L juglone showed the inhibition rate of much less than ten . The improved steric

L juglone showed the inhibition rate of much less than ten . The improved steric hindrance with the annulated phenyl ring caused detrimental effects on binding 7-methyl juglone using the target enzyme. The methylation of 7-methyl juglone led to a drop within the CA Ⅱ Inhibitor Purity & Documentation activity at low concentrations, and 7-methyl juglone methyl ether (22) didn’t show any inhibitory effects towards the target enzyme in the concentration of 0.1 mM. Protection from the phenolic hydroxyl group with a methoxy methyl ether moiety also had deleterious effects because the Mpro inhibition price of compound 24 was reduce than 5 at concentrations of significantly less than 1.0 mM. By contrast, each acylation and benzylation with the phenolic hydroxyl group of 7-methyl juglone brought on an increase in potency at the concentration of 0.1 mM. The benzylated compound 25 exhibited an IC50 value of 160.68 17.83 nM towards the target enzyme (Table S3), which was much less than three-quarters of the value for the acylated derivative 23 (IC50 220.90 14.03 nM). Molecular docking. To be able to achieve an insight into the binding interaction of investigated naphthoquinones with SARS-CoV-2 Mpro enzyme, we performed molecular docking studies according to the crystal structures of Mpro in complex using the peptide-like inhibitor N3 (PDB ID: 6LU7). As shown in Fig. 3, each juglone (a), propionyl juglone (b) and 2-acetyl-8-methoxy-1,4naphthoquinone (c) tightly fit the active web-site cavity with the enzyme. Juglone was bound towards the target enzyme with the calculated binding power of .6771 kJ/mol. The docking outcomes indicated that the C(1) carbonyl group formed a hydrogen bond with Gly143 amino acid residue. An additional hydrogen bonding interaction among the phenolic hydroxyl group and Glu166 was also observed. The molecular docking study of propionyl juglone with all the crystal structure of Mpro (Fiure 3, b) showed that this ligand fit well into the substrate binding internet site of Mpro enzyme. Propionyl juglone was bound for the target enzyme with the calculated binding power of 7.3199 kJ/mol, which was the lowest worth for all the predicted 30 binding models in MOE molecular docking. The oxygen atom of the C(4) carbonyl group underwent simultaneous Hbonding interactions with all the backbone NH of Gly143 and also the hydroxyl group of Ser144. 2-Acetyl-8-methoxy-1,4-naphthoquinone (15) as the mostFig. 2. SARs evaluation of juglone and its derivatives as SARS-CoV-2 Mpro inhibitors.J. Cui and J. JiaEuropean Journal of Medicinal Chemistry 225 (2021)Fig. 3. The predicted binding modes of juglone (a), propionyl juglone (b) and 2-acetyl-8-methoxy-1,4-naphthoquinone (c) inside the active internet site cavity of Mpro.potent inhibitor against the target enzyme inside the study was also bound for the substrate binding web page of Mpro (Fig. 3, c). The C(4) carbonyl group was oriented towards the imidazole moiety of His41 using the formation of a hydrogen bonding interaction. The oxygen atom around the acetyl substitution also hydrogen bonded together with the backbone of NH of Gly143. The methoxy group of compound 15 was placed towards Glu166, and there was an H-bonding interaction between the oxygen atom within the methoxy group and NH in the amide backbone of Glu166. The tight binding interaction amongst 2acetyl-8-methoxy-1,4-naphthoquinone (15) and the target enzyme need to clarify its potent inhibitory activity against the Bcl-xL Inhibitor list enzymatic activity of Mpro. Cytotoxicity of Juglone and its derivatives. The ideal antivirus agents were those ones that acted by inhibiting viral replication, but devoid of cytotoxicity.