Synthesis, biological evaluation and docking study of possible antifungal compounds with a coumarin-containing triazole side chain

Due to increasing drug resistance by Candida species, especially in hospitals, the search for new antifungal agents has intensified. The incorporation of the coumarin scaffold into several nitrogen-containing heterocyclic moieties reportedly increases antimicrobial efficiency. The aim of this study was to design and synthesize a series of simple coumarin-linked triazole derivatives and test their possible antifungal activity against four Candida species. Docking simulations were conducted to explore the binding properties of the test compounds and compare them to reported data on fluconazole, the reference drug. Starting from 3acetylcoumarins, coumarins 2a-d, 3a-c and 4a-d were obtained in high yields. The concentration of each compound needed to inhibit the Candida species was determined by serial dilution. An inhibition of 62% of C. albicans was produced by 2b (300 μg/ml), 87% of C. tropicalis by 3a (100 μg/ml), 89% of C. parapsilosis by 3a (500 μg/ml), and 87% of C. glabrata by 4a (300 μg/ml). The values of antifungal activity were similar for the coumarin derivatives and fluconazole, the latter of which induced 90% inhibition of the four yeasts at 500 μg/ml. According to the docking simulations, the interactions at the active site of the lanosterol 1,4demethylase enzyme (CYP51) are similar for the test compounds and fluconazole. The subcellular location of the derivatives was identified as the mitochondrion. These coumarins are characterized by structural simplicity, with the simplest structures showing better antifungal activity than fluconazole. Further research is needed to isolate CYP51 and directly test its inhibition by coumarin derivatives.