Synthesis of vanillin derivatives with 1,2,3‐triazole fragments and evaluation of their fungicide and fungistatic activities

Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well‐known applications as an additive in food and cosmetics, it has also been reported that vanillin can inhibit fungi of clinical interest, such as Candida spp., Cryptococcus spp....

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Published in:Archiv der Pharmazie (Weinheim) 2023-06, Vol.356 (6), p.e2200653-n/a
Main Authors: Gazolla, Poliana A. R., Aguiar, Alex R., Costa, Maria C. A., Oliveira, Osmair V., Costa, Adilson V., Silva, Cleiton M., Nascimento, Claudia J., Junker, Jochen, Ferreira, Rafaela S., Oliveira, Fabrício M., Vaz, Boniek G., Carmo, Paulo H. F., Santos, Daniel A., Ferreira, Márcia M. C., Teixeira, Róbson R.
Format: Article
Language:English
Subjects:
4D‐SAR analysis
antifungal properties
CuAAC click reaction
molecular docking
vanillin triazole derivatives
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Summary:Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well‐known applications as an additive in food and cosmetics, it has also been reported that vanillin can inhibit fungi of clinical interest, such as Candida spp., Cryptococcus spp., Aspergillus spp., as well as dermatophytes. Thus, the present work approaches the synthesis of a series of vanillin derivatives with 1,2,3‐triazole fragments and the evaluation of their antifungal activities against Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Cryptococcus gattii, Trichophyton rubrum, and Trichophyton interdigitale strains. Twenty‐two vanillin derivatives were obtained, with yields in the range of 60%–91%, from copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC) click reaction between two terminal alkynes prepared from vanillin and different benzyl azides. In general, the evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL−1. Except for compound 3b against the C. gattii R265 strain, all vanillin derivatives showed fungicidal activity for the yeasts tested. The predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the compounds indicated favorable profiles for drug development. In addition, a four‐dimensional structure‐activity relationship (4D‐SAR) analysis was carried out and provided useful insights concerning the structures of the compounds and their biological profile. Finally, molecular docking calculations showed that all compounds bind favorably at the lanosterol 14α‐demethylase enzyme active site with binding energies ranging from –9.1 to –12.2 kcal/mol. Twenty‐two vanillin derivatives with 1,2,3‐triazole fragments were synthesized and evaluated for their activities against a number of fungal strains. The evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL−1. All compounds bind favorably at the lanosterol 14α‐demethylase enzyme active site.
ISSN:0365-6233
1521-4184
DOI:10.1002/ardp.202200653