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

Madalena Pinto,Vitor Vasconcelos,Emília Sousa,Aldo Barreiro Felpeto,Micaela Freitas,Andreia Palmeira,Joana R. Almeida,Alexandre Campos,Isabel Cunha,Marta Correia-da-Silva,Maria V. Turkina

doi:10.3390/biom10081126

Madalena Pinto, Vitor Vasconcelos + Show 9 more

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https://doi.org/10.3390/biom10081126

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Abstract

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 (4, 5, 7, 10, 15 and 17) of the tested xanthones showed in vivo activity toward the settlement of Mytilus galloprovincialis larvae (EC50: 3.53–28.60 µM) and low toxicity to this macrofouling species (LC50 > 500 µM and LC50/EC50: 17.42–141.64), and two of them (7 and 10) showed no general marine ecotoxicity (<10% of Artemia salina mortality) after 48 h of exposure. Regarding the mechanism of action in mussel larvae, the best performance compounds 4 and 5 might be acting by the inhibition of acetylcholinesterase activity (in vitro and in silico studies), while 7 and 10 showed specific targets (proteomic studies) directly related with the mussel adhesive structure (byssal threads), given by the alterations in the expression of Mytilus 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.

Highlights

Biofouling is the temporary or permanent adhesion of organisms on water submerged man-made surfaces
The following 19 xanthone derivatives were synthesized according to previously described procedures [21,22,23,24]: 1-hydroxy- (1), 2-hydroxy-(2), 3-hydroxy-(3), 4-hydroxy-(4), 1,2-dihydroxy-(5), 2,3-dihydroxy-(6), 3,4-dihydroxy-(7), 3,6-dihydroxy-(8), 1,3-dihydroxy-2-methyl-(9), 4-dihydro-12-hydroxy-2,2-dimethyl-2H,6H-pyrano [3,2-b]xanthone (10), 2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-7H-1,4-dioxino[2,3-c]-(11)
The synthesis of the following thioxanthone derivatives was performed according to described procedures [25]: 1-(Isobutylamino)-4-propoxy-9H-thioxanthen-9-one (12), 1-((2(diethylamino)ethyl)amino)-4-propoxy-9H-thioxanthen-9-one (13), 1-[(3,4-dimethoxybenzyl)amino]4-propoxy-9H-thioxanthen-9-one (14), 1-[11]-4-propoxy-9H-thioxanthen-9-one (15), 1-[(3,4,5trimethoxyphenyl)amino]-4-propoxy-9H-thioxanthen-9-one (16), 1-(piperidin-1-yl)-4-propoxy-9Hthioxanthen-9-one (17), 1-[(3,5-dimethoxyphenyl)amino]-4- propoxy-9H-thioxanthen-9-one (18), and 1-[2-(phenylamino)ethyl]amino]-4-propoxy-9H-thioxanthen-9-one (19)

Summary

Introduction

Biofouling is the temporary or permanent adhesion of organisms on water submerged man-made surfaces It starts with the adsorption of a film of molecules and particles a few minutes after immersion, followed by the adhesion of bacteria, cyanobacteria, unicellular algae, and protozoa that form biofilms (microfouling) [1]. These organisms release biochemical cues that transmit specific information to the environment [2]. Biniofmoorlmecualetsio2n02t0o, 1t0h, e11e2n6 vironment [2] Such cues reach conspecifics and organisms of other spe2coife1s7, influencing the settlement, and metamorphosis of specific macrofouling species [3]

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