Synthetic Cinnamides and Cinnamates: Antimicrobial Activity, Mechanism of Action, and In Silico Study

Abstract

The severity of infectious diseases associated with the resistance of microorganisms to drugs highlights the importance of investigating bioactive compounds with antimicrobial potential. Therefore, nineteen synthetic cinnamides and cinnamates having a cinnamoyl nucleus were prepared and submitted for the evaluation of antimicrobial activity against pathogenic fungi and bacteria in this study. To determine the minimum inhibitory concentration (MIC) of the compounds, possible mechanisms of antifungal action, and synergistic effects, microdilution testing in broth was used. The structures of the synthesized products were characterized with FTIR spectroscopy, 1 H-NMR, 13 C-NMR, and HRMS. Derivative 6 presented the best antifungal profile, suggesting that the presence of the butyl substituent potentiates its biological response (MIC = 626.62 μM), followed by compound 4 (672.83 μM) and compound 3 (726.36 μM). All three compounds were fungicidal, with MFC/MIC ≤ 4. For mechanism of action, compounds 4 and 6 directly interacted with the ergosterol present in the fungal plasmatic membrane and with the cell wall. Compound 18 presented the best antibacterial profile (MIC = 458.15 μM), followed by compound 9 (550.96 μM) and compound 6 (626.62 μM), which suggested that the presence of an isopropyl group is important for antibacterial activity. The compounds were bactericidal, with MBC/MIC ≤ 4. Association tests were performed using the Checkerboard method to evaluate potential synergistic effects with nystatin (fungi) and amoxicillin (bacteria). Derivatives 6 and 18 presented additive effects. Molecular docking simulations suggested that the most likely targets of compound 6 in C. albicans were caHOS2 and caRPD3, while the most likely target of compound 18 in S. aureus was saFABH. Our results suggest that these compounds could be used as prototypes to obtain new antimicrobial drugs.