Towards eco-friendly marine antifouling biocides – Nature inspired tetrasubstituted 2,5-diketopiperazines

Marine biofouling plagues all maritime industries at vast economic and environmental cost. Previous and most current methods to control biofouling have employed highly persistent toxins and heavy metals, including tin, copper, and zinc. These toxic methods are resulting in unacceptable environmental harm and are coming under immense regulatory pressure. Eco-friendly alternatives are urgently required to effectively mitigate the negative consequence of biofouling without causing collateral harm. Amphiphilic micropeptides have recently been shown to exhibit excellent broad-spectrum antifouling activity, with a non-toxic mode of action and innate biodegradability. The present work focused on incorporating the pharmacophore derived from amphiphilic micropeptides into a 2,5-diketopiperazine (DKP) scaffold. This privileged structure is present in a vast number of natural products, including marine natural product antifoulants, and provides advantages of synthetic accessibility and adaptability. A novel route to symmetrical tetrasubstituted DKPs was developed and a library of amphiphilic 2,5-DKPs were subsequently synthesised. These biodegradable compounds were demonstrated to be potent marine antifoulants displaying broad-spectrum activity in the low micromolar range against a range of common marine fouling organisms. The outcome of planned coating and field trials will dictate the future development of the lead compounds.