Alzheimer＇s disease （AD）, a fatal, progressive, neurodegener- ative disorder, is the most common cause of old-age demen- tia, accounting for 50-75% of dementia patients. Early stages of AD are marked by vocabulary ...Alzheimer＇s disease （AD）, a fatal, progressive, neurodegener- ative disorder, is the most common cause of old-age demen- tia, accounting for 50-75% of dementia patients. Early stages of AD are marked by vocabulary shrinkage, spatial disori- entation, depression, apraxia, and deterioration of recent forms of declarative memory. In course of time, the patients require close supervision due to the loss of cognitive and functional abilities, and at the terminal stages of the disease, all forms of memory are severely impaired with the patients needing nursing home care （World Alzheimer Report, 2013）.展开更多
Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer＇s drugs. A series of 5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester derivatives as the novel acetylcholinesterase inhibito...Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer＇s drugs. A series of 5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester derivatives as the novel acetylcholinesterase inhibitors was designed based on virtual screening methods. The target compounds were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, ^1H NMR, and ^13C NMR. The biological evaluation against human acetylcholinesterase in vitro indicated all the target compounds show more than 50% inhibition at 10μmol/L by means of the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer＇s disease and lay the foundation of searching for improved acetylcholinesterase inhibitors with the novel scaffolds.展开更多
Our earlier work showed that hydromethanol extract(HME)of Pleurotus fl orida had antioxidant and anticholinesterase potential.This study aimed at isolating the constituent responsible for the activities.HME was subjec...Our earlier work showed that hydromethanol extract(HME)of Pleurotus fl orida had antioxidant and anticholinesterase potential.This study aimed at isolating the constituent responsible for the activities.HME was subjected to bioactivity guided fractionation using in vitro anti-acetylcholinesterase(Ellman method)and antioxidant(DPPH scavenging assay).The most active constituent was evaluated in vivo employing i.c.v.streptozotocin(STZ)induced dementia in mice.Morris water maze test was used for evaluating memory,followed by biochemical estimations and histopathological studies.Bioactivity guided fractionation resulted in isolation of resveratrol(identifi ed by IR,NMR and MS)and its content in P.fl orida fruiting bodies was 0.0098%(m/m,by a validated TLC densitometric method).It improved STZ induced dementia and neurodegeneration in mice by reducing brain acetylcholinesterase action and oxidative stress.The observed effects might be the presence of resveratrol.Our results further endorse that P.fl orida derived resveratrol can be a promising therapy for Alzheimer’s disease.展开更多
A dammarane derivative dihydrojujubogenin-2-en-1-one, which possesses a skeleton and pharmacophore partially similar to those of Territrem B, a potent AChE inhibitor, was synthesized via three different paths. The ant...A dammarane derivative dihydrojujubogenin-2-en-1-one, which possesses a skeleton and pharmacophore partially similar to those of Territrem B, a potent AChE inhibitor, was synthesized via three different paths. The anti-AChE activity of this compound and related analogue was measured.展开更多
A mimetic synthesis of a potent acetylcholinesterase inhibitor, Territrem B, was carried out from the naturally occurring jujubosides. The anti-AChE activity of the product, which possesses the 2-en-1-one pharmacophor...A mimetic synthesis of a potent acetylcholinesterase inhibitor, Territrem B, was carried out from the naturally occurring jujubosides. The anti-AChE activity of the product, which possesses the 2-en-1-one pharmacophore and the aromatic ring, was measured. The aromatic ring moiety seemed to be less influencing when comparing with the 2-en-1-one moiety.展开更多
Huntington's disease(HD) is a neurodegenerative disease associated with cognitive deficits. Cognitive dysfunction may be present in the early stages of the disease, even before the onset of motor symptoms. The cog...Huntington's disease(HD) is a neurodegenerative disease associated with cognitive deficits. Cognitive dysfunction may be present in the early stages of the disease, even before the onset of motor symptoms. The cognitive dysfunction includes executive dysfunction, psychomotor symptoms, visuospatial deficits, perceptual deficits, memory loss and difficulty learning new skills. Acetylcholinesterase inhibitors have shown good effect in the treatment of other types of dementia and it is postulated that it might delay cognitive decline in HD. We reviewed the evidence for Acetylcholinesterase inhibitors in the treatment of cognitive decline and dementia associated with Huntington's disease. We identified 6 articles that investigated the role of Acetylcholinesterase inhibitors for treatment of cognitive deficits in Huntington's disease. Following the review, the authors concluded that there is limited evidence for the use of Acetylcholinesterase inhibitors for cognitive impairment in HD.展开更多
With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses a...With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop multi-functional agents, which can mainly serve as dual BACE 1 and AChE inhibitors. Depending on the scaffolds of (+)-(S)- dihydro-ar-tumerone and (-)-gallocatechin gallate, 3 series of new compounds have been designed, synthesized and evaluated, from which we have identified 2-(2-(3-methylbenzoyl)-3-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl) isoindoline-1,3-dione (3d) as a new cholinesterase and β-secretase dual inhibitor without toxicity. Furthermore, 3d also exhibits hydrogen peroxide scavenging activity which could help to reduce the reactive oxygen species (ROS) in the brain of AD patients.展开更多
基金in part supported by the German Ministry for Education and Research (BMBF) special network program KMU-Innovativ-2
文摘Alzheimer＇s disease （AD）, a fatal, progressive, neurodegener- ative disorder, is the most common cause of old-age demen- tia, accounting for 50-75% of dementia patients. Early stages of AD are marked by vocabulary shrinkage, spatial disori- entation, depression, apraxia, and deterioration of recent forms of declarative memory. In course of time, the patients require close supervision due to the loss of cognitive and functional abilities, and at the terminal stages of the disease, all forms of memory are severely impaired with the patients needing nursing home care （World Alzheimer Report, 2013）.
文摘Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer＇s drugs. A series of 5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester derivatives as the novel acetylcholinesterase inhibitors was designed based on virtual screening methods. The target compounds were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, ^1H NMR, and ^13C NMR. The biological evaluation against human acetylcholinesterase in vitro indicated all the target compounds show more than 50% inhibition at 10μmol/L by means of the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer＇s disease and lay the foundation of searching for improved acetylcholinesterase inhibitors with the novel scaffolds.
基金The study was funded by University Grants Commission under UGC BSR fellowship scheme(Award no.F.4.25-1/2013-14(BSR)/7-265/2009(BSR))The authors are thankful to Prof.Nirmal Singh and Mr.Pankaj Bhatia,Department of Pharmaceutical Sciences and Drug Research,Punjabi University,Patiala,India for their help in carrying out animal studies.The authors are also thankful to DBTIPLS project(Grant no:BT/PR4548/INF/22/146/2012),Punjabi University,Patiala,Punjab,India for providing HPTLC facility and Department of Pharmaceutical Sciences and Drug Research,Punjabi University,Patiala,India for providing the necessary laboratory facilities for this work.
文摘Our earlier work showed that hydromethanol extract(HME)of Pleurotus fl orida had antioxidant and anticholinesterase potential.This study aimed at isolating the constituent responsible for the activities.HME was subjected to bioactivity guided fractionation using in vitro anti-acetylcholinesterase(Ellman method)and antioxidant(DPPH scavenging assay).The most active constituent was evaluated in vivo employing i.c.v.streptozotocin(STZ)induced dementia in mice.Morris water maze test was used for evaluating memory,followed by biochemical estimations and histopathological studies.Bioactivity guided fractionation resulted in isolation of resveratrol(identifi ed by IR,NMR and MS)and its content in P.fl orida fruiting bodies was 0.0098%(m/m,by a validated TLC densitometric method).It improved STZ induced dementia and neurodegeneration in mice by reducing brain acetylcholinesterase action and oxidative stress.The observed effects might be the presence of resveratrol.Our results further endorse that P.fl orida derived resveratrol can be a promising therapy for Alzheimer’s disease.
文摘A dammarane derivative dihydrojujubogenin-2-en-1-one, which possesses a skeleton and pharmacophore partially similar to those of Territrem B, a potent AChE inhibitor, was synthesized via three different paths. The anti-AChE activity of this compound and related analogue was measured.
基金National Science Council, China (Taipei) under grant !NSC 87-2314-002-005
文摘A mimetic synthesis of a potent acetylcholinesterase inhibitor, Territrem B, was carried out from the naturally occurring jujubosides. The anti-AChE activity of the product, which possesses the 2-en-1-one pharmacophore and the aromatic ring, was measured. The aromatic ring moiety seemed to be less influencing when comparing with the 2-en-1-one moiety.
文摘Huntington's disease(HD) is a neurodegenerative disease associated with cognitive deficits. Cognitive dysfunction may be present in the early stages of the disease, even before the onset of motor symptoms. The cognitive dysfunction includes executive dysfunction, psychomotor symptoms, visuospatial deficits, perceptual deficits, memory loss and difficulty learning new skills. Acetylcholinesterase inhibitors have shown good effect in the treatment of other types of dementia and it is postulated that it might delay cognitive decline in HD. We reviewed the evidence for Acetylcholinesterase inhibitors in the treatment of cognitive decline and dementia associated with Huntington's disease. We identified 6 articles that investigated the role of Acetylcholinesterase inhibitors for treatment of cognitive deficits in Huntington's disease. Following the review, the authors concluded that there is limited evidence for the use of Acetylcholinesterase inhibitors for cognitive impairment in HD.
文摘With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop multi-functional agents, which can mainly serve as dual BACE 1 and AChE inhibitors. Depending on the scaffolds of (+)-(S)- dihydro-ar-tumerone and (-)-gallocatechin gallate, 3 series of new compounds have been designed, synthesized and evaluated, from which we have identified 2-(2-(3-methylbenzoyl)-3-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl) isoindoline-1,3-dione (3d) as a new cholinesterase and β-secretase dual inhibitor without toxicity. Furthermore, 3d also exhibits hydrogen peroxide scavenging activity which could help to reduce the reactive oxygen species (ROS) in the brain of AD patients.
