Advancing infection therapy: the role of novel menthol-based antimicrobials

In this work, 17 derivatives were synthesised by combining halogenated and non-halogenated cinnamoyl scaffolds with menthol and tested against a panel of Gram-positive and Gram-negative bacteria. Among the synthesised derivatives, <b>MF1</b> and <b>MCl2</b> demonstrated enhanced therapeutic potential. <b>MF1</b> showed the most potent antimicrobial activity (MIC values ranging from 8 to 64 mg/L against <i>E. faecium</i>), representing a significant improvement over menthol, with a five-fold reduction in MIC₅₀. Additionally, <b>MF1</b> effectively reduced biofilm biomass production by 50% in <i>S. aureus</i> and by 20% in <i>P. aeruginosa</i> at sub-MIC concentrations. <b>MCl2</b> reduced biomass by up to 40% in <i>A. baumannii</i> at the lowest subMIC concentrations tested (0.06 x MIC). Moreover, <b>MCl2</b> showed potential as a wound healing agent promoting fibroblast-mediated repair within just 24 h. Notably, both compounds exhibited no cytotoxic effects. Molecular docking and molecular dynamics simulations confirmed strong binding affinity and high stability of <b>MF1</b> and <b>MCl2</b> with the target protein.