Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer's disease

García-Font, Nuria; Hayour, Hasna; Belfaitah, Ali; Pedraz, Jorge; Moraleda, Ignacio; Iriepa, Isabel; Bouraiou, Abdelmalek; Chioua, Mourad; Marco‐Contelles, José; Oset-Gasque, María Jesús

doi:10.1016/j.ejmech.2016.04.023

Cited by 45 publications

(17 citation statements)

References 41 publications

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“…The human neuroblastomas cell line SH-SY5Y were cultured in Dulbecco's: Ham's F12, 1:1 [vol/vol] containing 3.15 mg/mL glucose, 2.5 mM Glutamax and 0.5 mM sodium pyruvate DMEM/F-12, GlutaMAX™; GIBCO, Life Technologies, Madrid (Spain), 1% Antibiotique-Antimitotic (Gibco; Life Technologies, Madrid, Spain) (containing 100 ui/mL penicillin, 100 mg/mL de streptomycin and 0.25 mg de amphotericine B), 1% gentamicine 15 mg/mL (Sigma-Aldrich, Madrid, España) and 10% Foetal Calf Serum (FCS) (Gibco; Life Technologies, Madrid, Spain) as described 27 . Cultures were seeded into flasks containing supplemented medium and maintained at 37 °C in a humidified atmosphere of 5% CO 2 and 95% air.…”

Section: Methodsmentioning

confidence: 99%

“…To this end, we used the XTT cell viability test, a colorimetric assay that detects the cellular metabolic activities. Based on a previous work from our laboratory 27 , we selected the appropriate experimental conditions and tested the neuroprotective effect of HBNs 1–9 at different concentrations (0.1–1,000 μM), added 10 min before the administration of O10 μM /R30 μM (O/R), and using PBN , at the same concentrations (0.1–1,000 μM), as a reference compound 28 .…”

Section: Neuroprotection Studiesmentioning

confidence: 99%

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Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models

Chamorro

Diez‐Iriepa

Merás-Sáiz

et al. 2020

Sci Rep

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We herein report the synthesis, antioxidant power and neuroprotective properties of nine homo-bisnitrones HBNs 1-9 as alpha-phenyl-N-tert-butylnitrone (PBN) analogues for stroke therapy. In vitro neuroprotection studies of HBNs 1-9 against Oligomycin A/Rotenone and in an oxygen-glucosedeprivation model of ischemia in human neuroblastoma cell cultures, indicate that (1Z,1′Z)-1,1′-(1,3phenylene)bis(N-benzylmethanimine oxide) (HBN6) is a potent neuroprotective agent that prevents the decrease in neuronal metabolic activity (EC 50 = 1.24 ± 0.39 μM) as well as necrotic and apoptotic cell death. HBN6 shows strong hydroxyl radical scavenger power (81%), and capacity to decrease superoxide production in human neuroblastoma cell cultures (maximal activity = 95.8 ± 3.6%), values significantly superior to the neuroprotective and antioxidant properties of the parent PBN. The higher neuroprotective ability of HBN6 has been rationalized by means of Density Functional Theory calculations. Calculated physicochemical and ADME properties confirmed HBN6 as a hit-agent showing suitable drug-like properties. Finally, the contribution of HBN6 to brain damage prevention was confirmed in a permanent MCAO setting by assessing infarct volume outcome 48 h after stroke in drug administered experimental animals, which provides evidence of a significant reduction of the brain lesion size and strongly suggests that HBN6 is a potential neuroprotective agent against stroke. Bis-nitrones are well-known antioxidant and neuroprotective agents showing high clinical potential. For instance, bis-nitrone W-AZN (Fig. 1), an azulenyl spin trap possessing neuroprotective effects in an animal model of

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Section: Methodsmentioning

confidence: 99%

Section: Neuroprotection Studiesmentioning

confidence: 99%

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models

Chamorro

Diez‐Iriepa

Merás-Sáiz

et al. 2020

Sci Rep

Self Cite

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“…The human neuroblastoma cell line SHSY5Y was cultured in Dulbecco’s modified Eagle’s medium: Ham’s F12 medium as described in ref (16). For assays, SHSY5Y cells were subcultured in 96- or 48-well plates at a seeding density of (0.50–1) or (2–2.5) × 10 5 cells per well, respectively.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Neuroprotective Properties of N-Substituted C-Dialkoxyphosphorylated Nitrones

et al. 2019

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Herein, we report the synthesis and neuroprotective power of some N-substituted C -(dialkoxy)phosphorylated nitrones 4a – g , by studying their ability to increase the cell viability, as well as their capacity to reduce necrosis and apoptosis. We have identified ( Z )- N - tert -butyl-1-(diethoxyphosphoryl)methanimine oxide ( 4e ) as the most potent, nontoxic, and neuroprotective agent, with a high activity against neuronal necrotic cell death, a result that correlates very well with its great capacity for the inhibition of the superoxide production (72%), as well as with the inhibition of lipid peroxidation (62%), and the 5-lipoxygenase activity (45%) at 100 μM concentrations. Thus, nitrone 4e could be a convenient promising compound for further investigation.

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“…García-Font et al . [138] designed, synthesized and evaluated a new, racemic, diversely functionalized 2-chloroquinolin-3-yl substituted PyranoTacrines (PTs) 5, 6 . Compound 6 (IC 50 = 0.48 ± 0.05 mM) are potent, mixed-type ( 6 : K i = 0.0142 ± 0.003 mM), and selective AChE inhibitors, binding at both catalytic and peripheral anionic sites of the enzyme.…”

Section: New Multifunctional Analogues and Hybrids Of Tacrinementioning

confidence: 99%

“…Compounds 5 and 6 are neuroprotective agents at low µM concentrations upon decreased viability of SHSY5Y cells (SHSY5Y) induced by oxidative stress, and stimulators of GSK3β-dependent tau phosphorylation. Molecules 5 and 6 effectively counteract Aβ-aggregation on exposure to Aβ 1-40 , as well as Aβ 1-40 aggregation-dependent tau-oligomerization and phosphorylation in 396 Ser, which could be ascribed to the anti-aggregating properties shown in vitro [138].…”

Section: New Multifunctional Analogues and Hybrids Of Tacrinementioning

confidence: 99%

Therapeutic Potential of Multifunctional Tacrine Analogues

Przybyłowska

Kowalski

Dzierzbicka

et al. 2019

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Tacrine is a potent inhibitor of cholinesterases (acetylcholinesterase and butyrylcholinesterase) that shows limiting clinical application by liver toxicity. In spite of this, analogues of tacrine are considered as model inhibitor of cholinesterases in the therapy of Alzheimer's disease. The interest in these compounds is mainly related to a high variety of their structure and biological properties. In the present review, we have described the role of cholinergic transmission and treatment strategies in Alzheimer's disease as well as the synthesis and biological activity of several recently developed classes of multifunctional tacrine analogues and hybrids, which consist a new paradigm to treat Alzheimer's disease. We have also reported potential of these analogues in the treatment of Alzheimer's diseases in various experimental systems.

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Potent anticholinesterasic and neuroprotective pyranotacrines as inhibitors of beta-amyloid aggregation, oxidative stress and tau-phosphorylation for Alzheimer's disease

Cited by 45 publications

References 41 publications

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models

Synthesis and Neuroprotective Properties of N-Substituted C-Dialkoxyphosphorylated Nitrones

Therapeutic Potential of Multifunctional Tacrine Analogues

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