Synthesis, Antibacterial Activity, and Mechanism of C-6 Aminated β-Carboline Derivatives Against MRSA

Background: The escalating spread of drug-resistant bacteria is intensifying the antibiotic resistance crisis, necessitating the urgent development of novel antimicrobial agents to address the resulting high global mortality rates and significant socioeconomic burden. Objectives: This study aimed to aminate the C-6 position of β-carboline and investigate the antibacterial activity and mechanism of action of the derivatives. Results: For the first time, 16 derivatives with various nitrogen-containing moieties, including aliphatic- and phenyl-amino, imidazolium, pyridinium, and quinolinium, were synthesized via amination at the C-6 position of β-carboline. These compounds exhibited moderate to good activity against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and Bacillus subtilis, with minimum inhibitory concentration (MIC) values ranging from 1.56 to 100 μg/mL. The study reveals that elongating an alkyl chain, incorporating a cationic scaffold, and expanding a π-delocalized system can enhance antibacterial activity. The most potent derivative from each series was selected for further mechanistic investigation against MRSA. All studied compounds demonstrated low hemolytic activity and low cytotoxicity. Studies on the antibacterial mechanism indicated that the compounds exert their antibacterial effects by disrupting bacterial cell walls and membranes. Additionally, two of the compounds were found to potentially disrupt the secondary structure of DNA. All tested compounds exhibited antibiofilm activity. Conclusions: Our findings demonstrate that amination modification at the C-6 position of β-carboline can enhance antibacterial activity by disrupting the cell wall membranes and interacting with bacterial DNA. These results provide a basis for further optimization of antibacterial agents based on β-carboline.