Design, Synthesis, and Biological Activity of New Triazole and Nitro-Triazole Derivatives as Antifungal Agents

Abstract

In this study two series of fluconazole derivatives bearing nitrotriazole (series A) or piperazine ethanol (series B) side chain were designed and synthesized and then docked in the active site of lanosterol 14α-demethylase enzyme (1EA1) using the Autodock 4.2 program (The scripps research institute, La Jolla, CA, USA). The structures of synthesized compound were confirmed by various methods including elemental and spectral (NMR, CHN, and Mass) analyses. Then antifungal activities of the synthesized compound were tested against several natural and clinical strains of fungi using a broth microdilution assay against several standard and clinical fungi. Nitrotriazole derivatives showed excellent and desirable antifungal activity against most of the tested fungi. Among the synthesized compounds, 5a-d and 5g, possessing nitrotriazole moiety, showed maximum antifungal activity, in particular against several fluconazole-resistant fungi.

Keywords: antifungal; docking; fluconazole; lanosterol 14α-demethylase; nitrotriazole; synthesis.

Scheme 1

Synthesis of the new fluconazole compounds; conditions: (a) AlCl₃, 1,2-dichloroethane, chloroacetyl chloride, 25–30 °C; (b) 1H-1,2,4-triazole, NaHCO₃, toluene, reflux; (c) trimethylsulfoxonium iodide (TMSI), NaOH, tetraethylammonium bromide (TEAB), dichloromethane, toluene, 60 °C; (d) EtOH, Et₃N, 3-nitro-1,2,4 triazol, 80 °C; (e) EtOH, Et₃N, 2-(piperazin-1-yl) ethanol, 80 °C.

Figure 1

Visualizing the active site in the presence of ligands: left (5b), right (5g).