Design, synthesis, evaluation and QSAR analysis of N1-substituted norcymserine derivatives as selective butyrylcholinesterase inhibitors

Takahashi, Jun; Hijikuro, Ichiro; Kihara, Takeshi; Murugesh, Modachur G.; Fuse, Shinichiro; Kunimoto, Ryo; Tsumura, Yoshinori; Akaike, Akinori; Niidome, Takuro; Okuno, Yasushi; Takahashi, Takashi; Sugimoto, Hachiro

doi:10.1016/j.bmcl.2010.01.057

Cited by 16 publications

(11 citation statements)

References 18 publications

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“…We have developed and reported one-pot, or one-flow, multicomponent coupling methods for the efficient synthesis of organic compounds. [26][27][28][29][30][31][32][33] As part of our drug development research into Alzheimer's disease [31,34,35] based on triarylpyrazoles, we decided to develop a rapid, one-pot approach for the synthesis of a structurally diverse triarylpyrazole library. In this paper, we report the regioselective onepot, three-component synthesis of 1,3,4-and 1,3,5-triarylpyrazoles from readily available starting materials: aryl aldehydes, aryl hydrazines, and 1-and 2-aryl-1-alkenyl sulfones (Scheme 1, b).…”

Section: Introductionmentioning

confidence: 99%

Regioselective, One‐Pot, Three‐Component Synthesis of 1,3,4‐ and 1,3,5‐Triarylpyrazoles from 1‐ and 2‐Aryl‐1‐alkenyl Sulfones

et al. 2015

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Section: Introductionmentioning

confidence: 99%

Regioselective, One‐Pot, Three‐Component Synthesis of 1,3,4‐ and 1,3,5‐Triarylpyrazoles from 1‐ and 2‐Aryl‐1‐alkenyl Sulfones

et al. 2015

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“…Besides AChE, BChE has been suggested as alternative target, [6] based on the fact that BChE expression significantly increases in CNS glial cells and Aβ plaques in the late stage of AD, therewith suggesting a role in the disease progression [7–9] . Some selective BChE‐Is [10–12] proved to reduce fibrils’ deposition, ameliorating cognitive impairment in AD animal models, [13,14] and efforts have been devoted to the identification of novel AChE/BChE‐based multitarget‐directed ligands (MTDLs), simultaneously affecting multiple biochemical pathways and dysfunctions [15] …”

Section: Introductionmentioning

confidence: 99%

Evaluation of Water‐Soluble Mannich Base Prodrugs of 2,3,4,5‐Tetrahydroazepino[4,3‐b]indol‐1(6H)‐one as Multitarget‐Directed Agents for Alzheimer's Disease

et al. 2020

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Different Mannich base derivatives have been studied with the aim of addressing the poor aqueous solubility of the recently disclosed 6‐phenethyl‐2,3,4,5‐tetrahydroazepino[4,3‐b]indol‐1(6H)‐one (1), a human butyrylcholinesterase inhibitor (hBChE, IC5013 nM) and protective agent in NMDA‐induced neurotoxicity, in in vivo assays. The N‐(4‐methylpiperazin‐1‐yl)methyl derivative 2 c showed a 50‐fold increase in solubility in pH 7.4‐buffered solution, high stability in serum and (half‐life >24 h) and rapid (<3 min) conversion to 1 at acidic pH. Although less active than 1, 2 c retained moderate hBChE inhibition (IC50=3.35 μM) and a significant protective effect against NMDA‐induced neurotoxicity at 0.1 μM. Moreover, 2 c resulted a weaker serum albumin binder than 1, could pass the blood–brain barrier, and exerted negligible cytotoxicity on HepG2 cells. These findings suggest that 2 c could be a water‐soluble prodrug candidate of 1 for oral administration or a slow‐release injectable derivative in in vivoAlzheimer's disease models.

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“…However, the influence of BChE on the pathology of AD is unclear , and the development of selective BChE inhibitors is currently in the focus of scientific interest . In this context polyphenols , quinazolimines , several nucleoside analogs , cymserin and norcymserin derivatives have previously been investigated in more detail.…”

Section: Introductionmentioning

confidence: 99%

Gypsogenin Derivatives: An Unexpected Class of Inhibitors of Cholinesterases

Heller

Schwarz

Weber

et al. 2014

Archiv der Pharmazie

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Gypsogenin (1) was obtained by acidic hydrolysis from its saponin. While the parent compound 1 acted as a selective inhibitor for butyrylcholinesterase (from equus) possessing a moderate mixed-type inhibition of the enzyme, Ki values as low as 2.67 ± 0.59 μM were determined for (3β,4α) 3-O-acetyl-olean-12-ene-23,28-dinitrile (11) and acetylcholinesterase (AChE, from electric eel). Thus, 11 possesses one-fifth of the inhibitory activity of the "gold standard" galantamine hydrobromide; this compound is one of the first pentacyclic triterpenoids described as a potent AChE-selective inhibitor.

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Design, synthesis, evaluation and QSAR analysis of N1-substituted norcymserine derivatives as selective butyrylcholinesterase inhibitors

Cited by 16 publications

References 18 publications

Regioselective, One‐Pot, Three‐Component Synthesis of 1,3,4‐ and 1,3,5‐Triarylpyrazoles from 1‐ and 2‐Aryl‐1‐alkenyl Sulfones

Regioselective, One‐Pot, Three‐Component Synthesis of 1,3,4‐ and 1,3,5‐Triarylpyrazoles from 1‐ and 2‐Aryl‐1‐alkenyl Sulfones

Evaluation of Water‐Soluble Mannich Base Prodrugs of 2,3,4,5‐Tetrahydroazepino[4,3‐b]indol‐1(6H)‐one as Multitarget‐Directed Agents for Alzheimer's Disease

Gypsogenin Derivatives: An Unexpected Class of Inhibitors of Cholinesterases

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