Two Novel 1,4‐Naphthoquinone Derivatives as Potent Agents Against Multidrug‐Resistant Staphylococcus aureus and Pathogenic Gram‐Positive Bacteria

Drug-resistant bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA) and Quinolone-resistant S. aureus (QRSA), are a growing problem, creating a need for the development of novel antimicrobial agents. In this study, we designed and synthesized two novel 1,4-naphthoquinone derivatives, LHN-1034 and LHN-1035, and evaluated their antibacterial efficacy. Both compounds exhibited great antimicrobial activity against a group of Gram-positive bacteria, including MRSA and QRSA, with Minimum Inhibitory Concentrations (MICs) ranging from 50 to 100 µM. Mechanism studies revealed that the antibacterial effect is oxygen-dependent. The compounds act as redox-cycling agents that induce intracellular reactive oxygen species (ROS), which disrupts cell membrane integrity and leads to cell lysis. In silico assessments predict low intestinal absorption and skin permeability, suggesting these compounds are suited for topical application. In conclusion, LHN-1034 and LHN-1035 are candidates for developing topical agents against resistant Gram-positive infections.