Design, Molecular Modeling and Synthesis of Fluconazole Derivatives Targeting Sterol 14-Alpha Demethylase

The Enzyme Sterol 14-α demethylase is involved in ergosterol biochemical synthesis pathway, which is necessary for the formation of cell membranes in fungi. This research aims to design, develop, and synthesize new fluconazole derivatives that inhibit the enzyme Sterol 14-α demethylase and therefore target ergosterol synthesis. Molecular modeling studies of the studied compounds were undertaken using The Molegro program (MVD) and the compounds binding energies were calculated to evaluate their effectiveness. After calculating the binding energies, we noticed that the compound (a6) has the highest binding energy (ΔG = -208.84 kcal/mol) compared with the Fluconazole (The native ligand) (ΔG= -134.09 kcal\mol) and the reference compound (ox diazole fluconazole derivative) (ΔG = -192.49Kcal\mol), where this one was selected from previous studies as reference for comparing. One characterized compound was selected and synthesized with a good yield, by reacting fluconazole with chloroacetic acid in an alkaline aqueous medium. Then the compound b1 that we synthesized it was identified by Mass Spectra, Infrared absorption Spectroscopy, and Nuclear Resonance Spectroscopy among other analytical methods.