Design, synthesis and antifungal activities of novel 1,2,4-triazole derivatives

• Published in: European journal of medicinal chemistry 2011-07, Vol.46 (7), p.3142-3148
• Main Authors: Xu, Jianming, Cao, Yongbing, Zhang, Jun, Yu, Shichong, Zou, Yan, Chai, Xiaoyun, Wu, Qiuye, Zhang, Dazhi, Jiang, Yuanying, Sun, Qingyan
• Format: Article
• Language: English
• Subjects: 1,2,4-Triazole; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal activity; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Biological and medical sciences; Candida albicans - drug effects; Candida albicans - growth & development; Catalytic Domain; Cryptococcus neoformans - drug effects; Cryptococcus neoformans - growth & development; Cytochrome P-450 Enzyme Inhibitors - chemical synthesis; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Drug Design; Fluconazole - pharmacology; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - chemistry; Medical sciences; Microbial Sensitivity Tests; Molecular Docking Simulation; Pharmacology. Drug treatments; Piperazine; Piperazines - chemistry; Sterol 14-Demethylase - chemistry; Structure-Activity Relationship; Synthesis; Triazoles - chemical synthesis; Triazoles - pharmacology; Voriconazole - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.02.042

A series of novel 1,2,4-triazole derivatives with a 4-(4-substitutedphenyl) piperazine side chain were designed and synthesized based on the structure of lanosterol 14α-demethylase (CYP51). Their antifungal activities against eight human pathogenic fungi were evaluated in vitro by measuring the minimal inhibitory concentrations. Nearly all tested compounds were found to be more potent against Candida albicans than control drug fluconazole. Noticeably, the MIC 80 value of compounds 6, 7, 9, 14 and 29 is 16 times lower than that of voriconazole against C. albicans. The activities of compounds 7 and 21 against Cryptococcus neoformans in vitro are comparable to that of voriconazole with a MIC 80 value of 0.0156 μg/mL. Moreover, the molecular model for the binding between compound 7 and the active site of CACYP51 was provided based on the computational docking results. A series of novel triazole derivatives were synthesized and tested for antifungal activities in vitro. The results indicated that all title compounds exhibited activities against fungi tested to some extent. [Display omitted] ► On the basis of the active site of CYP51, a series of novel triazole derivatives with a 4-(4-substitutedphenyl) piperazine side chain have been designed and synthesized as antifungal agents. The in vitro antifungal activities of all title compounds were evaluated against eight human pathogenic fungi which are often encountered clinically. Compared with their aromatic analogues, our present results clearly showed that the introduction of aliphatic side chain with a proper length greatly enhanced the antifungal activity of these title compounds against Candida species and the introduction of fluorine atom to the phenyl group is not necessary to improve their antifungal activities. The obtained results demonstrated that for antifungal activity of these novel triazole derivatives it is very helpful to introduce the 4-(4-substitutedphenyl) piperazine as side chains, especially a aliphatic side chain at the position 4 of the terminal phenyl group, to interact with the residues of the narrow hydrophobic cleft of CYP51 and adjust the physicochemical properties of the whole title molecules.