Targeted synthesis of alkylated coumarin derivatives as SARS-CoV-2 main protease inhibitors: Cascade addition, alkylation, molecular docking, and ADME evaluation

This study focuses on the synthesis of alkylated coumarin derivatives as SARS-CoV-2 main protease inhibitors using a one-pot cascade addition followed by alkylation. Three different types of coumarins (1, 3, and 5) were used as starting materials, and a cascade addition followed by alkylation reaction was employed to efficiently obtain a range of novel compounds. A total of 12 derivatives (2a, 2b, 2c, 2d, 4a, 4b, 4c, 4d, 4e, 6a, 6b, and 6c) were synthesized with high yields (80–95 %), confirmed using 1H NMR, 13C NMR, HRMS, and single-crystal X-ray diffraction techniques. Molecular docking studies, conducted with AutoDock Vina, demonstrated strong binding affinities of the derivatives to the SARS-CoV-2 main protease, with binding energies ranging from (−5.4 kcal/mol to −6.0 kcal/mol). Among these, compounds 4c, 4d, and 6c, exhibited the strongest binding interactions, particularly with key active site residues, including His41, Met49, Gly143, Cys145, and Met165, which are essential for protease inhibition. These binding energies outperformed the reference drug hydroxychloroquine (HCQ with binding energy of −5.5 kcal/mol), highlighting their strong inhibitory potential. Physicochemical and ADME (absorption, distribution, metabolism, and excretion) analysis showed that all synthesized compounds met key drug-likeness criteria, including Lipinski's, Veber's, Egan's, Ghose's, and Muegge's rules. The derivatives displayed molecular weights ranging from 300.31 g/mol to 423.50 g/mol, logP values between 2.25 and 3.74, and TPSA values of 69.67 Ų to 78.90 Ų, suggesting favourable oral bioavailability. These findings suggest that the synthesized compounds are promising candidates for further development as SARS-CoV-2 main protease inhibitors.