Inhibitory Effects of <i>Mangifera indica</i> Secondary Metabolites and Their Synthetic Derivatives against SARS-CoV-2 M^pro and NS2B/NS3 (ZIKV and DENV-2)

Chemical studies of <i>Mangifera indica</i> twigs yielded two compounds, identified as taraxerol (<b>1</b>) and methyl gallate (<b>2</b>). The galloyl moiety was suggested as a potential scaffold that can interfere with proteases by previous biological investigations on SARS-CoV-2 main protease (M^pro) inhibitors in combination with docking studies. Therefore, a series of 13 gallate esters were prepared by treating gallic acid with natural and non-natural alcohols. Their inhibitory effects were evaluated against M^pro and NS2B/NS3 of Zika and Dengue viruses. Among the obtained compounds, <b>2e</b> and <b>2i</b> were the most potent against M^pro with IC₅₀ values of 2.60 and 4.0 μM, respectively. Compounds <b>2f</b> and <b>2g</b> were more potent than others against ZIKV protease with IC₅₀ values of 2.7 and 1.9 μM, respectively. The bioactivity profile against DENV NS2B/NS3 was different with <b>2e</b> and <b>2f</b> showing moderate inhibition with IC₅₀ values of 66.0 and 59.29 μM, respectively. It was found that <b>2f</b> and <b>2g</b> inhibited ZIKV NS2B/NS3 via a noncompetitive mechanism. The study also showed that <b>2e</b> and <b>2f</b> could exert noncompetitive inhibition at the previously described allosteric pocket of flaviviral NS2B/NS3 proteases. Molecular docking revealed different types of interactions among the most prominent were hydrogen bonding with the galloyl moiety.