Abstract
An oxidising and substituting one-pot reaction strategy has been developed to synthesise dihydromyricetin derivatives with the aim of enhancing the inhibitory activity of dihydromyricetin against SARS-CoV-2. Different ω-methoxy-ω-oxeylkyl was introduced in C7-OH site and yielded eight analogs, all of them showed good inhibitory activity against SARS-CoV-2 3CLpro with IC50 values ranging from 0.72 to 2.36 μM. In the Vero E6-cell, compound 3 has a good activity of anti-SARS-CoV-2 virus (Omicron virus BA.5) in the prevention model, with an EC50 of 15.84 μM, and so do compound 10 in the therapeutic model, with an EC50 of 11.52 μM. The results suggest that the introduction of long chain ω-oxeylkyl at C7-OH facilitate the inhibition of viral replication in the therapeutic model, which is consistent with the binding energies predicted from molecular docking conclusions. It implies that dihydromyricetin derivatives have the potential to become effective inhibitors of SARS-CoV-2 Omicron and other viruses.
Keywords:
Dihydromyricetin; Omicron virus BA.5; SARS-CoV-2 3CLpro; flavone; synthesis.
MeSH terms
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Animals
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Antiviral Agents* / chemical synthesis
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Antiviral Agents* / chemistry
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Antiviral Agents* / pharmacology
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Chlorocebus aethiops
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Coronavirus 3C Proteases / antagonists & inhibitors
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Coronavirus 3C Proteases / metabolism
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Dose-Response Relationship, Drug
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Drug Design*
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Flavonols* / chemical synthesis
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Flavonols* / chemistry
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Flavonols* / pharmacology
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Humans
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Microbial Sensitivity Tests
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Molecular Docking Simulation
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Molecular Structure
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SARS-CoV-2* / drug effects
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Structure-Activity Relationship
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Vero Cells
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Virus Replication / drug effects
Substances
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dihydromyricetin
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Antiviral Agents
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Flavonols
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Coronavirus 3C Proteases
Grants and funding
This work was supported by the Natural Science Foundation of Hunan Province (No. 2021JJ30502), Scientific research project of Hunan Provincial Education Department (No. 21A0239), Open Fund Project of Hunan Province Laboratory of Natural Medicinal Resources and Functions (No. 2022ZYYGN01), Pharmaceutical Open Fund of Domestic First-class Disciplines of Hunan Province (No. 2021YX06) and Undergraduate Student Innovation and Entrepreneurship Training Program of National and Hunan Province (No. S202310541069, 2023–2246).