Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused of COVID-19 has posed a major global health crisis in 2019. Herein, six stilbene-coumarin derivatives were synthesized from the natural chalcone dimethylcardamonin (DMC, 5) isolated from Syzygium nervosum. Their antiviral potential against COVID-19 was evaluated by measuring the inhibition of the SARS-CoV-2 main protease (3CL^pro), a biological macromolecule, using FRET-based enzymatic assay. The results demonstrated that this scaffold effectively suppressed the proteolytic activity of 3CL^pro. Structure-activity relationship analysis indicated that an optimal alkyl substitution length at C-3 position of the coumarin ring comprises six carbon atoms. Among the synthesized derivatives, compound 7c exhibited the strongest inhibitory activity, with an IC<inf>50</inf> value of 20.73 µM, approximately four times more potent than the reference flavonoid baicalein. Furthermore, molecular dynamics simulation provided atomistic insights into the interactions between the stilbene-coumarin derivatives and 3CL^pro, revealing plausible binding orientations within the active site. Complementary, Molecular Mechanics Generalized Born Surface Area (MM-GBSA) and fragment molecular orbital (FMO) calculations highlighted key residues that play critical roles in stabilizing the binding of these compounds.