Citral derivatives as drug resistance reversal agents against Staphylococcus aureus: Synthesis, in vitro, and in silico investigations

Citral, a natural monoterpene aldehyde, is used in fragrances, food, and pharmaceuticals. However, its high hydrophobicity, volatility, and sensitivity to oxidative degradation limit its applications. This study aims to address these challenges by developing novel citral derivatives with antibacterial and drug resistance reversal properties. Citral was used as a primary synthon for the synthesis of chalcone-like derivatives (C-1 - C-6) via aldol condensation, and imine derivatives were obtained by condensing citral with hydrazine (C-7), heptyl amine (C-8), glycine ethyl ester (C-9), and 4-amino piperidine (C-10). Citral showed MICs of 500 and 1000 μg/mL against a sensitive strain of Staphylococcus aureus (MTCC-96) and a methicillin-resistant S. aureus (MRSA) clinical isolate, respectively. Compared with the parent compound citral, its derivatives C-6, C-8, and C-10 showed 8-fold greater antibacterial activity against the MRSA clinical isolate. In fixed-dose combinatorial studies, at a 10 μg/mL concentration of the derivatives, the MIC of ethidium bromide (EtBr, MIC 7.81 μg/mL) was reduced up to fourfold. The derivatives showed favorable physicochemical and ADMET profiles in in silico predictions and docked well with the efflux pump proteins NorA, NorB, and MepA, as well as the biofilm targets IcaA, IcaB, and IcaC. The binding affinities of C-4, C-8, and C-10 for biofilm protein icaC were further verified through 200 ns molecular dynamics simulations. Overall, C-8 and C-10 may be useful for developing safe and cost-effective treatments for S. aureus infections.