Synthesis and anti-SARS-CoV-2 evaluation of lipid prodrugs of β-D-N4-hydroxycytidine (NHC) and a 3′-fluoro-substituted analogue of NHC

Wen, Zhiping; Wang, Mengmeng; Li, Lingyun; Herdewijn, Piet; Snoeck, Robert; Andreï, Graciela; Liu, Zhaopeng; Liu, Chao

doi:10.1016/j.bioorg.2023.106527

Cited by 4 publications

(2 citation statements)

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“…Differences in the antiviral activity of the studied ether derivatives may be explained by differences in how they are hydrolysed and metabolised. Following oral administration, these NHC prodrugs undergo hydrolysis and subsequent metabolism, as previously shown for similar prodrugs [ 19 , 48 , 49 ]. In the derivatives of phenylpropionic acid and phenoxyacetic acid (SN_21-SN_23), the distance of the phenyl radical from the carbonyl of the ester group apparently leads to an easier nucleophilic attack of the OH-serine in the active site of the carboxylesterase on the ester group with the formation of an enzyme–substrate complex and subsequent hydrolysis, reduces the hydrolysis time and increases metabolism.…”

Section: Resultsmentioning

confidence: 71%

“…To overcome the limitations in the use of approved and developed drugs based on nucleoside analogues with anti-SARS-CoV-2 activity, the development of drugs with high oral bioavailability and high efficiency of metabolism to their triphosphate forms is required, which often leads to an increase in their antiviral activity [ 16 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Antiviral Activity of Novel β-D-N4-Hydroxycytidine Ester Prodrugs as Potential Compounds for the Treatment of SARS-CoV-2 and Other Human Coronaviruses

Darnotuk,

Siniavin,

Shastina

et al. 2023

Pharmaceuticals

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The spread of COVID-19 infection continues due to the emergence of multiple transmissible and immune-evasive variants of the SARS-CoV-2 virus. Although various vaccines have been developed and several drugs have been approved for the treatment of COVID-19, the development of new drugs to combat COVID-19 is still necessary. In this work, new 5′-O-ester derivatives of N4-hydroxycytidine based on carboxylic acids were developed and synthesized by Steglich esterification. The antiviral activity of the compounds was assessed in vitro—inhibiting the cytopathic effect of HCoV-229E, and three variants of SARS-CoV-2, on huh-7 and Vero E6 cells. Data have shown that most synthesized derivatives exhibit high activity against coronaviruses. In addition, the relationship between the chemical structure of the compounds and their antiviral effect has been established. The obtained results show that the most active compound was conjugate SN_22 based on 3-methyl phenoxyacetic acid. The results of this study indicate the potential advantage of the chemical strategies used to modify NHC as a promising avenue to be explored in vivo, which could lead to the development of drugs with improved pharmacological properties that potently inhibit SARS-CoV-2.

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Section: Resultsmentioning

confidence: 71%