RESUMO
Previously, 2-alkylchromans have been introduced as non-azole inhibitors of 14α-demethylase. Accordingly, we incorporated imidazole ring on the 3-position of 2-alkylchromanones to design new inhibitors of 14α-demethylase and potential antifungal agents. Thus, a series of 2-alkyl-3-imidazolylchromanones were synthesized starting from 2-hydroxyphenacyl bromide. The trans-configuration 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 14α-demethylase demonstrated that the di-axial form of compound 4d can be considered as active conformation.
Assuntos
Inibidores de 14-alfa Desmetilase/síntese química , Antifúngicos/síntese química , Cromonas/síntese química , Inibidores de 14-alfa Desmetilase/química , Inibidores de 14-alfa Desmetilase/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Cromonas/farmacologia , Fungos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
An efficient protocol has been developed for the preparation of a series of trans-3-imidazolylflavanones and (Z)-trans-3-imidazolylflavanone oximes, as potential antifungal agents, by the reaction of 2-imidazolyl-2'-hydroxyacetophenone with different benzaldehyde derivatives and subsequence oximation reaction. The stereochemical and conformational aspects of compounds were also assigned by (1)H NMR spectroscopy. The aryl group present at C-2 and the imidazole ring present at C-3 were assigned to occupy equatorial position in trans-3-imidazolylflavanones 3 and axial position in (Z)-trans-3-imidazolylflavanone oximes 4. Most of the 3-imidazolylflavanone derivatives containing a substituent on phenyl ring showed significant antifungal activity and modification of the 4-oxo group to oxime or substituent on phenyl ring produced changes in the antifungal activity profile of these compounds. Generally, 3'-chloro- analog of 3-imidazolylflavanone 3c exhibited better profile of antifungal activity against strains of fungi tested, superior than reference drug fluconazole.
