An efficient methodology was developed to avail novel N,N’-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 OSIRIS property explorer online, 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 to reference inhibitor N3 (-10.95 Kcal/mol), whereas, compounds S1, S2 and S4 recorded comparable binding energies -9.89 Kcal/mol, -10.84 Kcal/mol and -10.94 Kcal/mol with reference inhibitor N3, however much better than remdesivir (-9.85 Kcal/mol). In case of SARS-CoV-2 Mpro, all compounds S1-S4 with docking energy values as -7.28, -8.38, -8.31 and -7.34 Kcal/mol were found potent in comparison to reference inhibitor N3 (-6.31 Kcal/mol) as well as remdesivir (-6.33 Kcal/mol). Ligand efficiency values against the target SARS-CoV-2 proteins as well as α-glucosidase and DNA-(apurinic or apyrimidinic site) lyase inhibition results of these newly synthesized compounds were also found promising.
Fragment‐based
in silico
design of SARS CoV‐2 main protease inhibitors