Synthesis and Biological Evaluation of Tacrine‐Thiadiazolidinone Hybrids as Dual Acetylcholinesterase Inhibitors

Dorronsoro, Isabel; Alonso, D. A.; Castro, Ana; Monte, Maria del; Garcı́a-Palomero, Esther; Martı́nez, Ana

doi:10.1002/ardp.200400919

Cited by 18 publications

(13 citation statements)

References 19 publications

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“…During the past years, speculations have been made on the link between the inhibition of AChE and neuroprotection. It seems that inhibition of a peripheral site of AChE may be related to neuroprotection (Dorronsoro et al, 2005); this is likely because of the fact that this peripheral site might be involved in the formation and deposit of ␤-amyloid in the brain. Considering this hypothesis, perhaps the interaction with the peripheral site correlates better with the neuroprotective effects of these drugs than with its interaction with the active site of the enzyme; however, this still remains to be proven.…”

Section: Discussionmentioning

confidence: 99%

Unequal Neuroprotection Afforded by the Acetylcholinesterase Inhibitors Galantamine, Donepezil, and Rivastigmine in SH-SY5Y Neuroblastoma Cells: Role of Nicotinic Receptors

Arias

Gallego-Sandı́n²,

Villarroya³

et al. 2005

J Pharmacol Exp Ther

154

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Donepezil, rivastigmine, and galantamine are three drugs with acetylcholinesterase (AChE)-inhibiting activity that are currently being used to treat patients suffering from Alzheimer's disease. We have studied the neuroprotective effects of these drugs, in comparison with nicotine, on cell death caused by ␤-amyloid (A␤) and okadaic acid, two models that are relevant to Alzheimer's pathology, in the human neuroblastoma cell line SH-SY5Y. Galantamine and donepezil showed a U-shaped neuroprotective curve against okadaic acid toxicity; maximum protection was achieved at 0.3 M galantamine and at 1 M donepezil; at higher concentrations, protection was diminished. Rivastigmine showed a concentration-dependent effect; maximum protection was achieved at 3 M. When apoptosis was induced by A␤ [25][26][27][28][29][30][31][32][33][34][35] , galantamine, donepezil, and rivastigmine showed maximum protection at the same concentrations: 0.3, 1, and 3 M, respectively. Nicotine also afforded protection against A␤-and okadaic acid-induced toxicity. The neuroprotective effects of galantamine, donepezil, and nicotine were reversed by the ␣7 nicotinic antagonist methyllycaconitine but not by the ␣4␤2 nicotinic antagonist dihydro-␤-erythroidine. The phosphoinositide 3-kinase (PI3K)-Akt blocker 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) reversed the protective effects of galantamine, donepezil, and nicotine but not that of rivastigmine. In contrast, the bcl-2 antagonist ethyl[2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate (HA 14-1) reversed the protective effects of the three AChE inhibitors and that of nicotine. Our results show that galantamine, donepezil, and rivastigmine afford neuroprotection through a mechanism that is likely unrelated to AChE inhibition. Such neuroprotection seemed to be linked to ␣7 nicotinic receptors and the PI3K-Akt pathway in the case of galantamine and donepezil but not for rivastigmine.Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of dementia in the elderly population. Clinically, patients with AD show progressive deterioration of all cognitive functions, resulting in their incapacitation. AD is characterized by the presence of two kinds of abnormal protein deposits, amyloid plaques and neurofibrillary tangles (NFTs) in specific areas of the brain, and finally by the atrophy of the affected brain regions, which results from extensive losses of synapses and neurons (Terry et al., 1981(Terry et al., , 1991Price et al., 1991;Arriagada et al., 1992). Amyloid plaques are extracellular deposits containing ␤-amyloid peptide (A␤) as the major core deposits. A␤ is a 39-to 43-amino acid peptide fragment derived through proteolysis from an integral membrane protein known as A␤ precursor protein. The basis for the ␤-amyloid hypothesis arises from various studies showing that A␤ is toxic to neurons; for example, there is increased A␤ release and apoptotic cell

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Section: Discussionmentioning

confidence: 99%

Unequal Neuroprotection Afforded by the Acetylcholinesterase Inhibitors Galantamine, Donepezil, and Rivastigmine in SH-SY5Y Neuroblastoma Cells: Role of Nicotinic Receptors

Arias

Gallego-Sandı́n²,

Villarroya³

et al. 2005

J Pharmacol Exp Ther

154

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“…Substitution in the quinoline ring system produces different effects in their biological activity. As examples, compounds 1a-b were reported as antiparasitic agents [4] while tacrine-thiadiazolidinone hybrids 2 are acetylcholinesterase (AchE) inhibitors [5] (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Zeolites Promoting Quinoline Synthesis via Friedländer Reaction

et al. 2010

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Catalytic performance of zeolites H-BEA, H-MFI, H-FAU and H-MOR, exhibiting textural differences and with different Brønsted and Lewis acid sites concentration, have been studied in the synthesis of quinolines via Friedländer reaction. H-BEA and H-FAU efficiently promoted the condensation of 2-aminoaryl ketones 3 with ethyl acetoacetate (4a) or acetylacetone (4b) under mild reaction conditions, those being the first examples of zeolites as catalysts for this transformation. While H-FAUshowed similar catalytic behaviour than that reported for (Al)SBA-15 affording mixtures of quinolines 5 and quinolones 6, H-BEA mainly led to quinolines 5 in almost total selectivity and good yields. However, H-MFI and H-MOR zeolites afforded quinolones 6 as the major reaction product. Methodology reported here was found to be useful for the synthesis of biologically active compounds with excellent yields avoiding unnecessary purifications protocols and tedious work-up procedures.

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“…Competition assays of selective ligands for the peripheral anionic site on AChE, using propidium as reference, have indicated the influence of these compounds over the peripheral site. [17] Recently, two isomeric series of dual binding site AChE-Is have been designed and synthesized by hybridizing a unit of 6-chlorotacrine and pyrano[3,2-c]quinoline scaffold as the active site and peripheral site interacting moieties, respectively. These moieties are connected through an oligomethylene linker containing an amido group at a variable position.…”

Section: Dual Binding Site Ache-ismentioning

confidence: 99%

“…metabolites of mangrove fungus Xylaria sp. [11] Dual AChE and MAO inhibitors Coumarin derivatives, [12] 1-N-substituted thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazoline derivatives, [13] xanthones [14] Dual AChE and serotonin transporter inhibitors (S)-2j (RS-1259) [15] Dual binding site AChE inhibitors AP2238, [16] tacrine-thiadiazolidinone hybrids [17] Dual AChE and Abeta aggregation inhibitors Propidium-tacrine heterodimer, [18] tacripyrines (tacrine-dihydropyridine hybrids obtained by combining tacrine with nimodipine), [19] Congo red dye, [20] huperzine A (HupA)-based bivalent ligands [21] Dual AChE and NMDA inhibitors Bis (7)-tacrine, i.e. (1,7-N-heptylene-bis-9,9′-amino-1,2,3,4-tetrahydroacridine) [22] Dual AChE and b-secretase (BACE) inhibitors [23] Dual acetylcholinesterase inhibitors and antioxidants PMS777 [24] Psychosis Dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors…”

Section: Dual Cholinesterase Inhibitorsmentioning

confidence: 99%

Dual inhibition: a novel promising pharmacological approach for different disease conditions

Patyar

Prakash

Medhi

2011

Journal of Pharmacy and Pharmacology

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To overcome the problems associated with polypharmacy, which include medication non compliance, adverse drug reactions, drug-drug interactions and increased pill-burden, various strategies, such as sustained-release drugs and fixed-dose combination regimens (polypills), have been developed. Out of these, a novel and very much promising approach is the use of dual-action drugs. Amongst the dual-action drugs, there is a class of compounds known as dual inhibitors, which possess the dual inhibitory activity. The most common examples of dual inhibitors are rivastigmine, ladostigil, asenapine, phenserine, amitriptyline, clomipramine, doxepin and desipramine. This review article focuses on the conventional drugs used in different diseases which possess dual inhibition activity as well as those which are still in the preclinical/clinical phase.

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Synthesis and Biological Evaluation of Tacrine‐Thiadiazolidinone Hybrids as Dual Acetylcholinesterase Inhibitors

Cited by 18 publications

References 19 publications

Unequal Neuroprotection Afforded by the Acetylcholinesterase Inhibitors Galantamine, Donepezil, and Rivastigmine in SH-SY5Y Neuroblastoma Cells: Role of Nicotinic Receptors

Unequal Neuroprotection Afforded by the Acetylcholinesterase Inhibitors Galantamine, Donepezil, and Rivastigmine in SH-SY5Y Neuroblastoma Cells: Role of Nicotinic Receptors

Zeolites Promoting Quinoline Synthesis via Friedländer Reaction

Dual inhibition: a novel promising pharmacological approach for different disease conditions

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