Structure-Activity Relationship Probing of the Natural Marine Antifoulant Barettin

The sponge derived 2,5-diketopiperazine metabolite barettin is a potent antifouling compound effective against the settlement and metamorphosis of barnacles. Simplified derivatives of barettin have previously been shown to display similar inhibitory properties. The synthetic derivative benzo[g]dipodazine has been reported to display significantly improved antifouling properties in comparison with the native barettin with inhibitory activities as low a 0.034 µM reported against barnacle cyprid settlement. In the current study we report the antifouling activity of 29 synthetic analogs designed and inspired by the potent antifouling effect seen for benzo[g]dipodazine. The library contains mainly not only dipodazine derivatives but also disubstituted diketopiperazines and compounds incorporating alternative heterocyclic cores such as hydantoin, creatinine, and rhodanine. Several of the prepared compounds inhibit the settlement of Amphibalanus improvisus cyprids at low micromolar concentrations, in parity with the natural barettin. While several highly active compounds were prepared by incorporating the benzo[g]indole as hydrophobic substituent, the remarkable antifouling effect reported for benzo[g]dipodazine was not observed when evaluated in our study.