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Tacrine Derivatives and Alzheimers Disease
Abstract
To date, the pharmacotherapy of Alzheimer's disease (AD) has relied on acetylcholinesterase (AChE) inhibitors (AChEIs) and, more recently, an N-methyl-D-aspartate receptor (NMDAR) antagonist. AD is a multifactorial syndrome with several target proteins contributing to its etiology. "Multi-target-directed ligands" (MTDLs) have great potential for treating complex diseases such as AD because they can interact with multiple targets. The design of compounds that can hit more than one specific AD target thus represents an innovative strategy for AD treatment. Tacrine was the first AChEI introduced in therapy. Recent studies have demonstrated its ability to interact with different AD targets. Furthermore, numerous tacrine homo- and heterodimers have been developed with the aim of improving and enlarging its biological profile beyond its ability to act as an AChEI. Several tacrine hybrid derivatives have been designed and synthesized with the same goal. This review will focus on and summarize the last two years of research into the development of tacrine derivatives able to hit AD targets beyond simple AChE inhibition.
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“In spite of that, thanks to its low-molecular weight and high synthetic accessibility, 16 has been widely exploited as a starting fragment of hybrids able to combine AChE inhibition with other additional effects and endowed with reduced hepatotoxicity.91”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [91]
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Chakhari, S., Marco, J. L., Iriepa, I., Carreiras, M. C., Chabchoub, F., Ismaïli, L., & Refouvelet, B. (2025) · Molecules · doi:10.3390/molecules30193930 · Cited by 3
“In addition to these features, oxidative stress and dysregulation of essential biometal homeostasis, including copper, iron, and zinc, play significant roles in the progression of AD [3–5].”
Eslami, M., Hashemianzadeh, S. M., Moghaddam, K. G., Khorsandi, L., & Sajadi, S. A. S. (2015) · RSC Advances · doi:10.1039/c5ra11346f · Cited by 3
Hara, Y., & Kawabe, H. (2019) · Springer eBooks · doi:10.1007/978-981-13-8906-1_11 · Cited by 3
Petrov, W., Ślebioda, D., Kozińska, R. B., Kukla, K., Petrov, P., Sroka, M., Tesyna, J., Puźniak, G., Kudliński, M., Rejda, T., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27135733 · Cited by 4
“Consequently, this results in an increased concentration of ACh at synapses and an improvement of cognitive function [32,35,38,43,44].”
InfluentialAN IN SILICO EVALUATION OF COCCINIA GRANDIS FRUITS AGAINST ALZHEIMERS DISEASE
Shalini, G., Ravikumar, P., & Jeyam, M. (2014) · Journal of Pharmaceutical and Scientific Innovation · doi:10.7897/2277-4572.034166 · Cited by 2
Grishchenko, M. V., Elkina, N. А., Махаева, Г. Ф., et al. (2022) · Russian Journal of General Chemistry · doi:10.1134/s1070363222110093 · Cited by 2
Lima, C. C., Silva, D. S. N., & de Sá, É. R. A. (2022) · OALib · doi:10.4236/oalib.1108469 · Cited by 1
“In addition, tacrine has also been discontinued in the United States because of its problem with toxicity [16] [17].”
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Nanotechnological Applications in the Diagnosis and Treatment of Alzheimer’s Dementia
Singh, P. N. D., Mishra, G., Pottoo, F. H., Zeleke, M. M., & Ewunetei, A. (2022) · Springer eBooks · doi:10.1007/978-981-16-7606-2_22 · Cited by 1
Strategies for Multi‐target Drug Discovery
Shi, D., & Li, X. (2024) · Wiley eBooks · doi:10.1002/9781394182862.ch16 · Cited by 2
Alzheimer mit Hybridmolekülen in die Zange nehmen
Decker, M. W., & Wehle, S. (2013) · Nachrichten aus der Chemie · doi:10.1002/nadc.201390272
Đào, T. T., Son, T. T., Vi, N. T. C., Trí, L. M., & Minh, T. K. (2017) · Y HOC TP HO CHI MINH · doi:10.32895/ump.mpr.1.1.15/suffix · Cited by 1
New Tacrine derivatives and Tacrine-Chitosan systems for application against degenerative diseases
Carrillo, A. J. G., Franconetti-García, A., & Cabrera‐Escribano, F. (2019) · International Electronic Conference on Synthetic Organic Chemistry (ECSOC) · doi:10.3390/ecsoc-23-06499
Current awareness in geriatric psychiatry
(2010) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2400
Synthesis, Docking, and Biological Studies of Pyrazine Derivatives as Antimycobacterial Agents
Gangarapu, N. R., Ranganatham, A., Reddy, E. K., Kumar, C. K., Yellappa, S., Chandrasekhar, K. B., & Manickan, E. (2024) · Medicinal Chemistry · doi:10.2174/0115734064337815241115050020
Ma, C. J. (2025) · Natural Product Sciences · doi:10.20307/nps.2025.31.1.55
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Prabakaran, A., Sivaperuman, A., Natarajan, R., Nagarajan, N. C., & Solomon, V. R. (2026) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/0113895575422492251116190843 · Cited by 1
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Small Molecules as Anti-Alzheimer’s Scaffolds
Hazra, R., Roy, S., Gayen, S., Parui, A., Arshad, A., Roy, N., & Sarkar, A. N. (2026) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9798898815646126010013
Metadata
- Authors
- Tumiatti, V., Minarini, A., Bolognesi, M. L., Milelli, A., Rosini, M., & Melchiorre, C.
- Affiliations
- University of Bologna (IT)
- Corresponding author
- Rosini, M.
- Melchiorre, C.
- Venue
- Current Medicinal Chemistry
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2010-06-01
- Volume
- 17
- Issue
- 17
- Pages
- 1825-1838
- ISSN
- 0929-8673 (ISSN-L)
- OpenAlex
- W2121322934
- Cited by
- 225
- References
- 0
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 8 · 2023: 4 · 2022: 18 · 2021: 14 · 2020: 13 · 2019: 28 · 2018: 12 · 2017: 22 · 2016: 19 · 2015: 16 · 2014: 17 · 2013: 14 · 2012: 12
- FWCI
- 9.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Keywords
- tacrine derivatives, Alzheimer's disease, acetylcholinesterase inhibitors, multi-target-directed ligands, NMDA receptor antagonists, drug repurposing
- MeSH terms
- Acetylcholinesterase, Alzheimer Disease, Cholinesterase Inhibitors, Humans, Models, Molecular, Structure-Activity Relationship, Tacrine, Amyloid beta-Peptides
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