Novel 23-Hydroxybetulinic Acid Derivatives: Semi-Synthesis and Antibacterial Activity

A novel series of 23-hydroxybetulinic acid derivatives were designed and synthesized, in which some compounds displayed good antibacterial activity with MIC values of 4–16 μg/mL against gram-positive bacteria and moderate inhibitory activity (16–32 μg/mL) against gram-negative bacteria. 23-O-6-Aminohexyl[3,2-b]pyrazine oleanan-28,19β-lactone demonstrated the most potent antibacterial activity against S. aureus, B. subtilis, E. coli, and P. aeruginosa with MICs ranging from 4 to 16 μg/mL. Additional testing against drug-resistant bacteria (MRSA and K. pneumonia) showed 23-O-6-aminohexyl[3,2-b]pyrazine oleanan-28,19β-lactone also possessed good antibacterial activity (4–32 μg/mL). In addition, this lactone interacted effectively with cell membranes, posed negligible cytotoxicity to mammalian cells, and rapidly curbed the growth of MRSA and E. coli, while not significantly enhancing bacterial resistance. The subsequent assay of bactericidal time-kill kinetics revealed that 23-O-6-aminohexyl[3,2-b]pyrazine oleanan-28,19β-lactone showed excellent bactericidal activity against MRSA at 3MIC (> 6 log₁₀ CFU/mL reduction) after 9 h, whereas the positive control group only demonstrated inhibitory activity. Additionally, study of drug-likeness properties suggest that these molecules may have drug-likeness characteristics, potentially improving membrane absorption and bioavailability.