Design, Synthesis and Biological Exploration of Novel N -(9-Ethyl-9 H -Carbazol-3-yl)Acetamide-Linked Benzofuran-1,2,4-Triazoles as Anti-SARS-CoV-2 Agents: Combined Wet/Dry Approach Targeting Main Protease (M pro ), Spike Glycoprotein and RdRp

A novel series of substituted benzofuran-tethered triazolylcarbazoles was synthesized in good to high yields (65-89%) via -alkylation of benzofuran-based triazoles with 2-bromo- -(9-ethyl-9 -carbazol-3-yl)acetamide. The inhibitory potency of the synthesized compounds against SARS-CoV-2 was evaluated by enacting molecular docking against its three pivotal proteins, namely, M (main protease; PDB ID: 6LU7), the spike glycoprotein (PDB ID: 6WPT), and RdRp (RNA-dependent RNA polymerase; PDB ID: 6M71). The docking results indicated strong binding affinities between SARS-CoV-2 proteins and the synthesized compounds, which were thereby expected to obstruct the function of SARS proteins. Among the synthesized derivatives, the compounds , , , and exposited the best binding scores of -8.77, -8.76, -8.87, and -8.85 Kcal/mol against M , respectively, -6.69, -6.54, -6.44, and -6.56 Kcal/mol against the spike glycoprotein, respectively, and -7.61, -8.10, -8.01, and -7.54 Kcal/mol against RdRp, respectively. Furthermore, the binding scores of (-8.83 Kcal/mol) and (-8.92 Kcal/mol) against 6LU7 are worth mentioning. Regarding the spike glycoprotein, , , and expressed high binding energies of -6.43, -6.38, and -6.41 Kcal/mol, accordingly. Correspondingly, the binding affinity of (-7.62 Kcal/mol) against RdRp is also noteworthy. Furthermore, the potent compounds were also subjected to ADMET analysis to evaluate their pharmacokinetic properties, suggesting that the compounds , , , and exhibited comparable values. These potent compounds may be selected as inhibitory agents and provide a pertinent context for further investigations.