targeting immunotherapies for Alzheimer’s disease. J. Control. Release. 2024;375:346–365. doi: 10.1016/j.jconrel.2024.09.012. – DOI – PubMed
    1. Yang Y., Wei S., Tian H., Cheng J., Zhong Y., Zhong X., Huang D., Jiang C., Ke X. Adverse event profile of memantine and donepezil combination therapy: A real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023. Front. Pharmacol. 2024;15:1439115. doi: 10.3389/fphar.2024.1439115. – DOI – PMC – PubMed

Publication types

MeSH terms

Substances

Grants and funding

BLACK HAWK: Best lions mane supplement for men

Read the original publication:

New Insights into the Development of Donepezil-Based Hybrid and Natural Molecules as Multi-Target Drug Agents for Alzheimer's Disease Treatment – PubMed