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Design and Synthesis of New Antifungals based on N- Un-substituted Azoles as 14α Demethylase Inhibitor

Author(s):

Asghar Davood*, Aneseh Rahimi, Maryam Iman, Parisa Azerang, Soroush Sardari and Arash Mahboubi   Pages 1 - 9 ( 9 )

Abstract:


Objective(s): Azole antifungal agents, which are widely used as antifungal antibiotics, inhibit cytochrome P450 sterol 14α-demethylase (CYP51). Nearly all azole antifungal agents are N-substituted azoles. In addition, an azolylphenalkyl pharmacophore is uniquely shared by all azole antifungals. Due to importance of nitrogen atom of azoles (N-3 of imidazole and N-4 of triazole) in coordination with heme in the binding site of the enzyme, here a group of N- un-substituted azoles in which both of nitrogen is un-substituted was reported.

Materials and Methods: Designed compounds were synthesized by reaction of imidazole-4-carboxaldehyde with appropriate arylamines and subsequently reduced to desired amine derivatives. Antifungal activity against Candida albicans and Saccharomyces cervisiae were done using a broth micro-dilution assay. Docking studies were done using AutoDock.

Results: Antimicrobial evaluation revealed that some of these compounds exhibited moderate antimicrobial activities against tested pathogenic fungi, wherein compound 3, 7 and 8 were potent. Docking studies propose that all of the prepared azoles interacted with 14α-DM, wherein azole-heme coordination play main role in drug-receptor interaction.

Conclusion: Our results offer some useful references in order to molecular design performance or modification of this series of compounds as a lead compound to discover new and potent antimicrobial agents.

Keywords:

Antifungal, Azole, Docking, Imidazole, 14α demethylase, imidazole-4- carboxaldehyde

Affiliation:

Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Department of pharmaceutics, Shahid Beheshti University of Medical Sciences, Tehran



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