From Natural Xanthones to Synthetic C-1 Aminated 3,4-Dioxygenated Xanthones as Optimized Antifouling Agents

Abstract

Biofouling, which occurs when certain marine species attach and accumulate in artificial submerged structures, represents a serious economic and environmental issue worldwide. The discovery of new non-toxic and eco-friendly antifouling systems to control or prevent biofouling is, therefore, a practical and urgent need. In this work, the antifouling activity of a series of 24 xanthones, with chemical similarities to natural products, was exploited. Nine (1, 2, 4, 6, 8, 16, 19, 21, and 23) of the tested xanthones presented highly significant anti-settlement responses at 50 μM against the settlement of mussel Mytilus galloprovincialis larvae and low toxicity to this macrofouling species. Xanthones 21 and 23 emerged as the most effective larval settlement inhibitors (EC50 = 7.28 and 3.57 µM, respectively). Additionally, xanthone 23 exhibited a therapeutic ratio (LC50/EC50) > 15, as required by the US Navy program attesting its suitability as natural antifouling agents. From the nine tested xanthones, none of the compounds were found to significantly inhibit the growth of the marine biofilm-forming bacterial strains tested. Xanthones 4, 6, 8, 16, 19, 21, and 23 were found to be non-toxic to the marine non-target species Artemia salina (<10% mortality at 50 μM). Insights on the antifouling mode of action of the hit xanthones 21 and 23 suggest that these two compounds affected similar molecular targets and cellular processes in mussel larvae, including that related to mussel adhesion capacity. This work exposes for the first time the relevance of C-1 aminated xanthones with a 3,4-dioxygenated pattern of substitution as new non-toxic products to prevent marine biofouling.

Natural and Synthetic Xanthone Derivatives Counteract Oxidative Stress via Nrf2 Modulation in Inflamed Human Macrophages

“…Xanthones 2 – 11 , 13 – 37 , 39 , and 40 ( Table 1 ) were previously synthesized in our laboratory in the scope of other projects via three traditional methods ( Scheme 1 ) [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]: condensation of salicylic acid or salicylic ester with a phenol derivative (a), via benzophenone (b), or via diphenyl ether intermediates (c).…”

Novel metabolite madeirone and neomarinone extracted from Streptomyces aculeoletus as marine antibiofilm and antifouling agents

“…This napyradiomycins displayed settlement results of M. galloprovincialis larvae with an EC 50 of less than 5 μg/mL and a LC 50 /EC 50 ratio greater than 15 (Pereira et al, 2020). Further, the EC 50 of (2) was lower than that of other synthesized compounds or compounds from distinct bioresources (Neves et al, 2021;Pereira et al, 2021;Resende et al, 2021).…”

Research Progress on New Environmentally Friendly Antifouling Coatings in Marine Settings: A Review

“…The secondary metabolite xanthone derivatives, which are widely present in marine and terrestrial plants and animals, have been shown to have antifouling activity yet are still not used for marine antifouling. Resende et al [ 47 ] explored the antifouling activity of a series of 24 synthetic xanthone analogs for the first time to further explore the potential of xanthone derivatives for antifouling. The test results showed that xanthones 21 and 23 (the chemical molecular structure is shown in Figure 8 ) were the most effective in inhibiting larval sedimentation (EC 50 of 7.28 and 3.57 µM, respectively), and, with a therapeutic ratio (LC 50 /EC 50 ) > 15 for xanthone 23, this synthetic analog has great potential for marine antifouling applications.…”