Amides Derived from Vanillic Acid: Coupling Reactions, Antimicrobial Evaluation, and Molecular Docking

Abstract

A series of amides derived from vanillic acid were obtained by coupling reactions using PyBOP ((Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate) and DCC (Dicyclohexylcarbodiimide) coupling reagents. These were submitted to biological evaluation for species of Candida, Staphylococcus, and Pseudomonas. The microdilution method in broth was used for the antimicrobial testing to determine the Minimum Inhibitory Concentration (MIC) and to verify the likely mechanism of action for antifungal activity. The ten amides were obtained with yields ranging from 28.81 to 86.44%, and three compounds were novel. In the antibacterial evaluation, the amides (in their greatest concentrations) were bioactive against Staphylococcus aureus strain ATCC 25925. Meanwhile, all of the tested amides presented antifungal activity against at least one strain. The amide with best antifungal profile was compound 7, which featured an MIC of 0.46 μmol/mL, and a mechanism of action involving the plasma membrane and fungal cell wall. The presence of a methyl group in the para position of the aromatic ring is suggested which enhances the activity of the compound against fungi. Docking studies of the ten compounds using the protein 14α-demethylase as a biological target were also performed. The biological results presented good correlation with molecular docking studies demonstrating that a possible site of antifungal action for bioactive amides is the enzyme 14α-demethylase.

Antifungal Activity of N-(4-Halobenzyl)amides against Candida spp. and Molecular Modeling Studies

“…Interestingly, amide 14 was more potent than its analogue 9 , suggesting that the presence of the spacer between the carbonyl group and the trisubstituted aromatic ring results in lower inhibitory potency against both Candida species. These findings agree with literature reports, such as the activity of syringic acid (MIC = 50 µg/mL) against Candida albicans [ 46 ], the precursor of derivative 14 (MIC of 31.25 µg/mL), and other benzamides also bioactive against species of this genus of fungi [ 40 ].…”

“…According to the predicted free energies of binding, the most probable targets of compound 16 in C. krusei are ALDH1, MAPK3, PPCTI2, ALDH4 and PPCTI-D. Previous studies showed that amides derived from vanillic acid (highly similar to the compounds studied herein) interfere with the synthesis of ergosterol in C. guilliermondii [ 40 ]. Among the targets belonging to the ergosterol synthesis pathway, the firsts in the ranked list are ERG13, ERG11 and ERG9 at positions 8, 9 and 10, respectively.…”

Cytotoxic and Antifungal Amides Derived from Ferulic Acid: Molecular Docking and Mechanism of Action

“…The organic phase was dried with anhydrous Na 2 SO 4 and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate, 7 : 3) to obtain the described compounds [36]. Spectroscopic data for the compounds in this study are available in the Supplementary Materials (available here).…”

“…In contrast, analog (with a 4-methylbenzyl group) showed activity against strains of C. tropicalis and C. krusei, with MIC of 1.68 μmol/mL for both strains, but it was inactive against C. albicans. In another study, Oliveira et al [36] showed that the 4methylbenzylamide derived from vanillic acid has activity against the C. glabrata strain. This data shows the antifungal ability of 7.…”

“…Analogue 6 showed activity against the strains of C. albicans and C. krusei with a minimum inhibitory concentration (MIC) of 1.85 μmol/mL and 0.82 μmol/mL, respectively. Oliveira et al [36] used vanillic acid as the starting material to prepare an amide containing the benzyl substituent, and it only showed activity against C. albicans with IC 50 value 3.88 μmol/mL. In contrast, analog (with a 4-methylbenzyl group) showed activity against strains of C. tropicalis and C. krusei, with MIC of 1.68 μmol/mL for both strains, but it was inactive against C. albicans.…”