Compounds with the dioxopyrimidine cycle inhibit cholinesterases from different groups of animals

Anikienko, K. A.; Bychikhin, E. A.; Резник, В. С.; Akamsin, D.; Galyametdinova, I. V.

doi:10.1016/j.cbi.2008.05.037

Cited by 11 publications

(10 citation statements)

References 9 publications

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“…The drawbacks could be overcome by using inhibitors capable of inactivating AChE selectively. A new set of promising compounds, the alkylammonium derivatives of 6‐methyluracil (ADEMS), have been recently synthesized and identified as inhibitors of AChE in vitro with inhibitory constants between 7 × 10 8 and 3 × 10 9 M −1 ·min −1 (Anikienko et al ., 2008). During exercise of dogs and rats on the treadmill, these compounds displayed surprising effects.…”

Section: Introductionmentioning

confidence: 99%

“…For this question, three 6‐methyluracil derivatives were compared in terms of their effect on MEPC. We also determined whether the difference in the sensitivity of the diaphragm and EDL to ADEMS compounds could be explained by the differing expression levels of butyrylcholine esterase (BuChE) in these muscles, as it was shown in vitro that some ADEMS inhibit BuChE at concentrations much higher than those inhibiting AChE (Anikienko et al ., 2008). The differences in sensitivity of the AChE itself to ADEMS between the diaphragm and EDL were assessed.…”

Section: Introductionmentioning

confidence: 99%

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Different sensitivities of rat skeletal muscles and brain to novel anti‐cholinesterase agents, alkylammonium derivatives of 6‐methyluracil (ADEMS)

Петров

Yagodina

Valeeva

et al. 2011

British J Pharmacology

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The rat respiratory muscle diaphragm has markedly lower sensitivity than the locomotor muscle extensor digitorum longus (EDL) to the new acetylcholinesterase (AChE) inhibitors, alkylammonium derivatives of 6-methyluracil (ADEMS). This study evaluated several possible reasons for differing sensitivity between the diaphragm and limb muscles and between the muscles and the brain. EXPERIMENTAL APPROACHIncreased amplitude and prolonged decay time of miniature endplate currents were used to assess anti-cholinesterase activity in muscles. In hippocampal slices, induction of synchronous network activity was used to follow cholinesterase inhibition. The inhibitor sensitivities of purified AChE from the EDL and brain were also estimated. KEY RESULTSThe intermuscular difference in sensitivity to ADEMS is partly explained caused by a higher level of mRNA and activity of 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracildibromide (C-547)-resistant BuChE in the diaphragm. Moreover, diaphragm AChE was more than 20 times less sensitive to C-547 than that from the EDL. Sensitivity of the EDL to C-547 dramatically decreased after treadmill exercises that increased the amount of PRiMA AChE(G4), but not ColQ AChE(A12) molecular forms. The A12 form present in muscles appeared more sensitive to C-547. The main form of AChE in brain, PRiMA AChE(G4), was apparently less sensitive because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL. CONCLUSIONS AND IMPLICATIONSOur findings suggest that ADEMS compounds could be used for the selective inhibition of AChEs and as potential therapeutic tools. AbbreviationsAChE, acetylcholinesterase; ADEMS, alkylammonium derivatives of 6

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Different sensitivities of rat skeletal muscles and brain to novel anti‐cholinesterase agents, alkylammonium derivatives of 6‐methyluracil (ADEMS)

Петров

Yagodina

Valeeva

et al. 2011

British J Pharmacology

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“…Nucleic acid bases, in particular uracils, connected to 1,2,3-triazole ring through a hydrocarbon tether attract interest from the viewpoint of biological activity. We anticipated that uracil derivatives containing a 1,2,3-triazole fragment would provide stronger binding to a biological target, which should enhance their physiological effect or even change the kind of biological activity [14][15][16]. It was also interesting to elucidate the possibility for regioselective synthesis of 1,2,3-triazole derivatives having N-alkyl-substituted uracil fragments as substituents with a view to obtain acyclic and macrocyclic structures with three-dimensional architecture.…”

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confidence: 99%

1,3-dipolar cycloaddition reactions in the series of N-alkynyl-substituted uracils

et al. 2012

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Reactions of 1-(ω-bromoalkyl)-3,6-dimethyluracils and 1,3-bis(ω-bromoalkyl)-6-methyluracils with sodium azide gave the corresponding mono-and bis-azides. 1,3-Dipolar cycloaddition of the latter with prop-2-yn-1-ol, hex-1-yne, and dec-1-yne in the presence of copper(I) ions afforded acyclic and macrocyclic uracil derivatives containing 1,4-disubstituted 1,2,3-triazole fragments, which were subjected to quaternization with propyl iodide and methyl p-toluenesulfonate at the 1,2,3-triazole nitrogen atom.

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“…For instance, the derivatives of nucleotide bases, in particular, of uracyls, connected with hydrocarbon bridges with N-, S-, O-heterocycles are very important. It is presumed that uracyl derivatives due to stronger binding with the biotarget may enhance the physiologic effect or even modify the biological activity of a specifi c pharmacophore connected to uracyl, in our case fi ve-membered N-, S-, O-heterocycles [7][8][9].…”

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Uracyl derivatives functionalized with N-, S-, O-heterocycles

et al. 2011

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Reactions of 1,3-bis(bromopentyl)-5(6)-substituted uracyls with a series of fi ve-membered heterocycles containing in the ring N, S, or O atoms and a mercapto group as a substituent at the carbon atom of the ring afforded uracyl derivatives of acyclic and macrocyclic structure with 2-thiobenzoxazole, 2-thio-5-methyl-1,3,4-thiadiazole, 2-thiobenzimidazole, and 2,5-dithio-1,3,4-thiadiazole fragments. N atoms of benzoxazole and imidazole fragments of compounds obtained undergo alkylation and quaternization with alkyl iodides and alkyl tosylates.Heterocyclic systems, in particular, fi ve-membered systems containing in the ring N, S, O atoms, exhibit a wide range of biological action. Versatile derivatives of fi ve-membered N-, S-, O-heterocycles containing diverse substituents were synthesized and their biological activity was investigated [1-6]. Compounds of three-dimensional architecture of acyclic or macrocyclic structure containing various number of heterocycles connected by some bridges are far less understood. For instance, the derivatives of nucleotide bases, in particular, of uracyls, connected with hydrocarbon bridges with N-, S-, O-heterocycles are very important. It is presumed that uracyl derivatives due to stronger binding with the biotarget may enhance the physiologic effect or even modify the biological activity of a specifi c pharmacophore connected to uracyl, in our case fi ve-membered N-, S-, O-heterocycles [7-9].This report described the synthesis of compounds consisting of 5-or 6-substituted uracyls connected by methylene chains to versatile fi ve-membered heterocycles. To obtain a uniform reaction course we used heterocycles with a mercapto group attached to a carbon atom of the ring.The choice of initial compounds included the possibility to vary the heteroatoms in the heterocycle composition (N, O, S), to have in the heterocycle composition alongside the mercapto group also another reaction center, in particular, an imide function, and to vary the number of mercapto groups in the heterocyclic fragment. As a result the following heterocycles were used: 2-mercaptobenzoxazole (I), 2-mercapto-5-methyl-1,3,4-thiadiazole (II), 2-mercaptobenzimidazole (III), and 2,5-dimercapto-1,3,4-thiadiazole (IV). The following uracyl derivatives were applied containing haloalkyl substituents: 1,3-bis(bromopentyl)-6-methyluracyl (V) and 1,3-bis(bromopentyl)-5-bromouracyl (VI). The bromine atom was inserted into the uracyl fragment aiming further to replace it by another substituent, e.g., by amino group.The use of DMF as the solvent and sodium hydride as the salt-forming reagent in the reaction of replacing bromine in the 1,3-bis(bromoalkyl)uracyls with heterocyclic fragment was an approach which had been suffi ciently successful in introducing purine derivatives into the alkylsubstituted uracyls [10].In the reaction of dibromide V with heterocycles I and II at room temperature in DMF in the presence of NaH products of substitution of both Br atoms, compounds VII and VIII, were obtained in 66 and 70% yield respecti...

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Compounds with the dioxopyrimidine cycle inhibit cholinesterases from different groups of animals

Cited by 11 publications

References 9 publications

Different sensitivities of rat skeletal muscles and brain to novel anti‐cholinesterase agents, alkylammonium derivatives of 6‐methyluracil (ADEMS)

Different sensitivities of rat skeletal muscles and brain to novel anti‐cholinesterase agents, alkylammonium derivatives of 6‐methyluracil (ADEMS)

1,3-dipolar cycloaddition reactions in the series of N-alkynyl-substituted uracils

Uracyl derivatives functionalized with N-, S-, O-heterocycles

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