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

Abstract

Fungal infections remain a high-incidence worldwide health problem that is aggravated by limited therapeutic options and the emergence of drug-resistant strains. Cinnamic and benzoic acid amides have previously shown bioactivity against different species belonging to the Candida genus. Here, 20 cinnamic and benzoic acid amides were synthesized and tested for inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019. Five compounds inhibited the Candida strains tested, with compound 16 (MIC = 7.8 µg/mL) producing stronger antifungal activity than fluconazole (MIC = 16 µg/mL) against C. krusei ATCC 14243. It was also tested against eight Candida strains, including five clinical strains resistant to fluconazole, and showed an inhibitory effect against all strains tested (MIC = 85.3–341.3 µg/mL). The MIC value against C. krusei ATCC 6258 was 85.3 mcg/mL, while against C. krusei ATCC 14243, it was 10.9 times smaller. This strain had greater sensitivity to the antifungal action of compound 16. The inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019 was also achieved by compounds 2, 9, 12, 14 and 15. Computational experiments combining target fishing, molecular docking and molecular dynamics simulations were performed to study the potential mechanism of action of compound 16 against C. krusei. From these, a multi-target mechanism of action is proposed for this compound that involves proteins related to critical cellular processes such as the redox balance, kinases-mediated signaling, protein folding and cell wall synthesis. The modeling results might guide future experiments focusing on the wet-lab investigation of the mechanism of action of this series of compounds, as well as on the optimization of their inhibitory potency.

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

“…For this test, the inoculum was prepared with sorbitol to a final concentration of 0.8 M. The plates were incubated, and readings were taken at 24 h and 48 h post-incubation. Caspofungin was used as a positive control at an initial concentration of 5 mg/mL [ 76 , 98 ].…”

“…Nystatin was used as a positive control. The plates were incubated, and readings were taken at 24 and 48 h [ 76 , 98 ].…”

“…The previously described homology-based target fishing approach was employed to identify potential targets for compounds 6 and 18, respectively, in C. albicans and S. aureus [ 74 , 98 ]. Potential targets for each compound were separately predicted using the Similarity Ensemble Approach (SEA) web server [ 99 ].…”

Use of Probiotics for Oral Candidiasis: State of the Art and Perspective. A Further Step Toward Personalized Medicine?

“…The fungal growth and its metabolism based on anaerobic glucose fermentation are also interrupted by weak organic acids such as benzoic, acetic, and sorbic acids-still produced by Lactobacilli-which inhibit the production of ATP, necessary to the yeast, and leading to ATP and RNA depletion, with fungicide effects [62].…”

3,5-Dinitrobenzoate and 3,5-Dinitrobenzamide Derivatives: Mechanistic, Antifungal, and In Silico Studies

“…Candida krusei (MIC � 3.74 mM), and Candida tropicalis (MIC � 3.74 mM). e data indicate that the presence of less bulky groups in the R side chain of this amide contributes to its bioactivity.Despite the literature reporting biological activity for various amides against Candida species[71,72], most of the amides evaluated(15,…”