Design and synthesis of N-benzylpiperidine–purine derivatives as new dual inhibitors of acetyl- and butyrylcholinesterase

Rodríguez‐Franco, María Isabel; Fernández‐Bachiller, María Isabel; Pérez, Concepción; Castro, Ana; Martı́nez, Ana

doi:10.1016/j.bmc.2005.07.019

Cited by 48 publications

(25 citation statements)

References 44 publications

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“…Hence, it is possible that dual inhibitors of both AChE and BuChE would represent a novel therapeutic approach for use in mild, moderate and, particularly, severe dementia [29] . Notably, rational approaches to generate multifunctional cholinesterase inhibitors have been reported by many research groups [30][31][32][33][34] . Moreover, a number of researchers have indicated that AD is related to changes in oxidative metabolism [35,36] .…”

Section: Discussionmentioning

confidence: 99%

Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors

et al. 2009

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Aim: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD). Methods: Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase (BuChE) were determined in vitro by modified Ellman's method. Cell viability was quantified by the reduction of MTT. Results: A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BuChE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BuChE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide (H 2 O 2 )-induced cytotoxicity in PC12 cells. Conclusion: Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clinical efficacies.

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Section: Discussionmentioning

confidence: 99%

Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors

et al. 2009

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“…3,4) Currently, AchE has a well established esterase activity, while the pharmacological role of BChE is not yet completely understood. BChE may have a compensatory role in the modulation of the hydrolysis of acetylcholine (ACh) in brain with degenerative changes.…”

Section: 2)mentioning

confidence: 99%

Design, Synthesis and Evaluation of Difunctionalized 4-Hydroxybenzaldehyde Derivatives as Novel Cholinesterase Inhibitors

Cao

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of difunctionalized 4-hydroxybenzaldehyde derivatives were designed, synthesized and evaluated as cholinesterase (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)) inhibitors. The results demonstrated that all the compounds had more potent AChE and BChE inhibitory activities than galanthamine-HBr, one of the best cholinesterase inhibitors known so far. The inhibition mechanism revealed that the best active compound 4e displayed a mix-type mode of AChE and BChE by its dual-site interactions with the catalytic triad active center and the peripheral anionic site (PAS) of enzyme. All these data suggested that further development of such compounds may be of interest.

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“…14,15 Several N-benzylpiperidine-purine, 3-Methylpyridinium, Novel Oximes, Phenitidine Derivatives, Phenyl Benzamide Derivatives and 2-thionaphthol analogues of berberine have evaluated for AChE and BChE inhibitory activity. 16,17,18,19,20 AD is associated with aging and more prone to geriatric persons. Since, humans and rats exhibit similar age-related alterations therefore, 21,22,23 estimation of age-related cognitive impairment and spatial memory deficit in aged rats may provide more beneficial information associated to humans.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of 4-Aminopyridine Analogues as Cholinesterase Inhibitors for Management of Alzheimer’s Diseases

Singh¹,

Sinha²,

Shirsat³

2018

IJPER

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Introduction: Alzheimer's disease (AD) is a slowly progressive devasting neurodegenerative disorder of central nervous system manifested by deterioration of memory, cognitive functions, behaviour change and impairment in performing activities of daily life. Neurochemical studies of patients suffering from AD demonstrate selective loss of cholinergic neurons, low concentration of acetylcholine (Ach) in the selective areas of brain such as cortex and hippocampus. Objective: A series of new semicarbazones of 4-aminopyridine has been designed, synthesized and evaluated for cognition enhancing activities through the inhibition of acetylcholinesterase (AChE) and by passive avoidance model. Material and methods: In the present study, ten new 4-Aminopyridine analogues were synthesized and characterized by analytic methods such as UV, IR, NMR, elemental analysis and for their inhibitory role on Acetylcholinesterase activity by applying the molecular docking studies and performed enzyme kinetics study by Ellman's spectrophotometric method. The synthesized analogues were then evaluated for antiamnesic and cognition enhancing activities by passive avoidance test. Results:The results illustrated a significant cognition enhancing effect on passive avoidance test with a significant reversal of scopolamine-induced amnesia, which is comparable with standard drug rivastigmine. The in-vitro study of synthesized analogues showed maximum activity of compound-3 and compound-9 compared to standard drug rivastigmine, whereas its enzyme kinetic study revealed a non-competitive inhibition of acetylcholinesterase (AChE) is held responsible to a possible interaction of analogue with the peripheral anionic site (PAS) of AChE and was also confirmed by molecular docking studies. Conclusion: On the basis of present study, we are concluding that hydroxyl substituted Compound 3 and 9 identified as most potent drug which can leads to the discovery and development of new Cognition enhancers in near future.

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Design and synthesis of N-benzylpiperidine–purine derivatives as new dual inhibitors of acetyl- and butyrylcholinesterase

Cited by 48 publications

References 44 publications

Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors

Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors

Design, Synthesis and Evaluation of Difunctionalized 4-Hydroxybenzaldehyde Derivatives as Novel Cholinesterase Inhibitors

Design, Synthesis and Evaluation of 4-Aminopyridine Analogues as Cholinesterase Inhibitors for Management of Alzheimer’s Diseases

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