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Objective: To evaluate the inhibitory activity of ferulic acid and four of its esterified derivatives (methyl, ethyl, propyl, and butyl) against resistance mechanisms in Staphylococcus aureus strains. Methods: Ferulic acid derivatives were obtained by esterification with methanol, ethanol, propanol, and butanol, and then characterized by hydrogen and carbon-13 nuclear magnetic resonance analysis. The minimum inhibitory concentrations (MIC) of ferulic acid and its esterified derivatives, ethidium bromide, and norfloxacin were obtained using the microdilution test, while the efflux pump inhibition test was conducted by examining reduction in the MICs of norfloxacin and ethidium bromide. Molecular docking was also carried out using the Schrodinger Suite 2015 molecular modeling software. A three-dimensional model of NorA efflux pump was generated using I-TASSER. The best scoring model was used as a receptor for ligand-receptor docking. Results: The methyl and butyl ester derivatives did not demonstrate significant antimicrobial activity. However, a significant synergic effect was evidenced when norfloxacin was combined with the ethyl and propyl esterified derivatives. The docking study demonstrated favorable energy of interaction between ferulate derivatives and NorA, and amino acid residues TYR57, TYR58, and LEU255 were present commonly in stabilizing all complexes. The PCA analysis corroborated the docking hypothesis that the lipophilic character and hydrogen bond interactions were the most relevant characteristics involved with NorA inhibitors. The pharmacokinetic parameters of ferulic acid derivatives showed good ADMET properties, demonstrating that they can be easily absorbed and have no effect or inhibit the cytochrome P450 enzyme complex, revealing their potential as drug candidates. Conclusions: This study provides strong evidence that the molecular basis for this activity is potentially due to the NorA efflux pump.

Objective: To evaluate the anti Candida activity of Hyptis martiusii decoction and its major compound, caffeic acid alone or in the presence of fluconazole, as well as their cytotoxic effect. Methods: The decoction was characterized using high performance liquid chromatography coupled with diode array detector. For the antifungal activity, the minimum inhibitory concentration (MIC) and the potential effect of the decoction with the fluconazole were evaluated by microdilution method using 96-well microtiter trays. The osmotic fragility test was performed using erythrocytes under saline stress. All tests were performed in triplicate. Results: The chemical characterization of the decoction was performed by high performance liquid chromatography and revealed the presence of seven compounds, including caffeic acid as major constituent. The antifungal tests demonstrated that both decoction (DHm) and caffeic acid obtained from Hyptis martiusii presented MIC and MFC ≥ 4096 μg/mL against Candida albicans and Candida tropicalis strains. However, in the presence of fluconazole, DHm and caffeic acid presented IC50 of 2.60 and 2.53 μg/mL respectively, demonstrating significant synergistic effects against Candida strains. The modulator activity of DHm might be due to the presence of caffeic acid. Moreover, DHm and caffeic acid did not cause significant hemolytic effects, indicating that they present low cytotoxicity. Conclusions: These data indicate that DHm potentiates the activity of the fluconazole, without enhancement of the toxicity, encouraging further toxicological, pharmacological and phytochemical studies to provide consistent evidence of the potential of this plant to be used in drug development.

Objective: To evaluate the trypanocidal, leishmanicidal and cytotoxic activity of Eugenia jambolana (E. jambolana) and Eugenia uniflora (E. uniflora) extracts and fractions. Methods: The products were characterized by LC–MS. Antiparasitic assays were performed and cytotoxicity was evaluated in fibroblastos. In vitro assays were performed using spectrophotometric evaluation. All assays were performed in thrice. Results: The results showed that the extracts and the tannic fraction from E. jambolana inhibited 100% of the epimastigote lines. The ethanolic extract was the most efficient in all concentrations tested against the three parasite strains. In the cytotoxicity assay the flavonoid fraction showed low toxicity. All E. uniflora samples showed cytotoxicity at the highest concentration tested, but the extract showed no toxic effect on the fibroblasts at the lowest concentration. The flavonoid and tannic fractions were more efficient against Leishmania braziliensis promastigotes compared to the extract. However, the extracts and the tannic fraction were more effective against Leishmania infantum strains. The effect on epimastigote cells was observed at all concentrations tested, with all E. uniflora samples. However, the samples were more effective at the highest concentration, where there was inhibition in 100% of the Trypanosoma cruzi strains. Conclusions: The species E. jambolana and E. uniflora presented antiparasitic activity against all tested parasite strains, indicating that these species can serve as an alternative therapy as they were efficient in the tests performed. The E. uniflora extract and the E. jambolana flavonoid fraction presented a low cytotoxicity, opening the floor for new biological studies.