Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property
Graphical abstract
Introduction
Alzheimer’s disease (AD), a typical neurodegenerative brain disorder characteristic of dementia, cognitive decline, severe behavioral disturbances and loss of basic abilities in daily living, is established as the fourth leading cause of death in the western countries following cardiovascular disease, cancer, and cerebrovascular disease.1, 2 It is predicted that the number of the affected persons will reach 115.4 million worldwide by 2050.3 Despite much attention paid to this disease, no curable treatment was developed due to its multifactorial pathogenesis. Several hypotheses based on its pathogenic factors have been put forward, including the decrease of cholinergic neurotransmitter, amyloid beta (Aβ) accumulation, neurofibrillary tangles (NFTs), oxidative stress, metal ions irregulation,4, 5 and so on. Among all of the hypotheses, the cholinergic hypothesis has been successfully applied in the development of cholinesterase inhibitors (ChEIs), since the cognitive and memory disturbance is to some extent due to the decrease of acetylcholine (ACh). There is no doubt that ChEIs can promote the level of synaptic ACh between synaptic nicotinic and muscarinic receptors through inhibition of cholinesterases (ChEs),6 but these inhibitors cannot halt the progress of AD. Therefore only a palliative treatment effect can be obtained.
Traditionally, the “one molecule, one target” paradigm, which is so-called single-target molecule, can generally offer limited or transient benefits.7 Facing the multifactorial pathogenesis of AD, developing a molecule with multiple pharmacological effects is a promising strategy in the research for new anti-AD drugs. In our previous studies, we used tacrine (Fig. 1), a potent acetylcholinesterase inhibitor (AChEI) but suffering from serious hepatotoxicity and cholinergic side effects,8 as the lead compound to construct various hybrid molecules consisting of two or more pharmacophores in one molecule. We found such hybrid compounds could simultaneously target different pathogenic factors of AD and consequently achieve improved therapeutic effects, suggesting that this may be a promising drug design strategy.9, 10
Curcumin (Fig. 1), a well-known polyphenolic compound in Asian food ingredient turmeric, was reported to have many important biological activities, including anti-inflammatory, antimicrobial, and anti-carcinogenic activities.11 Encouragingly, substantial evidences also suggested its potential therapeutic effect on AD through binding to Aβ oligomers/fibrils and altering Aβ aggregation, thus reducing the Aβ-inducing neuron toxicity.12, 13 Besides, curcumin in monoanionic form could be stabilized by chelating metal ions.14 It was well literatured that the imbalance of trace elements, such as copper (Cu2+) and iron (Fe2+) ions, made amyloid precursor protein dysfunctional and increased the production of reactive oxygen species (ROS) and oxidative stress which was to some extent related to the progress of AD.15, 16, 17 More importantly, some reported hybrids of curcumin or its analogues conjugations showed multifunctional application in Alzheimer either in detection or in therapy.18, 19, 20, 21 Taking these unique biochemical activities in consideration, we tried to combine the pharmacophores of curcumin with tacrine to form multi-target molecules, hoping such compounds could not only inhibit AChE, but also eliminate excessive metal ions and ROS (Fig. 1). To our interest, this hypothesis was well proved in our studies.
Section snippets
Chemistry
The synthesis of F, L and K series was depicted in scheme 1. Tacrine and its derivatives were prepared using reported method (Scheme 1).22 To increase the yield of compounds D, the silica gel chromatogram that was pretreated with concentrated aqueous ammonia was applied for purification. The intermediate E was synthesized through a condensation reaction of compounds D with the protected compound 1b, which was further deprotected with p-toluenesulfonic acid monohydrate (PTSA) to give the target
Conclusion
In a conclusion, a series of tacrine and curcumin hybrids were designed and synthesized with the hypothesis to obtain multifunctional compounds that could simultaneously targets the ChE and Aβ pathways of AD. In Ellman’s assays, all of the synthesized compounds showed positive inhibitory effects both on AChE and BuChE. Particularly, the potency of K3-2 against AChE is even higher than that of tacrine, which is probably because K3-2 is a dual inhibitor towards both CAS and PAS of AChE.
General chemical methods
All of the reagents and solvents used were purchased from Sinopharm Chemical Reagent Co. The course of the reaction was monitored by thin layer chromatography (TLC) on glass plates coated with silica gel 60 GF254 from Qingdao Haiyang Chemical Co. Ltd. (China) with a UV lamp (254 nm). Melting points were determined using a capillary apparatus (RDCSY-I). IR spectra were measured on KBr pellets with a Nicolet IR200 FTIR spectrometer. All compounds synthesized were purified by column chromatography
Acknowledgments
This work is supported by Natural Science Foundation of Jiangsu Province (No. BK20151402) and the Fundamental Research Funds for the Central Universities (No. 3207045413). Dr. Fang is thankful to the support of the Open Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University.
References (31)
- et al.
Lancet
(2011) - et al.
Lancet
(2005) - et al.
Alzheimers Dement
(2013) - et al.
Lancet Neurol
(2003) - et al.
Lancet
(1989) - et al.
Bioorg Med Chem
(2016) - et al.
Bioorg Med Chem Lett
(2008) - et al.
Biochem Pharmacol
(2008) - et al.
J Biol Chem
(2005) - et al.
Trends Pharmacol Sci
(2009)
J Neurol Sci
Bioorg Med Chem
Neurobiol Dis
Sens Actuators, B Chem
Biochem Pharmacol
Cited by (37)
Curcumin hybrid molecules for the treatment of Alzheimer's disease: Structure and pharmacological activities
2024, European Journal of Medicinal ChemistrySynthesis, kinetic evaluation and molecular docking studies of donepezil-based acetylcholinesterase inhibitors
2022, Journal of Molecular StructureCitation Excerpt :Given the complex and multifactorial etiology of AD, this approach, also known as polypharmacology, can be highly beneficial for future AD therapeutic strategies. Many of these multitargeted efforts utilize acetylcholinesterase as one of the targets [19–21]. Therefore, there is clearly an interest for the development of new AChE inhibitors with improved potencies that can be used in future multitarget drug discoveries of novel AD therapeutics.
Synthesis, biological evaluation and modeling of hybrids from tetrahydro-1H-pyrazolo[3,4-b]quinolines as dual cholinestrase and COX-2 inhibitors
2020, Bioorganic ChemistryCitation Excerpt :Accordingly, the design of dual acting compounds capable of inhibiting both AChE and COX-2 could present a potential safe and effective treatment for AD. Resulting from the previous findings, it is our strategy (Fig. 1) in the present study to design a group of compounds having 4-phenyltetrahydroquinoline nucleus as anchoring fragment to AChE based on its structural similarity to tacrine [43–48]. A chloro substituent was introduced to the p-position of the phenyl ring due to its proven ability to improve the AChE inhibitory activity and reduce the hepatotoxicity that is usually associated with the use of tacrine and its related analogs [49–52].
Curcumin analogues and their hybrid molecules as multifunctional drugs
2019, European Journal of Medicinal ChemistryCitation Excerpt :Also, the compounds had good antioxidant activity due to their oxygen radical absorbance capacity due to the curcumin part effect. In addition, the compounds displayed in vitro positive metal ions-chelating ability [102]. Signal transducer and activator of transcription 3 (STAT3) is a type of potential cytosolic transcription factor.