Design, Synthesis, and Antibacterial Activity of Long-Chain Alkyl-Substituted DemethyloxyAaptamine Derivatives

Demethyloxyaaptamine, isolated from the marine sponge Aaptos aaptos, features a 1H-benzo[de][1,6]naphthyridine core and exhibits potent antibacterial activity. To systematically investigate its underexplored antibacterial properties and facilitate structural optimization, we constructed a focused library of 28 C-3 alkylamino–substituted derivatives of demethyloxyaaptamine via regioselective functionalization. In vitro evaluation against Staphylococcus aureus revealed that several derivatives possess minimum inhibitory concentrations (MICs) superior to vancomycin. Structure–activity relationship analysis (SAR) demonstrated that the incorporation of moderately hydrophobic alkylamino groups at the C-3 position markedly improved antimicrobial efficacy. Mechanistic investigations demonstrated that these compounds inhibit bacterial growth by targeting bacterial membrane. Together, these findings validate demethyloxyaaptamine as a privileged scaffold for targeting drug-resistant Gram-positive pathogens and deliver critical SAR insights to guide the design of next-generation antibiotics.