Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer’s disease

Huang, Wenhai; Lv, Dan; Yu, Haiping; Sheng, Rong; Kim, Sun Chol; Wu, Peng; Luo, Kedi; Li, Jia; Hu, Yongzhou

doi:10.1016/j.bmc.2010.06.042

Cited by 56 publications

(37 citation statements)

References 14 publications

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“…It is believed that these would lead to a more effective management of the disease. 28 Furthermore, it should be noted that the bioactivity of the flavonoids reported in this in vitro study might not translate to direct in vivo effect due to the low bioavailability of flavonoids. 29 …”

Section: Discussionmentioning

confidence: 90%

Antioxidative Properties and Effect of Quercetin and Its Glycosylated Form (Rutin) on Acetylcholinesterase and Butyrylcholinesterase Activities

Ademosun

Oboh

Bello

et al. 2016

J Evid Based Complementary Altern Med

126

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This study sought to investigate the anticholinesterase and antioxidative properties of quercetin and its glycosylated conjugate, rutin. The in vitro inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, inhibition of Fe 2þ -induced lipid peroxidation in rat's brain homogenates, radicals scavenging, and Fe 2þ -chelating abilities of the flavonoids were investigated in vitro with concentrations of the samples ranging from 0.06 to 0.6 mM. Quercetin had significantly higher AChE and BChE inhibitory abilities than rutin. Quercetin also had stronger inhibition of Fe 2þ -induced lipid peroxidation in rat's brain homogenates. Similarly, quercetin had higher radical scavenging abilities than rutin. Quercetin also had stronger Fe 2þ -chelating ability than rutin. The inhibition of cholinesterases and antioxidative properties are possible mechanisms by which the flavonoids can be used in the management of oxidative stress-induced neurodegeneration.

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Section: Discussionmentioning

confidence: 90%

Antioxidative Properties and Effect of Quercetin and Its Glycosylated Form (Rutin) on Acetylcholinesterase and Butyrylcholinesterase Activities

Ademosun

Oboh

Bello

et al. 2016

J Evid Based Complementary Altern Med

126

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“…Considering the very important role of BACE1 and metal ions in AD pathology, Huang et al focused on dual target ligands that can simultaneously affect BACE1 and metal ions [139]. A series of novel 1,3-diphenylurea derivatives was designed.…”

Section: Dual Acting Hybrids -Bace1 Inhibitor and Metal Chelatormentioning

confidence: 99%

Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Bajda

Guzior²,

Ignasik³

et al. 2011

CMC

219

131

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Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H(3) receptor antagonism, cannabinoid CB(1) receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.

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“…The complexation ability of compound w18 for Cu 2+ in methanol was studies by using UV-Vis spectrometry with wavelength ranging from 200 to 500 nm 52,53 . In Figure 7(A), UV-Vis spectra of w18 at increasing Cu 2+ concentration were shown.…”

Section: Metal Chelating Effectmentioning

confidence: 99%

Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase/monoamine oxidase inhibitors for the potential application against Alzheimer’s disease

Wang

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer’s disease

Cited by 56 publications

References 14 publications

Antioxidative Properties and Effect of Quercetin and Its Glycosylated Form (Rutin) on Acetylcholinesterase and Butyrylcholinesterase Activities

Antioxidative Properties and Effect of Quercetin and Its Glycosylated Form (Rutin) on Acetylcholinesterase and Butyrylcholinesterase Activities

Multi-Target-Directed Ligands in Alzheimer's Disease Treatment

Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase/monoamine oxidase inhibitors for the potential application against Alzheimer’s disease

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