Triazole derivatives with improved in vitro antifungal activity over azole drugs

Abstract

A series of triazole antifungal agents with piperidine side chains was designed and synthesized. The results of antifungal tests against eight human pathogenic fungi in vitro showed that all the compounds exhibited moderate-to-excellent activities. Molecular docking between 8d and the active site of Candida albicans CYP51 was provided based on the computational docking results. The triazole interacts with the iron of the heme group. The difluorophenyl group is located in the S3 subsite and its fluorine atom (2-F) can form H-bonds with Gly307. The side chain is oriented into the S4 subsite and formed hydrophobic and van der Waals interactions with the amino residues. Moreover, the phenyl group in the side chain interacts with the phenol group of Phe380 through the formation of π–π face-to-edge interactions.

Targeting CYP51 for drug design by the contributions of molecular modeling

“…The most active compound ( 6 ) (MIC 80 = 0.005 μg/mL against C. albicans and 0.032 μg/mL against T. rubrum and Microsporum gypseum) was docked in the active site of C. albicans CYP51 and showed the difluorophenyl group performing hydrophobic interactions with Phe126, Leu121, Tyr118, Met306, and Gly307. The side chain of the active compound ( 6 ) was oriented in the S4 pocket and formed hydrophobic and van der Waals interactions with Tyr64, Met92, Ala117, Tyr118, Phe228, Pro230, Leu376, Ile379, Phe380, and Met508 .…”

An insight on medicinal attributes of 1,2,4-triazoles

“…Design, synthesis and antifungal activities of large number of 1-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1 H -1,2,4-triazol-1-yl)propyl)-4-substituted derivatives 1 – 15 as fluconazole or voriconazole or ravuconazole analogues have been carried out by Chinese group(s) ( Fig. 3 ) [ [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] ]. Compound 1n (MIC 80 : 0.0156 μg/mL) exhibited 16 fold more antifungal activity than fluconazole against Candida albicans [ 23 ].…”

Novel Triazole Derivatives Containing Different Ester Skeleton: Design, Synthesis, Biological Evaluation and Molecular Docking

“…8,9) Moreover, CYP51 has been regarded by many researchers as a target for molecular docking and widely applied in the rational design of antifungal compounds. [10][11][12][13][14][15] Studies showed that 16) the antifungal triazoles featured a core structure composed of a triazole, a halophenyl ring, while differing in the side chains. The development of triazole drugs is primarily driven through structure optimization especially of the side chains as well as structure-activity relationship (SAR) study.…”