Effect of new derivatives of 6,7-dimethoxyquinazoline-4(3H)-one with amino acid residues and dipeptide fragments on the activity of the main protease (Mpro) and papain-like protease (PLpro) of SARS-CoV-2

Introduction . A novel coronavirus infection caused by the SARS-CoV-2 virus is a highly contagious disease with a signifi cant risk of complications up to mortality. The development of anti-SARS-CoV-2 drugs began almost immediately after the identifi cation of the virus, while two promising pharmacological targets were identifi ed: the main and papain-like proteases.

Aim . Evaluation of the eff ect of new derivatives of 6,7-dimethoxyquinazoline-4(3H)-one with amino acid residues and dipeptide fragments on the activity of SARS-CoV-2 proteases in vitro.

Materials and methods . The studied substances were obtained from commercially available 2-amino- 4,5-dimethoxybenzoic acid which were cyclized into 2-alkyl-6,7-dimethoxy-3,1-benzoxazine-4-ones, followed by reaction with amino acids and dipeptides. The changes in the activity of viral proteases were evaluated with spectrophotometry using the appropriate substrates. During the study, the half maximal inhibitory concentration (IC50) was calculated. 

Results . As a result, it was found that the obtained compounds exhibit pronounced inhibitory activity with respect to both the main and papain-like protease of SARS-CoV-2 with an IC50 range of 0.012–0.100 and 0.013-0.100 μM/ml, respectively. The most pronounced eff ect was shown for the 3h compound with a fragment of the glycyl-tryptophan dipeptide with the isopropyl radical, which reduced the activity of the main protease (IC50 0.012 ± 0.005 μM/ml) and the papainlike protease (IC50 0.013 ± 0.009 μM/ml).

Conclusion . Compound 3h containing the isopropyl radical and the glycyl-tryptophan dipeptide may become a promising object for further study and development of a new antiviral agent based on it.

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