Synthesis, activity, and docking studies of eugenol‐based glucosides as new agents against Candida sp

Seventeen new synthetic derivatives of eugenol (6, 8–15 and 8′‐15′) were planned following literature reports on antifungal activities of nitroeugenol and eugenol glucoside. The anti‐Candida activity of these compounds was investigated by in vitro assay, and the cytotoxicity evaluation was performed with the most active compounds. The peracetylated glucosides presented better biological results than their hydroxylated analogues. The glucoside 11, a 4‐nitrobenzamide, showed the best potency (MIC50 range 11.0–151.84 μm), the wider spectrum of action, and overall the best selectivity indexes, especially against C. tropicalis (~30) and C. krusei (~15). To investigate its possible mechanism of action, glucoside 11 was subjected to molecular docking studies with Candida sp. enzymes involved in ergosterol biosynthesis. Results have shown that the peracetyl glucosyl moiety and the 4‐nitrobenzamide group in 11 are effectively involved in its high affinity with the active site of squalene epoxidase. A new series of glucosides was synthesized and evaluated against pathogenic and opportunistic Candida sp. The 4‐nitrobenzamide glucoside 11 was the most promising derivative, showing fungistatic activity against all strains evaluated, mainly against C. troplicalis (MIC50 11.4 μm, SI 30) and C. krusei (MIC50 22.8 μm, SI 15). Docking studies suggest its action on fungal ergosterol biosynthesis once it showed high affinity to squalene epoxidase active site.