METABOLIC BRAIN DISEASE
·
2018
·Vol. 34
·期 1
·173-181
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IF 2.441
Sun Kaiyue,Bai Yuting,Zhao Rong,Guo Zijiao,Su Xiang,Li Peiqi,Yang Pengyu
The present study was designed to evaluate the effects of matrine (MAT) on scopolamine (SCOP)-induced learning and memory impairment. After successive oral administration of MAT to mice for three days at doses of 0.4, 2, and 10 mg/kg, we assessed improvements in learning and memory and investigated the mechanism of action of SCOP-induced amnesia. Donepezil at a dose of 3 mg/kg was used as a standard memory enhancer. MAT significantly improved SCOP-induced learning and memory impairment in novel object recognition and Y-maze tests at doses of 0.4, 2, and 10 mg/kg. Furthermore, MAT inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and decreased oxidative stress in the brain, as evidenced by increased total antioxidant capacity, total superoxide dismutase levels, and catalase activities as well as decreased malondialdehyde levels. Additionally, there was a significant negative correlation between the percentage of spontaneous alternation in the Y maze and AChE activity in the cortex and hippocampus. MAT ameliorated SCOP-induced amnesia by the inhibition of both AChE/BuChE activities and oxidative stress. This study provides further evidence to encourage the development of MAT as a drug for the prevention or treatment of Alzheimer’s disease.
研究领域:
神经科学
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药理学
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阿尔茨海默病研究
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2016
·Vol. 21
·期 2
·132
·
IF 2.465
Zeng Li,Chaoyu Mu,Bin Wang,Juan Jin
This study designed and synthesized a series of new graveoline analogs on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of these analogs was also evaluated. Results showed that the synthesized graveoline analogs displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (Selectivity Index from 45 to 486). When the two sites in the graveoline parent ring substituting phenyl and amino terminal had six chemical bonds (n= 3) and the terminal amino was piperidine, compound5cshowed the best activity. Furthermore, the mechanism of action and binding mode were explored by enzyme kinetic simulation, molecular docking, and thioflavin T-based fluorometric assay. Cytotoxicity assay showed that the low concentration of the analogs did not affect the viability of the neurocyte SH-SY5Y.Keywords:graveoline analogs;acetylcholinesterase (AChE);butyrylcholine esterase (BuChE);structure–function relationships (SARs);mechanism
研究领域:
神经科学
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药物化学
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老年医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2026
·
IF 5.3
Chengyao Wu,Yulu Ding,Xiaodan Liu,Shan Gao,Xiaoqing Wang,Wenjian Tang
Thymol, an isomer of carvacrol, exhibits anti-Aβ activity. Thymol carbamates were designed, and their inhibition on cholinesterase (ChE) activity was assessed and analysed, among them, TC-4, TC-6, H4 and H5 bearing cyclic amines exhibited nanomolar inhibitory activity with IC50 values of 13, 3.6, 47, and 12 nM. TC-6 bearing a piperidinyl moiety demonstrated nanomolar hBuChE inhibition (IC50 = 3.6 nM), >2,500-fold selectivity over hAChE, and pseudo-irreversible kinetics (Kd = 0.25 μM, k2 = 0.98 min−1). TC-6 exhibited low cytotoxicity, crossed the blood-brain barrier, and protected neurons against H2O2-induced damage. In Aβ1-42-induced AD mice, TC-6 (10 mg/kg) greatly enhanced cognitive abilities in MWM tests, reduced brain Aβ levels, and restored hippocampal neuron density. These results highlight TC-6 as a potent, brain-penetrant BuChE inhibitor with therapeutic potential for AD.
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DOI
PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2022
·
IF 5.756
Huan-Huan Li,Chengyao Wu,Shi-Long Zhang,Jian-Guo Yang,Hua-Li Qin,Wenjian Tang
Novel scaffolds are expected to treat Alzheimer’s disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1–K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC50 = 0.79 μM and 6.59 μM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (Ki = 0.77 μM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aβ1 − 42-induced cognitive impairment, and significantly prevented the effects of Aβ1 − 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.
研究领域:
药理学
·
神经科学
·
药物化学
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DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 17
·3489
·
IF 4.6
Xiaohua Wang,Minglan Ma,Yalan Feng,Jian Liu,Gang Wang
A novel series of multifunctional tacrine–quinoline hybrids were designed, synthesized, and evaluated as potential anti-Alzheimer’s agents. These compounds incorporate tacrine for cholinesterase’s inhibition and 8-hydroxyquinoline for metal chelation. Piperazine was selected as a linker to provide conformational flexibility and to create favorable cation–π interactions with residues in the mid-gorge region of AChE, enhancing dual-site binding with AChE to inhibit Aβ aggregation. In vitro studies demonstrated submicromolar inhibitory activity toward both AChE and BuChE, particularly for compounds16e(IC50= 0.10 μM for AChE, 0.043 μM for BuChE) and16h(IC50= 0.21 μM for AChE, 0.10 μM for BuChE). These compounds also exhibited potent inhibition of self-induced Aβ1–42aggregation (16e: 80.5% ± 4.4%, 16h: 93.2% ± 3.9% at 20 μM). Kinetic analyses revealed mixed-type inhibition, suggesting dual binding to both CAS and PAS of AChE. UV–vis spectrometry confirmed the chelation of Cu2+and Zn2+ions by the 8-hydroxyquinoline moiety. These findings highlight the tacrine–quinoline scaffold as a promising platform for the discovery of a multitarget-directed anti-AD drug.
研究领域:
药物化学
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神经药理学
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生物有机化学
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药物设计
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阿尔茨海默病研究
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 6.514
Xia Jiang,Ziwen Zhang,Jiawei Zuo,Chengyao Wu,Liang Zha,Yingying Xu,Sheng Wang,Jingbo Shi,Xin-Hua Liu,Jing Zhang,Wenjian Tang
Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC 50 = 5.3 nM, SI > 4000), superior to CBD (IC 50 = 0.67 μM). C16 possessed BBB penetrating ability, benign safety, neuroprotection , antioxidant and pseudo-irreversible BuChE inhibition ( K d = 13 nM, k 2 = 0.26 min −1 ), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the A β 1−42 (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD .
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2020
·
IF 4.831
Shaochun Shi,Huibin Wang,Jian Wang,Yvxi Wang,Xiaobian Xue,Zilin Hou,Guo-Dong Yao,Xiao-Xiao Huang,Hongwei Zhao,Qingbo Liu,Shao-Jiang Song
7- O -galloyltricetiflavan (GTF), a natural flavonoid, is known to exert anti-oxidation and neuroprotective activity, which are related to the prevention of Alzheimer’s disease (AD). In this study, three series of GTF hybrids have been designed, synthesized and evaluated as multifunctional agents for treatment AD. The biological assays indicated that most of them showed strong inhibitory effect on self-induced β -amyloid (A β ) aggregation, and a significant ability to inhibit ChEs. Among them, compound A15 exhibited best inhibition of A β aggregation (78.81% at 20 μM), potent AChE inhibitory potencies (IC 50 , 0.56 μM), and compound C4 presented the highest ability to inhibit BuChE (IC 50 , 5.77 μM). Furthermore, kinetic, molecular modeling and molecular dynamics studies revealed that A15 and C4 could interact with the catalytic active site of AChE and BuChE, respectively. In addition, compounds A15 and C4 could cross the blood–brain barrier in vitro. More importantly, A15 and C4 also showed excellent neuroprotective activities against H 2 O 2 -induced human neuroblastoma SH-SY5Y cells damage and nearly no toxicity on SH-SY5Y cells. All of these outstanding in vitro results indicated A15 and C4 as the leading structure worthy of further investigation.
研究领域:
药理学
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神经科学
·
药物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2019
·
IF 4.027
Yu-Heng Hu,Jie Yang,Yun Zhang,Ke-Chun Liu,Teng Liu,Jie Sun,Xiao-Jing Wang
The work is focused on the design of drugs that prevent and treat Alzheimer’s disease (AD) and its complications. A series of 3–(4-aminophenyl)-coumarin derivatives designed, synthesised, fully characterised and evaluated in vitro/vivo. The biological assay experiments showed that some compounds displayed a clearly selective inhibition for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among all compounds, compound 4m exhibited the highest AChE inhibition with an IC50 value of 0.091 ± 0.011 µM and compound 4k exhibited the highest BuChE inhibition with an IC50 value of 0.559 ± 0.017 µM. A zebrafish behaviour analyser (Zebrobox) was used to determine the behavioural effects of the active compound on the movement distance of the aluminium chloride-induced zebrafish. Compound 4m offered a potential drug design concept for the development of therapeutic or preventive agents for AD and its complications.
研究领域:
药理学
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神经科学
·
药物设计
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DOI
PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2021
·
IF 5.051
Chengyao Wu,Guijuan Zhang,Zai-Wei Zhang,Xia Jiang,Ziwen Zhang,Huanhuan Li,Hua-Li Qin,Wenjian Tang
To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; –OCH3 > –CH3 > –Cl (–Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aβ1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aβ1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.
研究领域:
神经科学
·
药理学
·
药物化学
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DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2018
·
IF 2.881
Xin Lu,Si-yu He,Qi Li,Hongyu Yang,Xueyang Jiang,Hongzhi Lin,Yao Chen,Wei Qu,Feng Feng,Yaoyao Bian,You Zhou,Haopeng Sun
In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer’s disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine . Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer’s disease.
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产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2021
·
IF 3.512
Lin-Xi Wan,Yong-Qi Zhen,Zhen-Xiang He,Yang Zhang,Lan Zhang,Xiaohuan Li,Feng Gao,Xian-Li Zhou
A new series of N-aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald–Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, N-(4-(trifluoromethyl)phenyl)-tacrine (3g) and N-(4-methoxypyridin-2-yl)-tacrine (3o) showed the most potent activity against AChE (IC50 values of 1.77 and 1.48 μM, respectively). The anti-AChE activity of 3g and 3o was 3.5 times more than that of tacrine (IC50 value of 5.16 μM). Compound 3o also displayed anti-BuChE activity with an IC50 value of 19.00 μM. Cell-based assays against HepG2 and SH-SY5Y cell lines revealed that 3o had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in SH-SY5Y cells. The advantages including synthetic accessibility, high potency, low toxicity, and adjunctive neuroprotective activity make compound 3o a new promising multifunctional candidate for the treatment of Alzheimer’s disease.
研究领域:
药物化学
·
药理学
·
神经科学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2023
·
IF 3.8
Junjie Wang,Hui Zhou,Yang Li,Yeshu Mu,Jinghua Li,Chen Hong,Wen Luo
A novel series of benzo[ cd ]indol-2(1 H )-one-donepezil (BIO-DPZ) hybrids (5a-m, 6a-k) was designed, synthesized and evaluated as cholinesterase inhibitors and living cell imaging agents. These compounds were potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compound 6a exhibited the strongest inhibitory activity against AChE with an IC 50 value of 0.16 μM. Compound 6i had the strongest inhibition of BuChE with an IC 50 value of 5.37 μM. Kinetic and molecular modeling studies showed that 6a bound both catalytic active site and peripheral anionic site of AChE. Compounds 6a and 6i both showed lower SH-SY5Y, HepG2 and HL-7702 cytotoxicity than the mitoxantrone. Promisingly, the most active compound, 6a, was successfully used in living SH-SY5Y cell imaging and had predictable lipophilicity and blood-brain-barrier permeation properties. These hybrids should undergo further systematic study in the treatment of Alzheimer's disease.
研究领域:
药理学
·
神经科学
·
药物化学
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DOI
高影响因子
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