Phidianidine A and Synthetic Analogues as Naturally Inspired Marine Antifoulants.

Christophe Labriere,Johan Svenson,Henrik Pavia,Hugo Denardou,Claire Hellio,Lindon W K Moodie,Karine Réhel,Jørn H Hansen,Vijayaragavan Elumalai,Gunnar Cervin,Tiffany Le Norcy,Jannie Staffansson

doi:10.1021/acs.jnatprod.0c00881

Abstract

Stationary and slow-moving marine organisms regularly employ a natural product chemical defense to prevent being colonized by marine micro- and macroorganisms. While these natural antifoulants can be structurally diverse, they often display highly conserved chemistries and physicochemical properties, suggesting a natural marine antifouling pharmacophore. In our current report, we investigate the marine natural product phidianidine A, which displays several chemical properties found in highly potent marine antifoulants. Phidianidine A and synthetic analogues were screened against the settlement and metamorphosis of Amphibalanus improvisus cyprids, and several of the compounds displayed inhibitory activities at low micromolar concentrations with IC50 values down to 0.7 μg/mL observed. The settlement study highlights that phidianidine A is a potent natural antifoulant and that the scaffold can be tuned to generate simpler and improved synthetic analogues. The bioactivity is closely linked to the size of the compound and to its basicity. The study also illustrates that active analogues can be prepared in the absence of the natural constrained 1,2,4-oxadiazole ring. A synthetic lead analogue of phidianidine A was incorporated in a coating and included in antifouling field trials, where it was shown that the coating induced potent inhibition of marine bacteria and microalgae settlement.

Highlights

Stationary and slow-moving marine organisms regularly employ a natural product chemical defense to prevent being colonized by marine micro- and macroorganisms
A particular group of marine natural products (MNP) with broad antifouling activities are brominated dipeptidic derivatives often isolated from stationary marine organisms.[5]
The library of compounds was designed to probe the contribution of structure to the activity as previously successfully demonstrated for natural antifoulants.[35−37] With an emphasis on ease of preparation, only 1 was prepared with the 1,2,4-oxadiazole ring motif according to published routes.[38]

Summary

■ CONCLUSIONS

The antifouling potential of the MNP phidianidine A (1) has been established, and our study illustrates that 1 is a potent, nontoxic inhibitor of barnacle cyprid metamorphosis. The crude product was purified by silica gel column chromatography [(CH2Cl2: 100 to MeOH: 100)] to afford 8e as a pale-yellow oil (61 mg, 8%) 1H NMR (400 MHz, Methanol-d4) δ 7.68−7.56 (m, 1H), 7.15 (ddt, J = 8.9, 6.2, 2.8 Hz, 1H), 7.11−6.99 (m, 2H), 3.80−3.59 (m, 2H), 3.31−3.21 (m, 2H), 3.03−2.77 (m, 3H), 2.56−2.41 (m, 2H), 1.36−1.21 (m, 4H), 1.14− 0.94 (m, 4H). The diboc-intermediate compound (confirmed by HRMS) was used without further purification and dissolved in TFA:CH2Cl2 (1:1, 10 mL), and the reaction mixture was stirred at room temperature for 2 h, quenched with H2O, extracted with CH2Cl2 (2 × 10 mL), washed with H2O (2 × 10 mL), and the solvent was removed under reduced pressure to afford 9d as brown oil (19 mg, 26%).

Corresponding Author

■ ACKNOWLEDGMENTS

■ REFERENCES