Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies

Pietro, Ornella Di; Pérez-Areales, F. Javier; Juárez-Jiménez, Jordi; Espargaró, Alba; Clos, M. Victòria; Pérez, Belén; Lavilla, Rodolfo; Sabaté, Raimon; Luque, F. Javier; Muñoz‐Torrero, Diego

doi:10.1016/j.ejmech.2014.07.021

Cited by 58 publications

(44 citation statements)

References 56 publications

(61 reference statements)

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“…spatial, episodic and short‐ term and long‐term memory) in scopolamine‐induced and Aβ‐induced amnesia mouse models (Capurro et al ., ). In addition, several hybrid multifunctional compounds have been recently developed, synthesized and evaluated as potential multitarget drug candidates for AD, including: a chimeric molecule of tacrine and the selective MAO‐B inhibitor, selegiline (Lu et al ., ); o ‐hydroxyl and o ‐amino benzylamine‐tacrine hybrids (Mao et al ., ), a series of resveratrol derivatives (Lu et al ., ) and tetrahydrobenzo[h][1,6]naphthyridine‐6‐chlorotacrine hybrids, possessing ChE inhibitory and Aβ and tau anti‐aggregation activities (Di Pietro et al ., ).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 97%

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

Weinreb

Amit

Bar-Am

et al. 2015

British J Pharmacology

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Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid β peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology. The current review will discuss the potential benefits of novel multimodal neuroprotective, brain permeable drugs, recently developed by Youdim and collaborators, as a valuable therapeutic approach for AD treatment. The pharmacological and neuroprotective properties of these multitarget-directed ligands, which target MAO enzymes, the cholinergic system, iron accumulation and amyloid β peptide generation/aggregation are described, with a special emphasis on their potential therapeutic value for ageing and AD-associated cognitive functions. This review is conceived as a tribute to the broad neuropharmacology work of Professor Moussa Youdim, Professor Emeritus in the

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 97%

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

Weinreb

Amit

Bar-Am

et al. 2015

British J Pharmacology

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“…54,55 We have recently found that several classes of 6-chlorotacrine-and huprine-based hybrid compounds exhibit such a dual Aβ42 and tau anti-aggregating profile in a simple in vivo model of protein aggregation, namely in intact E. coli cells that overexpress these proteins. [37][38][39] To assess whether the novel levetiracetam-tacrine, levetiracetam-6-chlorotacrine and levetiracetam-huprine hybrids shared this dual anti-aggregating profile, they were subjected to the E. coli assay, which is based on monitoring the changes in the fluorescence of thioflavin S after in vivo staining of the amyloid-containing insoluble inclusion bodies 56 that are formed upon expression and subsequent aggregation of the heterologous proteins in the bacteria. 57 In contrast with the rather low anti-aggregating activity found for racemic and enantiopure tacrine-based hybrids 5 and 6, especially in the case of (R)-5, the levetiracetam-huprine hybrids 10 and 11 exhibited a moderately potent Aβ42 and tau anti-aggregating activity, with percentages of inhibition around 30% and 50%, respectively, at 20 µM (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies

et al. 2015

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We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as β-amyloid (Aβ)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aβ42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.

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“…[26] Therefore, they seem well suited to the search for new molecules with different moieties of interest that are able to interact with various pathological events in connection with AD. [4,[27][28][29] Particularly interesting among these types of reactions is the Ugi four-component reaction (U-4CR). This transformation allows the creation of up to five points of structural diversity in one pot which can be very useful for the expeditious synthesis of bioactive molecules for multifactorial diseases such as AD.…”

Section: Introductionmentioning

confidence: 99%

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

et al. 2014

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Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β-amyloid (Aβ) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM), affording good neuroprotection against toxic insults such as Aβ1-40 , Aβ1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 μM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.

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Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies

Cited by 58 publications

References 56 publications

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

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