Synthesis and Biological Evaluation of Novel Cinnamic Acid-Based Antimicrobials

(1) Background: The main antimicrobial resistance (AMR) nosocomial strains (ESKAPE pathogens such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are the most widespread bacteria in cutaneous infections. In this work, we report the synthesis, in silico skin permeability prediction, and antimicrobial, antibiofilm, and wound healing properties of novel cinnamic acid-based antimicrobials (DM1–11) as novel antibacterial drugs for the treatment of ESKAPE-related skin infections. (2) Meth-ods: Antimicrobial and wound healing scratch assays were performed to evaluate the antibacterial properties of DM1–11. In silico skin permeability capabilities of DM1–11 were evaluated using Swiss-ADME online database. Cytotoxicity assays were performed on keratinocytes and fibroblasts. (3) Results: DM2, bearing a catechol group on the aromatic ring of the cinnamic portion of the molecule, possesses a significant antibacterial activity against S. aureus (MIC range 16–64 mg/L) and contrasts the biofilm-mediated S. epidermidis infection at low concentrations. Wound healing assays showed that wound closure in 48 h was observed in DM2-treated keratinocytes with a better healing pattern at all the used concentrations (0.1, 1.0, and 10 µM). A potential good skin permeation for DM2 that could guarantee its effectiveness at the target site was also observed. Cytotoxicity studies revealed that DM2 may be a safe compound for topical use. (4) Conclusions: Taking together, all these data confirm that DM2 could represent a safe wound healing topical agent for the treatment of skin wound infections caused by two of the main Gram-positive bacteria belonging to ESKAPE microorganisms.