Application of partially aromatic ortho-quionone-methides for the synthesis of novel naphthoxazines with improved antibacterial activity

Starting from naphthols and morpholine and using ethyl glyoxylate as the aldehyde component in the modified Mannich reaction, new aminonaphthol derivatives substituted with 2- and 1-naphthol were synthesised. The stabilization of precursor bifunctional compounds via partially aromatic ortho-quinone methide intermediate was tested with different cyclic imines in [4 + 2] cycloaddition. Based on 1H NMR analysis, in the case of new α-amino acid esters the formation of a single product has been assumed. The NOE spectrum proved that the relative configuration of the newly formed stereogenic centres was trans. The compounds have also been tested in bacteria in order to reduce or reverse antibiotic resistance. Compounds 13 and 14 could inhibit the efflux pump system in susceptible and methicillin-resistant Staphylococcus aureus strains. [Display omitted] •By reacting 2- or 1-naphthol, morpholine and ethyl glyoxylate new substituted glycine precursors were synthesized.•The bifunctional precursors were transformed to new naphthoxazine-fused heterocycles via [4+2] cycloaddition.•The relative configurations of the newly generated stereogenic centres by using NMR spectroscopy were determined.•The antibacterial and efflux pump inhibiting activity of the new derivatives has also been tested.