| Summary: | The development of alternative ecological and effective antifouling technologies is still challenging. Synthesis of nature-inspired compounds has been exploited, given the potential to assure commercial supplies of potential ecofriendly antifouling agents. In this direction, the antifouling activity of a series of nineteen synthetic small molecules, with chemical similarities with natural products, were exploited in this work. Six (<b>4</b>, <b>5</b>, <b>7</b>, <b>10</b>, <b>15</b> and <b>17</b>) of the tested xanthones showed in vivo activity toward the settlement of <i>Mytilus galloprovincialis</i> larvae (EC<sub>50</sub>: 3.53–28.60 µM) and low toxicity to this macrofouling species (LC<sub>50</sub> > 500 µM and LC<sub>50</sub>/EC<sub>50</sub>: 17.42–141.64), and two of them (<b>7</b> and <b>10</b>) showed no general marine ecotoxicity (<10% of <i>Artemia salina</i> mortality) after 48 h of exposure. Regarding the mechanism of action in mussel larvae, the best performance compounds <b>4</b> and <b>5</b> might be acting by the inhibition of acetylcholinesterase activity (in vitro and in silico studies), while <b>7</b> and <b>10</b> showed specific targets (proteomic studies) directly related with the mussel adhesive structure (byssal threads), given by the alterations in the expression of <i>Mytilus</i> collagen proteins (PreCols) and proximal thread proteins (TMPs). A quantitative structure-activity relationship (QSAR) model was built with predictive capacity to enable speeding the design of new potential active compounds.
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