Chemical studies of Mangifera indica twigs yielded two compounds, identified as taraxerol (1) and methyl gallate (2). The galloyl moiety was suggested as a potential scaffold that can interfere with proteases by previous biological investigations on SARS-CoV-2 main protease (Mpro) 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 Mpro and NS2B/NS3 of Zika and Dengue viruses. Among the obtained compounds, 2e and 2i were the most potent against Mpro with IC50 values of 2.60 and 4.0 μM, respectively. Compounds 2f and 2g 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 2e and 2f showing moderate inhibition with IC50 values of 66.0 and 59.29 μM, respectively. It was found that 2f and 2g inhibited ZIKV NS2B/NS3 via a noncompetitive mechanism. The study also showed that 2e and 2f 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.
© 2024 The Authors. Published by American Chemical Society.