Three‐Dimensional Quantitative Structure–Activity Relationship, Antimicrobial Activity, and Molecular Docking Studies of C‐14 Chiral Matrine Derivatives as Potential Antibiotics

Antibiotic resistance is recognized as one of the top ten global public health threats, posing a significant challenge to human health. The stereochemistry of chiral molecules, alongside their specific interactions with biological targets, provides essential insights for the development of novel antibacterial agents, This study investigated the antibacterial activity of 32 previously synthesized 14-position chiral matrine derivatives. Among these derivatives, compound Q4 exhibited the strongest activity against Propionibacterium acnes, with a minimum inhibitory concentration (MIC) of 0.007 mg/mL, surpassing that of the positive control (MIC = 0.016 mg/mL). Additionally, compounds Q20 and Q2 demonstrated antibacterial activities comparable to the positive controls. The results indicated that R-configured compounds exhibited significantly greater antibacterial potency than their S-configured counterparts. A systematic analysis using three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling elucidated the relationship between molecular structure and antibacterial activity, emphasizing the predominance of steric fields over electrostatic fields, in alignment with experimental observations. Furthermore, molecular docking confirmed the binding interactions between compound Q4 and the target protein. In conclusion, We identified a series of matrine derivatives with notable antibacterial activity and constructed a 3D-QSAR model based on their MIC values. Among these, Q4 emerged as a promising antibacterial agent, warranting further development.