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Besides its well\u2010known applications as an additive in food and cosmetics, it has also been reported that vanillin can inhibit fungi of clinical interest, such as <jats:italic>Candida<\/jats:italic> spp., <jats:italic>Cryptococcus<\/jats:italic> spp., <jats:italic>Aspergillus<\/jats:italic> spp., as well as dermatophytes. Thus, the present work approaches the synthesis of a series of vanillin derivatives with 1,2,3\u2010triazole fragments and the evaluation of their antifungal activities against <jats:italic>Candida albicans<\/jats:italic>, <jats:italic>Candida glabrata<\/jats:italic>, <jats:italic>Candida parapsilosis<\/jats:italic>, <jats:italic>Candida tropicalis<\/jats:italic>, <jats:italic>Cryptococcus neoformans<\/jats:italic>, <jats:italic>Cryptococcus gattii<\/jats:italic>, <jats:italic>Trichophyton rubrum<\/jats:italic>, and <jats:italic>Trichophyton interdigitale<\/jats:italic> strains. Twenty\u2010two vanillin derivatives were obtained, with yields in the range of 60%\u201391%, from copper(I)\u2010catalyzed alkyne\u2010azide 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 &gt;512\u2009\u00b5g mL<jats:sup>\u22121<\/jats:sup>. Except for compound <jats:bold>3b<\/jats:bold> against the <jats:italic>C. gattii<\/jats:italic> 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\u2010dimensional structure\u2010activity relationship (4D\u2010SAR) 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 14<jats:italic>\u03b1<\/jats:italic>\u2010demethylase enzyme active site with binding energies ranging from \u20139.1 to \u201312.2\u2009kcal\/mol.<\/jats:p>","DOI":"10.1002\/ardp.202200653","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T05:54:56Z","timestamp":1678946096000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Synthesis of vanillin derivatives with 1,2,3\u2010triazole fragments and evaluation of their fungicide and fungistatic activities"],"prefix":"10.1002","volume":"356","author":[{"given":"Poliana A. 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