Discovery of 1-(3-(benzyloxy)pyridin-2-yl)-3-(2-(piperazin-1-yl) ethyl)urea: A new modulator for amyloid beta-induced mitochondrial dysfunction (original) (raw)
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A series of 2-(3-arylureido)pyridines and 2-(3-benzylureido)pyridines were synthesized and evaluated as potential modulators for amyloid beta (Ab)-induced mitochondrial dysfunction in Alzheimer's disease (AD). The blocking activities of forty one small molecules against Ab-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mito-chondrial membrane potential (DJm). The inhibitory activity of twenty five compounds against Ab-induced mPTP opening was superior to that of the standard cyclosporin A (CsA). Six hit compounds have been identified as likely safe in regards to mitochondrial and cellular safety and subjected to assessment for their protective effect against Ab-induced deterioration of ATP production and cytotoxicity. Among them, compound 7fb has been identified as a lead compound protecting neuronal cells against 67% of neurocytotoxicity and 43% of suppression of mitochondrial ATP production induced by 5 mM concentrations of Ab. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for these compounds with cyclophilin D (CypD) receptor as a major component of mPTP. Hence, this report presents compound 7fb as a new nonpeptidyl mPTP blocker which would be promising for further development of Alzheimer's disease (AD) therapeutics.
A novel series of twenty-six quinazoline-urea derivatives was designed and synthesized. Their blocking activities against b-amyloid peptide (Ab) induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measured the change of mitochondrial membrane potential. Seven compounds showed better inhibitory activities than the standard Cyclosporin A (CsA). The most active analogues were tested by MTT assay to evaluate their toxicity on the cellular survival; they revealed excellent cellular viability. To explain the difference in inhibitory activity, molecular docking study using (GOLD) program was performed for selected sets of the most active and inactive compounds on cyclophilin D (CypD) receptor as a major component of mPTP. Moreover, ADME profiling, in silico toxicity, drug-likeness, and drug-score studies were discussed. From these results, we report compound 31 as the most active nonpeptidyl mPTP blocker possessing quinazoline-urea scaffold; 2 folds of CsA activity, which would constitute a new direction for the design of novel mPTP modulators.
Mitochondrial permeability transition pore (mPTP) Ab-induced neurotoxicity Alzheimer's disease (AD) Thiourea Cyclophilin D Molecular docking a b s t r a c t Herein, we report synthesis and evaluation of new twenty six small molecules against b amyloid (Ab)-induced opening of mitochondrial permeability transition pore (mPTP) using JC-1 assay which measures the change of mitochondrial membrane potential (DJm). The neuroprotective effect of seventeen compounds against Ab-induced mPTP opening was superior to that of the standard Cyclosporin A (CsA). Fifteen derivatives eliciting increased green to red fluorescence percentage less than 40.0% were evaluated for their impact on ATP production, cell viability and neuroprotection against Ab-induced neuronal cell death. Among evaluated compounds, derivatives 9w, 9r and 9k had safe profile regarding ATP production and cell viability. In addition, they exhibited significant neuroprotection (69.3, 51.8 and 48.2% respectively). Molecular modeling study using CDocker algorithm predicted plausible binding modes explaining the elicited mPTP blocking activity. Hence, this study suggests compounds 9w, 9r and 9k as leads for further development of novel therapy to Alzheimer's disease.
European journal of medicinal chemistry, 2016
Current possibilities of Alzheimer's disease (AD) treatment are very limited and are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or N-methyl-D-aspartate receptor antagonist, memantine. Newly synthesized drugs affect multiple AD pathophysiological pathways and can act as inhibitors of cholinesterases (AChE, BuChE), inhibitors of monoamine oxidases (MAO-A, MAO-B), modulators of mitochondrial permeability transition pores, modulators of amyloid-beta binding alcohol dehydrogenase and antioxidants. Effects of clinically used as well as newly developed AD drugs were studied in relation to energy metabolism and mitochondrial functions, including oxidative phosphorylation, activities of enzymes of citric acid cycle or electron transfer system, mitochondrial membrane potential, calcium homeostasis, production of reactive oxygen species and MAO activity.
Mitochondrial membrane permeabilisation by amyloid aggregates and protection by polyphenols
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013
Alzheimer's disease and Parkinson's disease are neurodegenerative disorders characterised by the misfolding of proteins into soluble prefibrillar aggregates. These aggregate complexes disrupt mitochondrial function, initiating a pathophysiological cascade leading to synaptic and neuronal degeneration. In order to explore the interaction of amyloid aggregates with mitochondrial membranes, we made use of two in vitro model systems, namely: (i) lipid vesicles with defined membrane compositions that mimic those of mitochondrial membranes, and (ii) respiring mitochondria isolated from neuronal SH-SY5Y cells. External application of soluble prefibrillar forms, but not monomers, of amyloid-beta (Aβ 42 peptide), wild-type α-synuclein (α-syn), mutant α-syn (A30P and A53T) and tau-441 proteins induced a robust permeabilisation of mitochondrial-like vesicles, and triggered cytochrome c release (CCR) from isolated mitochondrial organelles. Importantly, the effect on mitochondria was shown to be dependent upon cardiolipin, an anionic phospholipid unique to mitochondria and a well-known key player in mitochondrial apoptosis. Pharmacological modulators of mitochondrial ion channels failed to inhibit CCR. Thus, we propose a generic mechanism of thrilling mitochondria in which soluble amyloid aggregates have the intrinsic capacity to permeabilise mitochondrial membranes, without the need of any other protein. Finally, six small-molecule compounds and black tea extract were tested for their ability to inhibit permeation of mitochondrial membranes by Aβ 42 , α-syn and tau aggregate complexes. We found that black tea extract and rosmarinic acid were the most potent mito-protectants, and may thus represent important drug leads to alleviate mitochondrial dysfunction in neurodegenerative diseases.
Molecules, 2020
Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar β-amyloid 1–42 (Aβ42), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA’s) scaffold were synthesized, screened toward cholinesterases and evaluated as ne...
Frontiers in Cellular Neuroscience, 2015
Alzheimer's disease (AD), the most prevalent dementia in the elderly, is characterized by progressive synaptic and neuronal loss. Mitochondrial dysfunctions have been consistently reported as an early event in AD and appear before Aβ deposition and memory decline. In order to define a new neuroprotectant strategy in AD targeting mitochondrial alterations, we develop tetrahydro-N,N-dimethyl-2,2-diphenyl-3furanmethanamine (ANAVEX2-73, AE37), a mixed muscarinic receptor ligand and a sigma-1 receptor (σ 1 R) agonist. We previously reported that ANAVEX2-73 shows antiamnesic and neuroprotective activities in mice injected intracerebroventricular (ICV) with oligomeric amyloid-β 25-35 peptide (Aβ 25-35 ). The σ1R is present at mitochondriaassociated endoplasmic reticulum (ER) membranes, where it acts as a sensor/modulator of ER stress responses and local Ca 2+ exchanges with the mitochondria. We therefore evaluated the effect of ANAVEX2-73 and PRE-084, a reference σ 1 R agonist, on preservation of mitochondrial integrity in Aβ 25-35 -injected mice. In isolated mitochondria from hippocampus preparations of Aβ 25-35 injected animals, we measured respiration rates, complex activities, lipid peroxidation, Bax/Bcl-2 ratios and cytochrome c release into the cytosol. Five days after Aβ 25-35 injection, mitochondrial respiration in mouse hippocampus was altered. ANAVEX2-73 (0.01-1 mg/kg IP) restored normal respiration and PRE-084 (0.5-1 mg/kg IP) increased respiration rates. Both compounds prevented Aβ 25-35 -induced increases in lipid peroxidation levels, Bax/Bcl-2 ratio and cytochrome c release into the cytosol, all indicators of increased toxicity. ANAVEX2-73 and PRE-084 efficiently prevented the mitochondrial respiratory dysfunction and resulting oxidative stress and apoptosis. The σ 1 R, targeted selectively or non-selectively, therefore appears as a valuable target for protection against mitochondrial damages in AD.
Biochemical and Biophysical Research Communications, 2001
Mitochondria have been implicated in the cytotoxicity of amyloid -peptide (A), which accumulates as senile plaques in the brain of Alzheimer's disease patients. Tauroursodeoxycholate (TUDC) modulates cell death, in part, by preventing mitochondrial membrane perturbation. Using electron paramagnetic resonance spectroscopy analysis of isolated mitochondria, we tested the hypothesis that A acts locally in mitochondrial membranes to induce oxidative injury, leading to increased membrane permeability and subsequent release of caspase-activating factors. Further, we intended to determine the role of TUDC at preventing A-induced mitochondrial membrane dysfunction. The results demonstrate oxidative injury of mitochondrial membranes during exposure to A and reveal profound structural changes, including modified membrane lipid polarity and disrupted protein mobility. Cytochrome c is released from the intermembrane space of mitochondria as a consequence of increased membrane permeability. TUDC, but not cyclosporine A, almost completely abrogated A-induced perturbation of mitochondrial membrane structure. We conclude that A directly induces cytochrome c release from mitochondria through a mechanism that is accompanied by profound effects on mitochondrial membrane redox status, lipid polarity, and protein order. TUDC can directly suppress Ainduced disruption of the mitochondrial membrane structure, suggesting a neuroprotective role for this bile salt.