AbstractNatural products with a sulfated scaffold have emerged as antifouling agents with low or nontoxic effects to the environment. In this study 13 sulfated polyphenols were synthesized and tested for antifouling potential using the anti-settlement activity of mussel (Mytilus galloprovincialis) plantigrade post-larvae and bacterial growth inhibition towards four biofilm-forming bacterial strains. Results show that some of these Nature-inspired compounds were bioactive, particularly rutin persulfate (2), 3,6-bis(β-D-glucopyranosyl) xanthone persulfate (6), and gallic acid persulfate (12) against the settlement of plantigrades. The chemical precursors of sulfated compounds 2 and 12 were also tested for anti-settlement activity and it was possible to conclude that bioactivity is associated with sulfation. While compound 12 showed the most promising anti-settlement activity (EC₅₀ = 8.95 μg.mL⁻¹), compound 2 also caused the higher level of growth inhibition in bacteria Vibrio harveyi (EC₂₀ = 12.5 μg.mL⁻¹). All the three bioactive compounds 2, 6, and 12 were also found to be nontoxic to the non target species Artemia salina (<10% mortality at 250 μM) and Vibrio fischeri (LC₅₀ > 1000 μg.mL⁻¹). This study put forward the relevance of synthesizing non-natural sulfated small molecules to generate new nontoxic antifouling agents.