An efficient methodology was developed to generate novel N,N0-dialkyl-2-thiobarbituric acid based sulfonamides S1–S4 in good to excellent yields 84%–95%. The synthesized compounds S1–S4 were docked to screen their in silico activities against two enzymes i.e., SARS-CoV-2 main protease enzyme with unliganded active site 2019-nCoV, coronavirus disease 2019, COVID-19 PDB ID: 6Y84 and SARS-CoV-2 Mpro PDB ID: 6LU7. Furthermore, some in silico physicochemical and physicokinetic properties were evaluated using the OSIRIS Property Explorer, Molinspiration property calculator, ADMET property calculator, and GUSAR to assess these compounds as potential candidates as lead compounds for the quest of SARS-CoV-2 main protease inhibitors. Molecular docking analyses of the synthesized compounds predicted that compound S3 is more potent as SARS-CoV-2 main protease inhibitor with binding energy –11.65 kcal/mol in comparison with reference inhibitor N3 –10.95 kcal/mol, whereas compounds S1, S2, and S4 recorded comparable binding energies –9.89, –10.84, and –10.94 kcal/mol with reference inhibitor N3, which were much better than remdesivir –9.85 kcal/mol. In case of SARSCoV- 2 Mpro, all compounds S1–S4 with docking energy values of –7.28, –8.38, –8.31, and –7.34 kcal/mol, respectively, were found to be potent in comparison with reference inhibitor N3 –6.31 kcal/mol and remdesivir –6.33 kcal/mol. Ligand efficiency values against the target SARS-CoV-2 proteins, as well as a -glucosidase and DNA-apurinic or apyrimidinic site lyase inhibition results of these newly synthesized compounds, were also found to be promising.