Imidazolylchromanones containing alkyl side chain as lanosterol 14α-demethylase inhibitors: synthesis, antifungal activity and docking study

Abstract

Previously, 2-alkylchromans have been introduced as non-azole inhibitors of 14a-demethylase. Accordingly, we incorporated imidazole ring on the 3-position of 2-alkylchromanones to design new inhibitors of 14a-demethylase and potential antifungal agents. Thus, a series of 2-alkyl-3-imidazolylchromanones were synthesized starting from 2-hydroxyphenacyl bromide. The transconfiguration of compounds was confirmed by NMR-spectroscopy. The antifungal activity of title compounds were evaluated against different fungi in comparison with fluconazole and miconazole. trans-2-(1-Pentyl)-3-imidazolylchroman-4-one (4d) showed the most potent activity against yeasts comparable to fluconazole. The experimental data based on 1 H NMR spectroscopy revealed that 2-alkyl side chain and 3-imidazolyl moiety in compound 4d exist predominantly in the di-equatorial conformation. While docking study with 14a-demethylase demonstrated that the di-axial form of compound 4d can be considered as active conformation.

Synthetic flavonoids with antimicrobial activity: a review

“…Trans ‐2‐(1‐pentyl)‐3‐imidazolylchroman‐4‐one showed the most potent activity against C. albicans and Saccharomyces cerevisiae , comparable to fluconazole (Emami et al . ). Tomasic and co‐workers reported thiazolidine‐2,4‐dione derivatives as inhibitors of E. coli MurD ligase—an enzyme involved in the formation of bacterial cell wall.…”

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“…According to the mechanism of action, there are six classes of antifungal agents: fungal ergosterol synthesis inhibitors (azoles: ketoconazole, fluconazole, and voriconazole), glucan synthesis inhibitors (echinocandins and caspofungin), ergosterol disruptors (polyenes antibiotics: amphotericin B), squalene epoxidase inhibitors (terbinafine and naftifine), chitin synthesis inhibitors (nikkomycin), and nucleic acid synthesis inhibitors (5-fluorocytosine) ( Figure 1) [3]. Due to its high therapeutic index, azoles are first-line drugs for the treatment of invasive fungal infections [4,5]. Most therapies, designed to treat fungal infections, target the ergosterol biosynthesis pathway or its end product [6].…”

Rigid 3D-spiro chromanone as a crux for efficient antimicrobial agents: synthesis, biological and computational evaluation

“…The formed precipitate was ltered off then puried using column chromatography (eluent: petroleum ether : ethyl acetate 3 : 1) to yield 7 as a colorless powder. Yield -cyclohexan]-7 yl) oxy)acetyl)-2,4-dihydro-3H-pyrazol-3-one (9). To a solution of 8 (2 mmol, 0.61 g) in absolute ethanol (25 mL) containing few drops of glacial acetic acid, ethyl acetoacetate (1 eq, 2 mmol, 0.25 mL) was added.…”