Abstract
Amides derived from ferulic acid have a wide spectrum of pharmacological activities, including antitumor and antifungal activity. In the present study, a series of ten amides were obtained by coupling reactions using the reagents (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and N,N′-dicyclohexylcarbodiimide (DCC). All the compounds were identified on the basis of their IR, 1H- and 13C-NMR, HRMS data, and with yields ranging from 43.17% to 91.37%. The compounds were subjected to cytotoxic tests by the alamar blue technique and antifungal screening by the broth microdilution method to determine the minimum inhibitory concentration (MIC). The amides 10 and 11 displayed the best result in both biological evaluations, and compound 10 was the most potent and selective in HL-60 cancer cells, with no cytotoxicity on healthy cells. This amide had antifungal activity in all strains and had the lowest MIC against Candida albicans and Candida tropicalis. The possible mechanism of antifungal action occurs via the fungal cell wall. Molecular modeling suggested that compounds 10 and 11 interact with the enzymes GWT1 and GSC1, which are essential for the development of C. albicans. The findings of the present study demonstrated that compounds 10 and 11 may be used as a platform in drug development in the future.
Highlights
Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a natural organic compound abundantly distributed in fruits and vegetables [1]
Based on the results of the free energies of binding calculations, we propose that the main mechanism of action of this series of compounds interfering with the cell wall integrity in C. albicans is likely through their binding to the GWT1 and GSC1 receptors
Our models suggest that the presence of the CH2 group between the amide nitrogen and the R group is essential for compounds 6-11 to be fully complementary with the GWT1 and GSC1 receptors
Summary
Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a natural organic compound abundantly distributed in fruits and vegetables [1] It is well known potent phenolic antioxidant that has the property of scavenging free radicals and induce antioxidant enzymes, such as catalase and superoxide dismutase (SOD) [2, 3], in order to protect cellular macromolecules of peroxidation and oxidative damage. The presence of these characteristics has been depicted from numerous studies reported in the literature that show the pharmacological activity of ferulic acid in experimental models related to several pathologies, including diabetes, neurodegenerative diseases, and cardiovascular disease [4, 5]. The stimulation of the detoxification enzyme seems to be another mechanism responsible for its anticarcinogenic action [9]
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