Synthesis and Antiviral Properties against SARS-CoV-2 of Epoxybenzooxocino[4,3-b]Pyridine Derivatives

Stalinskaya, Alena L.; Martynenko, Nadezhda V.; Shulgau, Zarina; Shustov, Alexandr V.; Keyer, Viktoriya V.; Кулаков, И. В.

doi:10.3390/molecules27123701

Cited by 11 publications

(5 citation statements)

References 42 publications

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“…Gilead Sciences researchers discovered that adenosine C-nucleoside with 1'-CN modification had potent anti-Ebola virus action in Hela cells and human umbilical vein endothelial cells. Remdesivir is the name of this potent substance (9). A nucleoside analogue called remdesivir (GS-5734; Gilead Sciences Inc., USA) functions as a competitive inhibitor of viral RNA-dependent RNA polymerase.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Remdesivir Derivate as a Generation of Anti-COVID-19 Drugs Through Acetylation Reactions

2023

ARI

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Remdesivir, a competitive inhibitor of viral RNA-dependent RNA polymerase, is the drug of choice for anti-COVID-19 treatment. However, the instability of these substances in plasma raises doubts about their therapeutic potency. Additionally, SARS-CoV-2-infected cells may exhibit a variety of antiviral behaviors due to intricate activation pathways. Therefore, this study aimed to develop a synthesis for the remdesivir derivative. The remdesivir derivative was synthesized using acetyl chloride as a reagent in a ratio of 1:3 in dichloromethane and tetrahydrofuran solvent at 30°C for 6 h. Thin-layer chromatography and spectrophotometers (1H NMR and 13C NMR) were used to identify the produced molecule, which was a brownish-yellow crystalline powder. The results of the synthesis yielded 0.8 gr (77.34%), and the Rf value of the remdesivir derivate was 0.54. The characterization with 1H NMR at δ2.5 ppm (3H, s) indicated the presence of a proton in the H-C-C=O structure caused by the substitution of the acetyl group in the remdesivir structure. The 13C NMR data indicated the presence of aromatic carbons, alkenes, C≡N, and carbon bonds with electronegative O. This remdesivir derivate chemical can be a potential candidate for an anti-COVID-19 drug that has more potency because it has substitutions of acetyl groups at positions 2' and 3' in the structure of remdesivir.

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Section: Discussionmentioning

confidence: 99%

Synthesis of Remdesivir Derivate as a Generation of Anti-COVID-19 Drugs Through Acetylation Reactions

2023

ARI

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“…In addition, we also tested modified 5H-5,11-epoxybenzo [7,8]oxocino [4,3b]pyridine 3a derivatives for antiviral and bacteriostatic activity [24,25]. One of the synthesized compounds demonstrated high cytotoxicity and clear inhibition of the SARS-CoV-2 virus replication [24]. At the same time, a number of synthesized oxocino [4,3-b]pyridine derivatives 3a showed pronounced and average anti-tuberculosis activity along with moderate antibacterial and antifungal activity [25].…”

Section: Synlettmentioning

confidence: 99%

“…This allows us to suppose the antiviral potential of the previously obtained epoxybenzo [7,8]oxocino [4,3-b]pyridine derivatives as synthetic analogues of natural integrastatins A, B. In addition, we also tested modified 5H-5,11-epoxybenzo [7,8]oxocino [4,3b]pyridine 3a derivatives for antiviral and bacteriostatic activity [24,25]. One of the synthesized compounds demonstrated high cytotoxicity and clear inhibition of the SARS-CoV-2 virus replication [24].…”

Section: Synlettmentioning

confidence: 99%

“…24 25 One of the synthesized compounds demonstrated high cytotoxicity and clear inhibition of the SARS-CoV-2 virus replication. 24 At the same time, a number of synthesized oxocino[4,3- b ]pyridine derivatives 3a showed pronounced and average antituberculosis activity along with moderate antibacterial and antifungal activity. 25 In this regard, the purpose of this study was to test the possibility of synthesizing pyrimidine structural analogues of natural integrastatins by the acid-catalyzed cyclization of salicylic aldehyde with pyrimidine 4-methyl-5-acetyl derivatives.…”

Section: Table 1 Reaction Of Pyrimidine 1...mentioning

confidence: 99%

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Synthesis of a New Heterocyclic System: Pyrimidine Structural Analogues of Natural Integrastatins A, B

Kulakov,

Chikunov,

Pustolaikina

et al. 2024

Synlett

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In this paper for the first time we report simple one-step synthesis of 5-methyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidine derivatives by acid-catalyzed cyclization reaction of various 4-methyl-5-acetyl pyrimidine derivatives with salicylic aldehyde. It was shown that 2-substituted 4-methyl-5-acetylpyrimidines successfully react to form a cyclization product. At the same time, 4-methyl-5-acetylpyrimidines with a substituent in the 6th position do not enter into the cyclization reaction. This may be caused by the negative effect of substituents in the 6th position, which hinder the free rotation of the acetyl group and prevent the formation of a stable pre-reaction complex. The structure of the obtained 5-methyl-11,12-dihydro-5H-5,11-epoxybenzo[7,8]oxocino[4,3-d]pyrimidine derivatives was confirmed using 1H, 13C spectroscopy, mass spectrometry and X-ray diffraction analysis.

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“…Epoxybenzo[7,8]oxocino[4,3- b ]pyridine derivatives were synthesized and tested for antiviral and bacteriostatic activities in our previous works. 14 15 One of the synthesized compounds demonstrated high cytotoxicity and pronounced inhibition of SARS-CoV-2 viral replication. It was also shown that a series of synthesized oxocino[4,3- b ]pyridine derivatives perform pronounced and moderate antituberculous activity along with moderate antibacterial and antifungal activity.…”

Section: Synthesismentioning

confidence: 99%

Synthesis of New Structural Analogues of Natural Integrastatins with a Basic Epoxybenzo[7,8]oxocine Skeleton: Combined Experimental and Computational Study

Kulakov,

Stalinskaya,

Chikunov

et al. 2023

Synthesis

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In this work, the cyclization reactivity of various 3-acetyl-2-methylpyridines (including 3-acetyl-2-methylquinoline) containing both electron donor and acceptor substituents with salicylaldehyde into epoxybenzooxocino[4,3-b]pyridine derivatives was studied. The reactions were carried out in mild (under room temperature or reflux in 2-propanol) and harsh (in a sealed glass ampoule) conditions. It was shown that 3-acetyl-2-methylpyridines with an aryl substituent in the 4-position do not react with salicylaldehyde either under normal convection heating conditions or under more severe conditions. This effect was explained by the steric hindrance of the substituents using quantum chemical calculations. It was found that electron donor substituents in 3-acetyl-2-methylpyridines significantly facilitate cyclization in epoxybenzooxocino[4,3-b]pyridines. The presence of electron acceptor substituents (NO2 group for example) in the 5-position of pyridine prevents cyclization under normal conditions, but gives a rather high conversion to oxocinopyridines under more specific conditions. This effect is quantum-chemically explained by the decrease in the basicity of pyridine. Pyridines with two pairs of methyl groups in ortho-positions to the acetyl group are capable to form mixtures of regioisomeric epoxybenzooxocinopyridines. Further, epoxybenzooxocinopyridines with methyl and acetyl groups can form a mixture of diastereomeric bisoxocins under more specific conditions. All 17 initial pyridines were studied quantum-chemically in order to understand what features of their structure and properties affect the success of the cyclization reaction and the yield of the target product. The pyridine molecules were calculated by the DFT RB3LYP/6-311++G(d,p) method taking into account the alcohol solvent within the CPCM model using Gaussian-2016 program. It was shown that the absence of steric hindrances in the form of bulky substituents in 4-position of pyridines is the main factor affecting the success of the cyclization reaction. Also, the yield of the target product is affected by the CH-acidity of the methyl group in 2-position, which, in turn, is affected by electron-donating and electron-withdrawing substituents in the 5- and 6-positions.

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Synthesis and Antiviral Properties against SARS-CoV-2 of Epoxybenzooxocino[4,3-b]Pyridine Derivatives

Cited by 11 publications

References 42 publications

Synthesis of Remdesivir Derivate as a Generation of Anti-COVID-19 Drugs Through Acetylation Reactions

Synthesis of Remdesivir Derivate as a Generation of Anti-COVID-19 Drugs Through Acetylation Reactions

Synthesis of a New Heterocyclic System: Pyrimidine Structural Analogues of Natural Integrastatins A, B

Synthesis of New Structural Analogues of Natural Integrastatins with a Basic Epoxybenzo[7,8]oxocine Skeleton: Combined Experimental and Computational Study

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