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

Demethyloxyaaptamine, isolated from the marine sponge <i>Aaptos aaptos</i>, features a <i>1H</i>-benzo[<i>de</i>][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. <i>In vitro</i> evaluation against <i>Staphylococcus aureus</i> 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.