Synthesis and antibacterial evaluation of a unique amide library based on the marine natural product 3,5-dibromo-4-methoxybenzoic acid

Chemical investigations of the Australian marine sponge Ianthella basta resulted in the isolation of six known secondary metabolites, which included bastadins 4 ( 1 ), 5, ( 2 ) 8 ( 3 ) and 13 ( 4 ), 3,5-dibromo-4-methoxybenzeneacetic acid ( 5 ) and 3,5-dibromo-4-methoxybenzoic acid ( 6 ). The screening of these metabolites for inhibitory activity towards Pseudomonas aeruginosa (strain PAO1) for planktonic cell growth and biofilm formation identified metabolite 6 as a biofilm inhibitor. Based on these data a 13 membered semisynthetic amide library was generated using metabolite 6 as a scaffold for medicinal chemistry studies. Whilst none of the new semisynthetic compounds increased inhibitory activity towards PAO1 compared to the original scaffold, additional screening of the natural and semisynthetic library against the clinically relevant strain PDO300 showed that some of the secondary metabolites inhibited planktonic growth and biofilm formation. Furthermore, all semisynthetic compounds displayed increased inhibitory activity of planktonic growth with N,N' -((butane-1,4-diylbis(azanediyl))bis(propane-3,1-diyl))bis(3,5-dibromo-4-methoxybenzamide) ( 19 ) displaying 46 % planktonic inhibition and 3,5-dibromo- N -(4-fluorophenethyl)-4-methoxybenzamide ( 14 ) inhibiting biofilm formation by 21 % at 50 μM. All semisynthetic derivatives were obtained in yields ranging from 3 % to 79 %, and in purities >95 %. All new natural product derivatives were fully characterized following 1D/2D NMR, LRESIMS and HRESIMS data analysis; two semisynthetic compounds were crystalline, which enabled X-ray diffraction studies. The new chemistry and biology reported here indicate that the bastadin and 3,5-dibromo-4-methoxybenzoic acid motifs warrant further investigation against P. aeruginosa . • Chemical investigations were carried out on the marine sponge Ianthella basta . • One natural product was used as a scaffold for medicinal chemistry. • 13 new amide derivatives were synthesised and fully characterised. • All compounds were evaluated for Pseudomonas aeruginosa activity. • One compound showed moderate P. aeruginosa PAO1 biofilm formation inhibition.