Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors

Qian, Shuai; He, Lisi; Mak, Marvin; Han, Yifan; Ho, Chun‐Yu; Zuo, Zhong

doi:10.1016/j.ijpharm.2014.10.058

Cited by 23 publications

(13 citation statements)

References 61 publications

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“…The reason for this phenomenon is the pathogenesis of AD is that the acetylcholine in the central nervous system that promotes the decrease of the neurotransmitter level and causes dementia symptoms. Donepezil is a cholinesterase inhibitor, and in vitro studies have shown that donepezil has a cholinesterase inhibitory effect that is several times higher than that of butyrylcholinesterase (20). Therefore, the combined use of donepezil is helpful for improvement of the sensitivity of AD treatment.…”

Section: Discussionmentioning

confidence: 99%

Effect of donepezil on Hcy level in serum of Alzheimer's disease patients and correlation analysis of Hcy and dyssomnia

et al. 2018

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Effect of donepezil on the homocysteine (Hcy) level in serum of Alzheimer's disease (AD) patients and correlation between Hcy and dyssomnia was investigated. A retrospective analysis of 124 AD patients in Zhengzhou University People's Hospital between January 2015 and October 2017 was performed, including 64 cases in the observation group and 60 cases in the control group. The control group was treated with folic acid, vitamin B12 and memantine hydrochloride tablet, and the observation group combined with donepezil on this basis, and both groups were treated for 4 months. The Hcy level before and after treatment was detected in the groups using ELISA method, dyssomnia score of patients was performed before and after treatment in the observation group according to Pittsburgh Sleep Quality Index (PSQI), and correlation analysis between the Hcy level before and after treatment and dyssomnia was performed in AD patients in the study group using Pearson's correlation analysis. The differences were statistically significant in the Hcy level before and after treatment in both groups (P<0.001). The Hcy level after treatment in the observation group was significantly lower than that in the control group (P<0.001). The dyssomnia score before treatment was higher that after treatment in the observation group (P<0.001). There was a positive correlation between the Hcy level before treatment and dyssomnia score (r=0.658, P<0.001). There was also a positive correlation between the Hcy level after treatment and dyssomnia score (r=0.670, P<0.001). Donepezil can effectively improve the sleep function of patients and reduce the Hcy level in serum in the treatment of AD patients. The application of donepezil was of great significance in the clinical treatment of AD patients.

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Section: Discussionmentioning

confidence: 99%

Effect of donepezil on Hcy level in serum of Alzheimer's disease patients and correlation analysis of Hcy and dyssomnia

et al. 2018

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“…Ongoing molecular research is expected to lead to a true understanding of the disease’s pathogenesis. The neuropathological alterations described above suggest that the target at these factors could create the possible and effective treatment of AD [1,2].…”

Section: Introductionmentioning

confidence: 99%

Discovery of New Cyclopentaquinoline Analogues as Multifunctional Agents for the Treatment of Alzheimer’s Disease

Czarnecka

Girek

Kręcisz

et al. 2019

IJMS

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Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (3e) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, 3e compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase’s inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of 3e compound. A LogP assay confirmed that 3e compound fulfills Lipinsky’s rule of five

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“…These results indicated that piperazine linker was better choice to achieve high selectivity. Recently, a series of bistacrine homodimers (5a-f of Figure 3) with various linkers (alkyl, ether, amine or amide) between two tacrine moieties, were investigated for their pharmacological, pharmacokinetic and physicochemical properties [37]. Among them the 5c showed highest AChE inhibitory activity (IC 50 = 1.1 nM) and 213 fold selectivity over BChE (IC 50 = 234 nM).…”

Section: Tacrine Analogsmentioning

confidence: 99%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

AND

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Alzheimer's Disease (AD) is characterized by the loss of memory and learning ability in elderly patients affecting large population worldwide. The enzyme Acetylcholinesterase (AChE), (E.C.3.1.1.7) plays a major role in the hydrolysis of the released neurotransmitter acetylcholine. Most of the clinically used drugs to treat AD are Acetylcholinesterase Inhibitors (AChEIs). These drugs can provide symptomatic benefits only and suffer with loss of therapeutic potential with time. Therefore, there is an urgent need of novel cholinesterase inhibitors with wider therapeutic window for the treatment of AD. The strategies targeting the AChE enzyme along with other target(s) like Butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals (Cu 2+ , Zn 2+ , or Fe 2+), antioxidant properties and free radical scavenging capacity have been mainly focused in the last five years. A number of hybrid molecules incorporating sub-structures with the desired well-established pharmacological profile into a single scaffold have been investigated. The main sub structures used in developing these molecules are derived from diverse chemical classes such as acridine, quinoline, carbamates, huperzine and other heterocyclic analogs. It has been followed by optimization of activity through structural modifications of the prototype molecules for developing the Structure Activity Relationship (SAR). This has led to the development of novel molecules with desired AChE inhibitory activity along with other desirable pharmacological properties. This review summarizes the current therapeutic strategies for the development of these AChEI in the last seven years.

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Synthesis, biological activity, and biopharmaceutical characterization of tacrine dimers as acetylcholinesterase inhibitors

Cited by 23 publications

References 61 publications

Effect of donepezil on Hcy level in serum of Alzheimer's disease patients and correlation analysis of Hcy and dyssomnia

Effect of donepezil on Hcy level in serum of Alzheimer's disease patients and correlation analysis of Hcy and dyssomnia

Discovery of New Cyclopentaquinoline Analogues as Multifunctional Agents for the Treatment of Alzheimer’s Disease

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

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