Synthesis and Analgesic Activity of New Heterocyclic Cyanothioacetamide Derivatives

Bibik, Igor V.; Bibik, E. Yu.; Dotsenko, V. V.; Фролов, К. А.; Кривоколыско, С. Г.; Аксенов, Н. А.; Аксенова, И. В.; Shcherbakov, S. V.; Ovcharov, S. N.

doi:10.1134/s107036322102002x

Cited by 18 publications

(6 citation statements)

References 60 publications

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“…A similar reaction with 5-methylisatin led to the formation of a mixture of 1 H-thiolate 14a and 3 H-thiolate 14b in a molar ratio of 7:3 and yield of 83%. In the context of our interest in exploring the chemistry of biologically active nicotinonitriles [70][71][72][73][74][75][76][77][78][79] and indole-nicotinonitrile hybrids [80], it seemed reasonable to prepare new 6′-amino-5′-cyano-2-oxo-1,2-dihydro-1′H-spiro[indole-3,4′-pyridine]-3′-carboxamides and to study their reactions and properties.…”

Section: Synthesismentioning

confidence: 99%

“…In the context of our interest in exploring the chemistry of biologically active nicotinonitriles [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ] and indole–nicotinonitrile hybrids [ 80 ], it seemed reasonable to prepare new 6′-amino-5′-cyano-2-oxo-1,2-dihydro-1′ H -spiro[indole-3,4′-pyridine]- 3′-carboxamides and to study their reactions and properties.…”

Section: Introductionmentioning

confidence: 99%

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New 6′-Amino-5′-cyano-2-oxo-1,2-dihydro-1′H-spiro[indole-3,4′-pyridine]-3′-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity

et al. 2023

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The purpose of this work was to prepare new isatin- and monothiomalondiamide-based indole derivatives, as well as to study the properties of the new compounds. The four-component reaction of 5-R-isatins (R = H, CH3), malononitrile, monothiomalonamide (3-amino-3-thioxo- propanamide) and triethylamine in hot EtOH yields a mixture of isomeric triethylammonium 6′-amino-3′-(aminocarbonyl)-5′-cyano-2-oxo-1,2-dihydro-1′H- and 6′-amino-3′-(aminocarbonyl)- 5′-cyano-2-oxo-1,2-dihydro-3′H-spiro[indole-3,4′-pyridine]-2′-thiolates. The reactivity and structure of the products was studied. We found that oxidation of spiro[indole-3,4′-pyridine]-2′-thiolates with DMSO-HCl system produced only acidification products, diastereomeric 6′-amino-5′-cyano-5-methyl-2-oxo-2′-thioxo-1,2,2′,3′-tetrahydro-1′H-spiro-[indole-3,4′-pyridine]- 3′-carboxamides, instead of the expected isothiazolopyridines. The alkylation of the prepared spiro[indole-3,4′-pyridine]-2′-thiolates upon treatment with N-aryl α-chloroacetamides and α-bromoacetophenones proceeds in a regioselective way at the sulfur atom. In the case of α-bromoacetophenones, ring-chain tautomerism was observed for the S-alkylation products. According to NMR data, the compounds consist of a mixture of stereoisomers of 2′-amino-6′-[(2-aryl- 2-oxoethyl)thio]-3′-cyano-2-oxo-1′H-spiro[indoline-3,4′-pyridine]-5′-carboxamides and 5′-amino- 3′-aryl-6′-cyano-3′-hydroxy-2-oxo-2′,3′-dihydrospiro[indoline-3,7′-thiazolo[3,2-a]pyridine]-8′-carboxamides in various ratios. The structure of the synthesized compounds was confirmed by IR spectroscopy, HRMS, 1H and 13C DEPTQ NMR studies and the results of 2D NMR experiments (1H-13C HSQC, 1H-13C HMBC). Molecular docking studies were performed to investigate suitable binding modes of some new compounds with respect to the transcriptional regulator protein PqsR of Pseudomonas aeruginosa. The docking studies revealed that the compounds have affinity for the bacterial regulator protein PqsR of Pseudomonas aeruginosa with a binding energy in the range of −5.8 to −8.2 kcal/mol. In addition, one of the new compounds, 2′-amino-3′-cyano-5-methyl- 2-oxo-6′-{[2-oxo-2-(p-tolylamino)ethyl]thio}-1′H-spiro-[indoline-3,4′-pyridine]-5′-carboxamide, showed in vitro moderate antibacterial effect against Pseudomonas aeruginosa and good antioxidant properties in a test with 1,1-diphenyl-2-picrylhydrazyl radical. Finally, three of the new compounds were recognized as moderately active herbicide safeners with respect to herbicide 2,4-D in the laboratory experiments on sunflower seedlings.

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Section: Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New 6′-Amino-5′-cyano-2-oxo-1,2-dihydro-1′H-spiro[indole-3,4′-pyridine]-3′-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity

et al. 2023

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“…3-Cyanopyridine-2(1H)-thiones belong to the most important groups of S,N-heterocyclic compounds. According to a number of studies, cyanothioacetamide derivatives can currently be considered promising for the search for new highly effective and safe drugs with a variety of pharmacodynamic effects (Krivokolysko et al 2021;Krivokolysko et al 2022;Bibik et al 2021). They are structurally similar to biologically active compounds that were useful for preparation of antihypertensive, antihistamine, antiparkinsonian, diuretic and antitumor drugs.…”

Section: Introductionmentioning

confidence: 99%

Empirical determination of the degree of analgesic activity of some new 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines based on a complex criterion

Bibik

Фролов

et al. 2023

RRP

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Introduction: It is revelant to solve the problem of anesthesia based on the research of new highly effective and safe medicines. Among modern studies, the preparation of heterocyclic compounds starting from cyanothioacetamide with analgesic and anti-inflammatory activities is of considerable interest. Materials and Methods: болевой синдром Results: It is shown that all the studied 1,4-dihydropyridines and condensed thieno[2,3-b]pyridines and reveal analgesic activity of varying degrees of severity, based on the values of the criterion Anat. Discussion: It was found that the most pronounced analgesic activity was shown by three studied samples: compounds AZ-023, AZ-331 and AZ-383. The complex criterion of analgesic activity of Anat for animals receiving a sample AZ-023 was 50.1, exceeding the indicator in the comparison group by 42 times. The values of this criterion in animals that had received samples AZ-331 and AZ-383 were the highest, namely 64.3 and 68.4, which is 53 and 57 times higher than that of sodium metamizole, respectively. Conclusion: The obtained results and the advantage of the studied samples over the reference drug determine the expediency of further preclinical studies and a detailed study of their acute and chronic toxicity, as well as hepato-, nephro-, hemato- and gastrotoxicity. Graphical Abstract

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“…Nitrogen-based heterocycles represent a major key structural basis for numerous commercialized approved drugs [9]. The unique physicochemical properties of these heterocycles have garnered increased attention in designing and synthesizing new molecules, several of which display significant biological activities [10][11][12][13][14][15][16][17]. Recently, several libraries of N-heterocyclic compounds have been prepared and assessed for their anti-SARS-CoV-2 activities [18][19][20], resulting in a considerable number of drug candidates currently in clinical trials [21,22].…”

Section: Introductionmentioning

confidence: 99%

Design of Novel Enantiopure Dispirooxindolopyrrolidine-Piperidones as Promising Candidates toward COVID-19: Asymmetric Synthesis, Crystal Structure and In Silico Studies

Toumi

Boudriga

Mandour³

et al. 2022

Molecules

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Despite the effectiveness of COVID-19 vaccines, there is still an urgent need for discovering new anti-viral drugs to address the awful spread and transmission of the rapidly modifiable virus. In this study, the ability of a small library of enantiomerically pure spirooxindolopyrrolidine-grafted piperidones to inhibit the main protease of SARS-CoV-2 (Mpro) is evaluated. These spiroheterocycles were synthesized by 1,3-dipolar cycloaddition of various stabilized azomethine ylides with chiral dipolarophiles derived from N-[(S)-(-)-methylbenzyl]-4-piperidone. The absolute configuration of contiguous carbons was confirmed by a single crystal X-ray diffraction analysis. The binding of these compounds to SARS-CoV-2 Mpro was investigated using molecular docking and molecular dynamics simulation. Three compounds 4a, 4b and 4e exhibited stable binding modes interacting with the key subsites of the substrate-binding pocket of SARS-CoV-2 Mpro. The synthesized compounds represent potential leads for the development of novel inhibitors of SARS-CoV-2 main protease protein for COVID-19 treatment.

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Synthesis and Analgesic Activity of New Heterocyclic Cyanothioacetamide Derivatives

Cited by 18 publications

References 60 publications

New 6′-Amino-5′-cyano-2-oxo-1,2-dihydro-1′H-spiro[indole-3,4′-pyridine]-3′-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity

New 6′-Amino-5′-cyano-2-oxo-1,2-dihydro-1′H-spiro[indole-3,4′-pyridine]-3′-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity

Empirical determination of the degree of analgesic activity of some new 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines based on a complex criterion

Design of Novel Enantiopure Dispirooxindolopyrrolidine-Piperidones as Promising Candidates toward COVID-19: Asymmetric Synthesis, Crystal Structure and In Silico Studies

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