Synthesis and antifungal activity of new Valine-azole hybrids

Abstract

Herein, the synthesis of six new derivatives via molecular hybridization of imidazole or triazole and valine methyl ester as a rational design for accessing new potential antifungal agents is presented. The title compounds have been prepared by a straightforward two-step synthetic strategy: treatment of L-valine methyl ester hydrochloride by bromoacetyl bromide with formation of a transient bromoacetamide (66% yield) followed by N-alkylation of substituted imidazoles or 1,2,4-triazoles leading to the corresponding title compounds (yield 17–85%). The synthesized compounds have been tested as antifungal agents on C. krusei, C. glabrata and C. parapsilosis yeasts. The most active imidazole derivative is characterized by 61.9, 87.2, and 45.9% growth inhibition, respectively. Molecular docking calculations indicate pi-pi interactions between the heme group and the imidazole ring in complex 2b/14-DM or pi-alkyl interactions in complexes 2a/14-DM and 3a/14-DM. For complexes 2a/14-DM and 3a/14-DM a carbon hydrogen bond has been predicted.