Design, synthesis, and biological activity evaluation of dihydromyricetin derivatives against SARS-CoV-2-Omicron virus

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 3CL^pro 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.

Graphical abstract

Figure 1.

The chemical structure of dihydromyricetin, myricetin, compounds a and b, CoViTris2020, ChloViD2020, and Taroxaz-104.

Scheme 1.

One-pot synthesis route of compounds 3–10.

Figure 2.

Inhibitory effect of compounds 1–10 against 3CL^pro at 1.0 μM. Note: n = 3, mean ± SD. Compared with the DHM: *p < .05 and **p < .01.

Figure 3.

SAR of dihydromyricetin derivatives inhibition SARS-CoV-2 3CL^pro.

Figure 4.

Molecular docking of compounds 1(DHM), 3, 5, and 10 with 3CL^pro. (A) Schematic diagram, (B) 3D enlargement, and (C) 2D schematic of the hydrogen-bond interaction between compounds 1, 3, 5, 10, and 3CL^pro, respectively.

Figure 5.

The chemical structure of compounds 3, 5, and 10.