Design, Synthesis, and Antibacterial Activity of Citral Derivatives Containing Schiff Base Structures

Abstract

The growing threat posed by antimicrobial resistance is making current therapies increasingly ineffective, underscoring the urgent need for novel antimicrobial agents. To address this challenge, a series of novel Schiff base‐containing citral derivatives were synthesized through structural modification of citral. Their antibacterial activities were evaluated by determining the minimum inhibitory concentrations (MICs) against Staphylococcus aureus , Escherichia coli , Pseudomonas aeruginosa , and Candida albicans . Compound A5 exhibited the most potent activity among the tested compounds against E. coli (MIC = 0.06 mg/mL), outperforming the positive control kanamycin sulfate (MIC = 0.08 mg/mL), highlighting its potential as an antibacterial drug candidate. To further explore its mechanism of action, we integrated 3D‐QSAR modeling with molecular docking simulations. The 3D‐QSAR rationalized the influence of molecular spatial conformation, charge distribution, hydrophobic interactions, and hydrogen bonding on antibacterial activity, while the molecular docking simulations deciphered the interaction pattern of compound A5 with the target bacterial protein. This combined approach provides a theoretical basis for understanding the antibacterial mechanism of citral derivatives and offers a novel strategy for the application of citral in medicinal chemistry.