- Synthesis of 4,6-Disubstituted 2-Thioxo-1,2-dihydropyridine-3-carbonitriles by the Reaction of Acetylenic Ketones with Cyanothioacetamide
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The reaction of acetylenic ketones with cyanothioacetamide in the presence of morpholine yields 4,6-disubstituted 2-thioxo-1,2-dihydropyridine-3-carbonitriles. Structure of the obtained compounds was proved using 2D NMR spectroscopy, as well as transformations into 3-aminothieno[2,3-b]pyridine-2-carboxamide derivatives.
- Buryi,Dotsenko,Levashov,Lukina, D. Yu.,Strelkov,Aksenov,Aksenova,Netreba
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- Novel nicotinonitrile-coumarin hybrids as potential acetylcholinesterase inhibitors: design, synthesis, in vitro and in silico studies
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Abstract: Alzheimer’s disease is a degenerative brain condition that is the leading cause of dementia affecting millions of people around the world. Therapeutic development has focused on the problem of the loss of basal forebrain cholinergic function, as it is the only evidence responsible for brain neurodegeneration in patients with Alzheimer’s disease. Several attempts to improve cholinergic neurotransmission have been investigated by minimizing synaptic degradation of acetylcholine using acetylcholinesterase inhibitors. In the current study, we explore the designing of a new series of nicotinonitrile-coumarin hybrids as potential acetylcholinesterase inhibitors. The new hybrids were prepared utilizing pyridine-2(1H)-thiones as starting precursors. The in vitro acetylcholinesterase (AChE) inhibitory activities were examined for the new nicotinonitrile-coumarin hybrid molecules, when compared with donepezil as a standard drug with IC50 of 14?nM. Coumarin derivative, linked to 6-(4-nitrophenyl)-4-phenylnicotinonitrile, showed more effective inhibitory activity than the reference donepezil with IC50 of 13?nM. The free radical-scavenging capabilities against DPPH of the new hybrid derivatives were screened. Additionally, their in vitro cytotoxic activities have been tested against various eukaryotic cells. Furthermore, docking study showed excellent interaction between nicotinonitrile-coumarin hybrids and AChE. Graphic abstract: [Figure not available: see fulltext.]
- Sanad, Sherif M. H.,Mekky, Ahmed E. M.
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p. 213 - 224
(2020/08/05)
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- Synthesis and in vitro study of new coumarin derivatives linked to nicotinonitrile moieties as potential acetylcholinesterase inhibitors
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The appropriate pyridine-2(1H)-thiones were reacted with an equivalent amount of 5-(chloromethyl)-2-hydroxybenzaldehyde in ethanol in the presence of potassium hydroxide to give the corresponding 2-hydroxybenzaldehyde derivatives in excellent yields. The latter derivatives were taken as key synthons for the preparation of the target hybrids. Therefore, 2-hydroxybenzaldehydes were reacted with benzoylglycine in acetic anhydride in the presence of fused sodium acetate at 100°C for 6 hours to afford a new series of nicotinonitrile-coumarin hybrids. The in vitro acetylcholinesterase inhibitory activities were estimated for the new coumarins. The results were expressed as the inhibition percentage of the tested hybrids at concentration of 25 nM, compared to donepezil as a reference (inhibition percentage of 70.5). Coumarin hybrids linked to 6-(4-nitrophenyl) or 6-(4-chlorophenyl)-4-phenylnicotinonitrile exhibited more effective inhibitory activities than donepezil with inhibition percentages of 94.1 and 72.3, respectively. The new coumarins were tested for their free radical-scavenging capabilities against DPPH. Furthermore, some new coumarins were tested for in vitro cytotoxic activity against each MCF-10A, MCF-7, Caco2, and HEPG2. The new hybrids showed cytotoxicity in micromolar range (IC50 of 3.5-13.9 μM) against all tested cell lines. These results clearly demonstrated that the hybrids being tested are not cytotoxic at the concentration required to inhibit acetylcholinesterase effectively.
- Mekky, Ahmed E. M.,Sanad, Sherif M. H.
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p. 4278 - 4290
(2020/09/12)
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- Experimental and theoretical study on the regioselective bis- and polyalkylation of 2-mercaptonicotinonitrile and 2-mercaptopyrimidine-5-carbonitrile derivatives
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The synthetic utility of 2-mercaptonicotinonitriles 3 and 4, as well as 2-mercapto-4-oxo-6-phenyl-1,4-dihydropyrimidine-5-carbonitrile 20 as building blocks for novel bis- and poly(pyridines), along with poly(pyrimidines) via alkylation with the corresponding bis- and poy(halo) compounds was investigated. Spectroscopic and theoretical studies confirmed the S-alkylation rather than the N-alkylation.
- Abd El-Fatah, Nesma A.,Darweesh, Ahmed F.,Mohamed, Adel A.,Abdelhamid, Ismail A.,Elwahy, Ahmed H.M.
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p. 1436 - 1450
(2017/02/18)
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- Synthesis of substituted pyrido[3′,2′:4,5]thieno[3,2-c]isoquinolin-5(6H)-ones and their sulfinyl and sulfonyl derivatives
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A method for the synthesis of previously unknown pyrido[3′,2′:4,5]thieno[3,2-c]isoquinolin-5(6H)-ones was suggested, which includes a condensation reaction of substituted 3-cyanopyridine-2(1H)-thiones with methyl 2-(chloromethyl)benzoate and subsequent treatment of the condensation products with potassium tert-butoxide. The oxidation of the condensation products to sulfoxides or sulfones and subsequent treatment of these compounds with potassium tert-butoxide led to substituted pyrido[3′,2′:4,5]thieno[3,2-c]isoquinolin-5(6H)-one 11-oxides or substituted pyrido[3′,2′:4,5]thieno[3,2-c]isoquinolin-5(6H)-one 11,11-dioxides.
- Kalugin,Shestopalov
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p. 523 - 530
(2017/09/15)
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- High-Throughput Screening and Hit Validation of Extracellular-Related Kinase 5 (ERK5) Inhibitors
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The extracellular-related kinase 5 (ERK5) is a promising target for cancer therapy. A high-throughput screen was developed for ERK5, based on the IMAP FP progressive binding system, and used to identify hits from a library of 57-617 compounds. Four distinct chemical series were evident within the screening hits. Resynthesis and reassay of the hits demonstrated that one series did not return active compounds, whereas three series returned active hits. Structure-activity studies demonstrated that the 4-benzoylpyrrole-2-carboxamide pharmacophore had excellent potential for further development. The minimum kinase binding pharmacophore was identified, and key examples demonstrated good selectivity for ERK5 over p38α kinase.
- Myers, Stephanie M.,Bawn, Ruth H.,Bisset, Louise C.,Blackburn, Timothy J.,Cottyn, Betty,Molyneux, Lauren,Wong, Ai-Ching,Cano, Celine,Clegg, William,Harrington, Ross. W.,Leung, Hing,Rigoreau, Laurent,Vidot, Sandrine,Golding, Bernard T.,Griffin, Roger J.,Hammonds, Tim,Newell, David R.,Hardcastle, Ian R.
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supporting information
p. 444 - 455
(2016/08/16)
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- DIARYLPYRIDINE ANTI-VIRAL COMPOUNDS
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Disclosed herein are compounds and related compositions for the treatment of viral infection, including RNA viral infection, and compounds that can modulate the RIG-I pathway in vertebrate cells, including compounds that can activate the RIG-I pathway.
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Paragraph 0121; 0122
(2016/03/19)
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- Synthesis of 2-thioxo-4,6-diphenyl-1,2-dihydronicotinonitrile via condensation of benzaldehyde with cyanothioacetamide and p-(1-styryl)morpholine
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2-Thioxo-4,6-diphenyl-1,2-dihydronicotinonitrile has been prepared via condensation of benzaldehyde with cyanothioacetamide and N-(1-styryl)morpholine; alkylation of the product with alkyl halides has afforded substituted 2-alkylsulfanyl-4,6-diphenylnicotinonitriles and 3-amino-2-acyl-4,6-diphenylthieno[2,3-b]pyridines.
- Dyachenko,Dyachenko
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p. 1447 - 1451
(2015/08/03)
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- INTEGRASE INHIBITORS - 2
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The present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof. Compounds of formula (I) are also provided.
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Page/Page column 18
(2008/06/13)
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- INTEGRASE INHIBITORS 3
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The present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof. Compounds of formula (I) are also provided.
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Page/Page column 26-27
(2008/06/13)
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- INTEGRASE INHIBITORS - 1
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The present invention describes a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof. Compounds of formula (I) are also provided.
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Page/Page column 17
(2010/11/28)
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- SUBSTITUTED PYRIDO[3',2':4,5]THIENO[3,2-D]PYRIMIDINE-2,4(1 H,3H)-DIONES AND -4(3H)-ONES, SUBSTITUTED THIENO[2,3-D:4,5-D']DIPYRIMIDINE-2,4(1 H,3H)-DIONES AND -4(3H)-ONES, SUBSTITUTED PYRIDO[3',2':4,5]FURO[3,2-D]PYRIMIDINE-2,4(1 H,3H)-DIONES AND -4(3H)-ONES, AND SUBSTITUTED FURO[2,3-D:4,5-D']DIPYRIMIDINE-2,4(1 H,3H)-DIONES AN
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The invention relates to novel pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2,4(1 H,3H)-diones and -4(3H)-one (X=C-H, Y=S), thieno[2,3-d:4,5-d']dipyrimidine-2,4(1 H,3H)-diones and -4(3H)-one (X=N, Y=S), in addition to pyrido[3',2':4,5]furo[3,2-d]pyrimidine-2,4(1 H,3H)-diones and -4(3H)-one (X=C-H, Y=0) and furo[2,3-d:4,5-d']dipyrimidine-2,4(1 H,3H)-diones and -4(3H)-one (X=N, Y=O) of general formulae 1a and 1b. The invention also relates to a method for the production thereof, pharmaceutical preparations containing said compounds and/or tautomers thereof and physiologically compatible salts which can be produced therefrom and/or solvates thereof, in addition to the pharmaceutical use of said compounds, tautomers thereof, salts or solvates, as inhibitors of TNFa-release.
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Page/Page column 68
(2010/02/15)
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- One-pot synthesis of 4,6-diaryl-3-cyanopyridine-2(1H)-thiones and their transformation to substituted thieno[2,3-b;4,5-b]dipyridines and pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines
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4,6-Diaryl-3-cyanopyridine-2(1H)-thiones were synthesized in one step by the reaction of elemental sulfur, malononitrile, and 2-aryl-1-aroylethylenes in the presence of excess triethylamine. The products were used in one-pot syntheses of substituted thien
- Shestopalov,Nikishin,Gromova,Rodinovskaya
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p. 2203 - 2206
(2007/10/03)
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- CYCLIZATION OF NITRILES. XVII. METHODS FOR THE PRODUCTION OF 4,6-DIARYL-3-CYANO-2(1H)-PYRIDINETHIONES AND THEIR MASS-SPECTROMETRIC INVESTIGATION
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The boundaries of the methods for the synthesis of 2(1H)-pyridinethiones were extended.The reactions of 3-aroyl-2-aryl- and 3-aroyl-2-aryl-1-bromo-1,1-dicyanopropanes with sodium and morpholinium hydrosulfides and thiourea and of arylidenecyanothioacetamides and 3-aryl-2,4,4-tricyano-3-butenethioamides with acetophenone, and 1-(1-piperidino)-1-phenylethylene, and also the reactions of monothiodibenzoylmethane and 1,3-diphenyl-1-(1-piperidino)-1-propene-3-one with cyanothioacetamide, leading to 4,6-diaryl-3-cyano-2(1H)-pyridinethiones, were investigated.The use of substituted cyanothioacetamides seems most promising.Mass-spectrometric investigation of the obtained thiones showed that the main direction in the dissociation of their molecular ions is the elimination of the H, HS., and CS particles with the formation of the thiazepinium and pyridinium ions and the corresponding radical-cation of pyrrole.
- Promonenkov, V. K.,Shestopalov, A. M.,Sharanin, Yu. A.,Litvinov, V. P.,Rodinovskaya, L. A.,et al.
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p. 1797 - 1802
(2007/10/02)
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- SYNTHESIS OF 3-CYANO-4,6-DIARYL-3,4-DIHYDROPYRIDINE-2-THIONES
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3-Cyano-4,6-diaryl-3,4-dihydropyridine-2-thiones have been synthesized for the first time by the condensation of arylideneacetophenones or 1-piperidino-1-phenyl-2-benzoylethane with cyanothioacetamide and the 1,1-dicyano-2-aryl-3-benzoylpropane with hydrogen sulfide in the presence of bases.It has been established by PMR spectroscopy that 3-cyano-3,4-dihydropyridine-2-thiones exist in solutions in the form of mixture of cis and trans isomers.
- Krauze, A. A.,Kalme, Z. A.,Pelcher, Yu. E.,Liepin'sh, E. E.,Dipan, I. V.,Dubur, G. Ya.
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p. 1202 - 1207
(2007/10/02)
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- SYNTHESIS OF 3-OXOISOTHIAZOLOPYRIDINES
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3-Oxoisothiazolopyridines were synthesized for the first time by the reaction of 3-cyanopyridine-2-thiones or bis(3-cyanopyridyl) disulfides with concentrated sulfuric acid.It is demonstrated that 3-carbamoylpyridine-2-thiones are formed as intermediates.The 3-oxoisothiazolopyridines were converted to 3-bromoisothiazolopyridines and pyridine-2-thiones.The bromination of pyridine-2-thione was studied.
- Krauze, A. A.,Bomika, Z. A.,Pelcher, Yu. E.,Mazheika, I. B.,Dubur, G. Ya.
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p. 385 - 390
(2007/10/02)
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- SYNTHESIS AND SOME REACTIONS OF 3-CYANOPYRIDINE-2-THIONES
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New method for the synthesis of 3-cyanopyridine-2-thiones by the reaction of δ-keto nitroles with sulfur and by condensation of chalcones or benzylideneacetone with cyanothioacetamide are given.The compounds obtained were used in various reactions for the preparation of alkylated products, disulfides, and condensed heterocycles, viz., thienopyridines and pyridothienopyrimidines.
- Krauze, A. A.,Bomika, Z. A.,Shestopalov, A. M.,Rodinovskaya, L. A.,Pelcher, Yu. E',et al.
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p. 279 - 284
(2007/10/02)
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