Design of Conformationally Constrained Azole Antifungals: Efficient Synthesis and Antifungal Activity of trans-3-Imidazolylflavanones

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.