Despite the significant development in vaccines and therapeutics cocktails, there is no specific treatment available for coronavirus disease 2019 (COVID‐19), caused by the new severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Targeting the main protease (Mpro) of SARS‐CoV‐2, which possesses a key role in producing the essential viral structural and functional proteins, can be considered an efficient way to control this potentially lethal infection. Recently, some of Michael acceptor‐pharmacophore containing inhibitors have been suggested as successful suppressors of the main protease. Here, we synthesized the Isatin‐based Schiff bases possessing the structural pattern of a Michael acceptor‐like portion employing synthesis procedures. In silico investigation of these compounds was not limited to the main protease. We have also evaluated their possible inhibitory activity against the other identified druggable targets using homology modeling, molecular docking, and molecular dynamics simulations. Our investigations revealed that the dimethyl biguanide carrying Schiff bases of Isatin‐derivatives have the best binding mode and interaction energy. The dimethyl biguanide moiety‐containing compounds have formed promising interactions with the key amino acid residues Cys145 and HIS41 of Mpro with a binding free energy of −7.6 kcal/mol which was lower than the positive control compound Carmofur (−6.3 kcal/mol). It also leads to the higher affinity and the much inhibitory potential against the SARS‐CoV‐2 RdRp and Spike glycoproteins, human TMPRSS2, and ACE2 receptors.
