Inhibitory Effects\nof Mangifera indica Secondary Metabolites\nand Their Synthetic Derivatives against SARS-CoV‑2\nM<sup>pro</sup> and NS2B/NS3 (ZIKV and DENV-2)

Chemical studies of Mangifera indica twigs yielded two compounds, identified as taraxerol (<b>1</b>) and methyl gallate (<b>2</b>). The galloyl moiety was suggested\nas a potential scaffold that can interfere with proteases by previous\nbiological investigations on SARS-CoV-2 main protease (M<sup>pro</sup>) inhibitors in combination with docking studies. Therefore, a series\nof 13 gallate esters were prepared by treating gallic acid with natural\nand non-natural alcohols. Their inhibitory effects were evaluated\nagainst M<sup>pro</sup> and NS2B/NS3 of Zika and Dengue viruses. Among\nthe obtained compounds, <b>2e</b> and <b>2i</b> were the\nmost potent against M<sup>pro</sup> with IC<sub>50</sub> values of\n2.60 and 4.0 μM, respectively. Compounds <b>2f</b> and <b>2g</b> were more potent than others against ZIKV protease with\nIC<sub>50</sub> values of 2.7 and 1.9 μM, respectively. The\nbioactivity profile against DENV NS2B/NS3 was different with <b>2e</b> and <b>2f</b> showing moderate inhibition with IC<sub>50</sub> values of 66.0 and 59.29 μM, respectively. It was\nfound that <b>2f</b> and <b>2g</b> inhibited ZIKV NS2B/NS3\nvia a noncompetitive mechanism. The study also showed that <b>2e</b> and <b>2f</b> could exert noncompetitive inhibition at the\npreviously described allosteric pocket of flaviviral NS2B/NS3 proteases.\nMolecular docking revealed different types of interactions among the\nmost prominent were hydrogen bonding with the galloyl moiety.