In search of a novel antifungal agent: probing molecular interactions of fluconazole and its analogues with model membranes by NMR and DSC techniques

Abstract

In search of a novel antifungal agent with high susceptibility and increased antifungal potency it is necessary to increase the overall lipophilicity of these agents. In view of that, we have synthesized different carboxylic acid ester analogues of fluconazole, such as fluconazole-benzoate, fluconazole-p-nitrobenzoate, fluconazole-p-methoxybenzoate and fluconazole-toluate, with varying degrees of lipophilicity. In order to probe molecular level interactions of these molecules with biomembrane, lipid bilayers prepared from l-α-dipalmitoyl phosphatidyl choline (DPPC) as the model membrane were used. Multinuclear and multidimensional nuclear magnetic resonance, differential scanning calorimetry and transmission electron microscopy was used to investigate the changes in the thermotropic properties, organization of the membrane and intermolecular interactions. Fluconazole and its analogues show varying degrees of changes in the DPPC bilayer's architecture and physico-chemical characteristics. This might influence important biological features of fungal biomembranes that could be responsible for their respective antifungal effects. The study indicates that fluconazole-p-methoxybenzoate is the most active among all analogues and therefore could be the most promising antifungal candidate.