Synthesis, Antibacterial Activity and 3D‐QSAR of Citral Derivatives as Potential Antimicrobials

Abstract The emergence of drug resistance has progressively diminished the efficacy of many antimicrobial agents, thereby underscoring the urgency of discovering novel antimicrobials. In this study, 26 citral derivatives were synthesized through structural modifications of citral monoterpenes, which exhibited diverse biological activities. Their antimicrobial efficacy was evaluated by determining the minimum inhibitory concentrations (MICs) against four microorganisms: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa , and Candida albicans . Our findings revealed that compound B4 demonstrated potent anti‐ Candida albicans activity, with an MIC of 0.05 mg/mL, outperforming the positive control drug fluconazole (MIC = 5.34 mg/mL). These results highlight the promising antibacterial properties of citral derivatives.To gain a deeper understanding of the underlying mechanisms, we employed 3D‐QSAR modeling to elucidate the impact of molecular spatial structure, charge distribution, hydrophobic interactions, and hydrogen bonding on the antibacterial activity of these compounds. Additionally, molecular docking simulations were conducted to unravel the interactions between compound B4 and bacterial proteins. This comprehensive investigation offers invaluable insights into the antimicrobial mechanisms of citral derivatives, providing theoretical support for their prospective application as antimicrobial agents and introducing innovative strategies to address the challenge of antimicrobial resistance.