Imidazolylchromanones containing non-benzylic oxime ethers: Synthesis and molecular modeling study of new azole antifungals selective against Cryptococcus gattii

•New azolylchromanone oxime ethers were designed as omoconazole analogs.•The antifungal activity of compounds was evaluated against different fungi.•All compounds showed potent activity against Cryptococcus gattii (MICs ≤4 μg/mL).•3-Chlorophenoxy analog 7c was the most potent compound (MIC = 0.5 μg/mL).

A series of imidazolylchromanone oximes containing phenoxyethyl ether moiety, as found in omoconazole, were synthesized and evaluated against yeasts (Candida albicans and Cryptococcus gattii) and filamentous fungi (Aspergillus fumigatus and Exophiala dermatitidis). Although the title compounds showed marginal activity against filamentous fungi but all of them exhibited potent activity against C. gattii (MIC values ≤4 μg/mL). Among them, (3-chlorophenoxy)ethyl analog 7c with MIC value of 0.5 μg/mL was the most potent compound. Further molecular docking studies provided a better insight into the binding of designed compounds within the homology modeled active site of CnCYP51 (Cryptococcus CYP51-14α-demethylase).

Graphical abstractA series of imidazolylchromanone oximes containing phenoxyethyl ether moiety were synthesized as omoconazole analogs. Compound 7c with MIC value of 0.5 μg/mL was the most potent compound against Cryptococcus gattii.Figure optionsDownload full-size imageDownload as PowerPoint slide