Structure−Activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone. 4. Further Investigation on the Inner Spacer

Tumiatti, Vincenzo; Milelli, Andrea; Minarini, Anna; Rosini, Michela; Bolognesi, María Laura; Micco, Marialuisa; Andrisano, Vincenza; Bartolini, Manuela; Mancini, Francesca; Recanatini, Maurizio; Cavalli, Andrea; Melchiorre, Carlo

doi:10.1021/jm8009684

Cited by 54 publications

(31 citation statements)

References 32 publications

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“…Most of the new hybrids could be classified as weak inhibitors of the AChE-induced Aβ aggregation, with expected IC 50 values in the high micromolar range, while the most potent described inhibitors display potencies in the low micromolar range. 21,23,26,27,30,33 Nevertheless, the inhibitory activity of the most potent hybrids, 26 and 27, is in the same range as that of other known dual binding site AChEIs. 20,22,24,28,29,31,32 The Aβ antiaggregating effect of the novel hybrids seems to depend on the position of the amido group within the linker, the hybrids of the second series being more potent than their counterparts of the first series.…”

Section: Pharmacology and Molecular Modelingmentioning

confidence: 93%

Pyrano[3,2-c]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

et al. 2009

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Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.

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Section: Pharmacology and Molecular Modelingmentioning

confidence: 93%

Pyrano[3,2-c]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

et al. 2009

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“…They have always been the concern of medicinal chemists as a universal template 15 . Our group has been involved in the development of polyamine conjugates as potential drugs for many years [16][17][18][19] .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of Genistein-polyamine Conjugates as Multi-functional Anti-Alzheimer Agents

Luo¹

2014

Med chem

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A series of genistein-polyamine conjugates (4a-4h) were designed, synthesized and evaluated as multi-functional anti-Alzheimer agents. The results showed that these compounds had significant cholinesterases (ChEs) inhibitory activity. Compound 4b exhibited the strongest inhibition to acetylcholinesterase (AChE) with an IC 50 value of 2.75 μmol/L, which was better than that of rivastigmine (5.60 μmol/L). Lineweaver-Burk plot and molecular modeling study showed that compound 4b targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, compound 4b showed potent metal-chelating ability. In addition, it was found that 4a-4h did not affect HepG-2 cell viability at the concentration of 10 μmol/L.

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“…It was thought that relying solely on the quantitative estimation of GH brain uptake could be misleading. Measuring GH brain levels would not guarantee its pharmacological efficiency; as GH-chitosan interaction might alter GH binding to the brain AChE enzyme via steric hindrance or any other mechanism; thus affecting the entire pharmacological profile of GH (Tumiatti et al, 2008). The protein level and activity of brain AChE were determined and considered potential markers of CX-NP2 efficacy (Nordberg et al, 2009).…”

Section: Determination Of Ache Protein Level and Activity In Rat Brainsmentioning

confidence: 99%

Pharmacological, toxicological and neuronal localization assessment of galantamine/chitosan complex nanoparticles in rats: future potential contribution in Alzheimer’s disease management

et al. 2016

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Purpose: Nasal galantamine hydrobromide (GH)/chitosan complex nanoparticles (CX-NP2) could have an improved therapeutic potential for managing Alzheimer's disease (AD). The current study aimed to investigate if the complexation reaction between GH and chitosan altered the pharmacological and toxicological profiles of the parent drug; GH. Methods: The nasal administration of CX-NP2 to male Wistar rats for 12 consecutive days was compared to negative control group, and oral and nasal GH solutions treated groups in 3 mg/kg daily GH dose. Brain acetylcholinesterase (AChE) protein level and activity were assessed. The in vivo toxicity of CX-NP2 was evaluated via monitoring the clinical signs throughout the study. Histopathological examination of brain sections was performed. The intracellular localization of CX-NP2 within brain neurons was investigated using transmission electron microscopy. Results: GH/chitosan complexation did not negatively alter the pharmacological efficiency of GH. Intriguingly, nasal CX-NP2 exhibited a significant decrease of AChE protein level and activity in rat brains compared to the oral and nasal GH solutions. No toxicity signs or histopathological manifestations were noticed. The nanoparticles were found intracellularly in the brain neurons. Conclusion:The pharmacological efficacy and in vivo safety of nasal CX-NP2 confirm their promising potential to contribute to the management of AD intranasally.

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Structure−Activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone. 4. Further Investigation on the Inner Spacer

Cited by 54 publications

References 32 publications

Pyrano[3,2-c]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

Pyrano[3,2-c]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

Design, Synthesis and Evaluation of Genistein-polyamine Conjugates as Multi-functional Anti-Alzheimer Agents

Pharmacological, toxicological and neuronal localization assessment of galantamine/chitosan complex nanoparticles in rats: future potential contribution in Alzheimer’s disease management

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