Prenylated phenylpropanoids from enzyme catalysis and their antibacterial activities.

Phenylpropanoids are a large class of natural products with C6-C3 as the backbone. Research has shown that prenyl units can increase the lipophilicity of compounds, enhance their affinity with biofilms, and improve their bioavailability. In this work, the prenylations of phenylpropanoids with three prenyl donors including dimethylallyl diphosphate (DMAPP), geranyl diphosphate (GPP), and farnesyl diphosphate (FPP) by two fungal prenyltransferases were investigated. A total of 11 products (1D1a, 1D1 - 1D3, 1G, 2D1 - 2D4, 2G, and 3G) were obtained, two of which are dearomative prenylated products (1D1a and 2D2), and one of which is a gem-diprenylated product (2D2). Ten products have not been reported prior to this study. The antibacterial activities of substrates (1-3) and nine products against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) were tested. In vitro, compound 1D2 displayed potent activity against S. aureus (MIC = 0.186 μM), a 5-fold potency increase than the clinical antibiotic ciprofloxacin (MIC = 0.945 μM) under identical assay conditions, suggesting 1D2 is a promising lead-like compound for developing new antibiotics. This work establishes a new synthetic strategy for prenylated phenylpropanoids, thereby expanding the structural diversity of this class of compounds. Furthermore, it provides a foundation for developing new therapeutic agents against S. aureus.