Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease

Greunen, Divan G. van; Westhuizen, C. Johan van der; Cordier, Werner; Nell, Margo; Stander, André; Steenkamp, Vanessa; Panayides, Jenny‐Lee; Riley, Darren L.

doi:10.1016/j.ejmech.2019.06.088

Cited by 25 publications

(26 citation statements)

References 30 publications

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“…17). 45 De Andrade et al replaced the 5,6-dimethoxy-1-indanone moiety of the donepezil structure with triazoles. This change resulted in a reduction in hAChE inhibition and an increase in hBuChE inhibitor activity.…”

Section: Replacement Of Indanone With Ferulic Acid Derivativesmentioning

confidence: 99%

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The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020

et al. 2021

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Section: Replacement Of Indanone With Ferulic Acid Derivativesmentioning

confidence: 99%

“…piperidine-4-carboxamide 42, which exhibited AChE inhibitory activity (IC 50 ¼ 0.41 mM) (Fig.21) 45. …”

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confidence: 96%

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020

et al. 2021

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“…At the same time, para N-benzylpiperidine carboxaldehyde (11) was obtained in 45% overall yield, through the N-benzylation of ethyl 4-piperidinecarboxylate (8), followed by a reduction of the ester (9) into the alcohol (10) and a final Swern oxidation of the latter (Scheme 3) [11][12][13].…”

Section: Molecules 2020mentioning

confidence: 99%

“…Further, a significant deshielding of the signal of the methylene proton was also observed for the E form (6.70 ppm) of 12, due to the cone-shaped shielding zone of the carbonyl group, versus those of the Z form (6.25 ppm) observed as a trace. At the same time, para N-benzylpiperidine carboxaldehyde (11) was obtained in 45% overall yield, through the N-benzylation of ethyl 4-piperidinecarboxylate (8), followed by a reduction of the ester (9) into the alcohol (10) and a final Swern oxidation of the latter (Scheme 3) [11][12][13]. At the same time, para N-benzylpiperidine carboxaldehyde (11) was obtained in 45% overall yield, through the N-benzylation of ethyl 4-piperidinecarboxylate (8), followed by a reduction of the ester (9) into the alcohol (10) and a final Swern oxidation of the latter (Scheme 3) [11][12][13].…”

Section: Molecules 2020mentioning

confidence: 99%

First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer’s Disease

et al. 2020

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Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM).

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“…Alzheimer's disease (AD) is an irreversible neurodegenerative disease [ 30 ] that is known to be the most common type of dementia, [ 31 ] accounting for approximately 60–80% of all cases in the world. [ 32 ] Acetylcholinesterase (AChE) is an important type of cholinesterase [ 33 ] that is responsible for the regulation [ 34 ] and degradation [ 35 ] of acetylcholine (ACh) in the central nervous system. An increment in ACh expression in the metabolism, owing to the inhibition of the AChE enzyme, leads to the enhancement of the cognitive abilities [ 36 ] such as language skills, attention span, and memory functions in AD.…”

Section: Introductionmentioning

confidence: 99%

Sulfonamides incorporating ketene N,S‐acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors

Istrefi

Türkeş

Arslan

et al. 2020

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In this study, 15 novel compounds in a series of sulfonamide-based ketenes (7a-o) were synthesized and characterized using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. All compounds were tested for their ability to inhibit the human carbonic anhydrase (hCA) isoforms I and II, and acetylcholinesterase (AChE). The halogen-appended compounds, 7g, 7o, and 7i, exhibited the highest hCA I/II and AChE inhibition, with the K I values in the low nanomolar range (K I = 9.01 ± 0.08, 7.41 ± 0.03, and 7.37 ± 0.31 nM, respectively), as compared with their corresponding parent 2-[2,2-dicyano-1-(phenylamino) vinylthio]-N-(4-sulfamoylphenyl)acetamide analogs 7a-o. Besides, derivatives 7c and 7e selectively inhibited the isoform hCA I, whereas compounds 7m and 7n selectively inhibited isoform hCA II. These findings indicated that all compounds can inhibit metabolic dysfunctions, such as edema, epilepsy, glaucoma, and Alzheimer's disease, by specifically targeting both the hCA isoforms and AChE expression.Herein, also the interactions between ligands and receptors were highlighted through in silico molecular docking studies. The molecular mechanics-generalized Born surface area method was utilized to compute the binding free energy and the energy contribution of the critical residues in the active site was estimated. All these results would help us to perfectly understand the relationship between activity and structural characteristics of derivatives and to further improve newly and highly effective analogs targeting hCA and AChE.

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Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease

Cited by 25 publications

References 30 publications

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020

First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer’s Disease

Sulfonamides incorporating ketene N,S‐acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors

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