Preparation and in vitro screening of symmetrical bispyridinium cholinesterase inhibitors bearing different connecting linkage—initial study for Myasthenia gravis implications

Musílek, Kamil; Komloova, Marketa; Zavadova, Vlasta; Holas, Ondřej; Hrabinová, Martina; Pohanka, Miroslav; Dohnal, Vlastimil; Nachon, Florian; Doležal, Martin; Kuča, Kamil; Jung, Young‐Sik

doi:10.1016/j.bmcl.2010.01.034

Cited by 36 publications

(21 citation statements)

References 28 publications

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“…The following compounds were prepared according to published methods:p ropane-1,3-diyl bis(trifluoromethanesulfonate) (21), [44,45] 2-tert-butylpyridine (17), [27] 2-(pyridin-3-yl)propan-2-ol (9), [33] rac-nicotine (rac-26), [28] 1-(tert-butyl)-1H-imidazole (41) [29] and the 4-tertbutyl-substituted pyridine derivatives 4-(tert-butyl)-3-methylpyridine (33), 4-(tert-butyl)-3-methoxypyridine (31), 4-(tert-butyl)-3chloropyridine (28), 3-bromo-4-(tert-butyl)pyridine (29), 4-(tert-butyl)pyridine-3-carbonitrile (30), ethyl 4-(tert-butyl)pyridine-3-carboxylate (36), 4-(tert-butyl)-3-fluoropyridin-1-ium chloride (27), 4-(tertbutyl)-3-phenylpyridine (34), 4-(tert-butyl)-N,N-dimethylpyridine-3carboxamide (32), and 4-(tert-butyl)-3-ethynylpyridine (35). [30] Generalprocedures Synthesis of symmetric bispyridinium compounds by N-alkylation with 21 (GP1): 21 (1.0 equiv) was carefully added to asolution of the corresponding pyridine derivative (2.5 equiv) in CH 2 Cl 2 (0.8 mL mmol À1 )o rt ot he neat pyridine derivative (2.5 equiv) at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…[35][36][37] However,when these reaction conditions were used for the synthesis of compounds of type I and II, in most cases, only an egligible conversion but substantive decomposition of reactants occurred. [35][36][37] However,when these reaction conditions were used for the synthesis of compounds of type I and II, in most cases, only an egligible conversion but substantive decomposition of reactants occurred.…”

Section: Preparation Of the Target Compoundsmentioning

confidence: 99%

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Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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A novel series of 30 symmetric bispyridinium and related N-heteroaromatic bisquaternary salts with a propane-1,3-diyl linker was synthesized and characterized for their binding affinity at the MB327 binding site of nicotinic acetylcholine receptor (nAChR) from Torpedo californica. Compounds targeting this binding site are of particular interest for research into new antidotes against organophosphate poisoning, as therapeutically active 4-tert-butyl-substituted bispyridinium salt MB327 was previously identified as a nAChR re-sensitizer. Efficient access to the target compounds was provided by newly developed methods enabling N-alkylation of sterically hindered or electronically deactivated heterocycles exhibiting a wide variety of functional groups. Determination of binding affinities toward the MB327 binding site at the nAChR, using a recently developed mass spectrometry (MS)-based Binding Assay, revealed that several compounds reached affinities similar to that of MB327 (pK =4.73±0.03). Notably, the newly prepared lipophilic 4-tert-butyl-3-phenyl-substituted bispyridinium salt PTM0022 (3 h) was found to have significantly higher binding affinity, with a pK value of 5.16±0.07, thus representing considerable progress toward the development of more potent nAChR re-sensitizers.

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Section: Methodsmentioning

confidence: 99%

Section: Preparation Of the Target Compoundsmentioning

confidence: 99%

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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“…Novel donepezil-tacrine and oxoisoaporphine-tacrine congeners hybrid related derivatives, coumarin and huperzine A derivatives have exhibited high AChE inhibitory activity with IC 50 values in the nanomolar range, and ability to bind simultaneously to both peripheral and catalytic sites of the enzyme. For the reason, these dual binding site inhibitors are promising compounds for developing disease-modifying drugs for the future treatment of AD [58-62], Additionally, new synthesized symmetrical bispyridinium and carbamate anti-AChE compounds inhibit the enzyme in micromolar concentrations, making them the potential candidates for the treatment of AD [63, 64]. …”

Section: Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

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Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.

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“…Recently, three new reversible inhibitors of AChE – K298 [1,8‐bis(isoquinolinium)‐oct‐1,8‐diyl dibromide], K344 [1,10‐bis(pyridinium) decan dibromide] and K474 [1,8‐bis(4‐tert‐butylpyridinium)‐oct‐1,8‐diyl dibromide] (fig. 1) were developed at our Department of Toxicology [15–17] to improve the efficacy of pharmacological pre‐treatment against nerve agents.…”

mentioning

confidence: 99%

“…Recently, three new reversible inhibitors of AChE -K298 [1,8- fig. 1) were developed at our Department of Toxicology [15][16][17] to improve the efficacy of pharmacological pre-treatment against nerve agents.…”

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confidence: 99%

A Comparison of the Efficacy of Newly Developed Reversible Inhibitors of Acetylcholinesterase with Commonly Used Pyridostigmine as Pharmacological Pre‐Treatment of Soman‐Poisoned Mice

Kassa¹,

Musílek²,

Koomlova³

et al. 2011

Basic Clin Pharma Tox

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The ability of three newly developed reversible inhibitors of acetylcholinesterase (AChE) (K298, K344 and K474) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was compared. Neither pyridostigmine nor new reversible inhibitors of AChE were able to increase the LD 50 value of soman. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of AChE was not able to protect mice against soman-induced lethal acute toxicity. The pharmacological pre-treatment with pyridostigmine alone or with K474 was able to slightly increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice, but the increase in the efficacy of antidotal treatment was not significant. The other newly developed reversible inhibitors of AChF (K298, K344) were completely ineffective. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of AChF is not promising.

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Preparation and in vitro screening of symmetrical bispyridinium cholinesterase inhibitors bearing different connecting linkage—initial study for Myasthenia gravis implications

Cited by 36 publications

References 28 publications

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

A Comparison of the Efficacy of Newly Developed Reversible Inhibitors of Acetylcholinesterase with Commonly Used Pyridostigmine as Pharmacological Pre‐Treatment of Soman‐Poisoned Mice

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