Structure-Antifouling Activity Relationship and Molecular Targets of Bio-Inspired(thio)xanthones.

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 (, , , , and ) of the tested xanthones showed in vivo activity toward the settlement of larvae (EC: 3.53-28.60 µM) and low toxicity to this macrofouling species (LC > 500 µM and LC/EC: 17.42-141.64), and two of them ( and ) showed no general marine ecotoxicity (<10% of mortality) after 48 h of exposure. Regarding the mechanism of action in mussel larvae, the best performance compounds and might be acting by the inhibition of acetylcholinesterase activity (in vitro and in silico studies), while and showed specific targets (proteomic studies) directly related with the mussel adhesive structure (byssal threads), given by the alterations in the expression of 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.