Design, synthesis, and in vitro evaluation of novel triazole analogues featuring isoxazole moieties as antifungal agents

• Published in: Bioorganic chemistry 2020-08, Vol.101, p.103982-103982, Article 103982
• Main Authors: Xie, Fei, Ni, Tingjunhong, Ding, Zichao, Hao, Yumeng, Wang, Ruina, Wang, Ruilian, Wang, Ting, Chai, Xiaoyun, Yu, Shichong, Jin, Yongsheng, Jiang, Yuanying, Zhang, Dazhi
• Format: Article
• Language: English
• Subjects: Antifungal activity; Antifungal Agents - pharmacology; Antifungal Agents - therapeutic use; Candida albicans - drug effects; Humans; Isoxazoles - chemistry; Molecular Docking Simulation - methods; Molecular Structure; Structure-Activity Relationship; Synthesis; Triazole; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - therapeutic use
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103982

Twenty-six novel triazole analogues featuring isoxazole moieties were designed and synthesized by replacing 4-cyanophenylthioazole moiety in ravuconazole with substituted phenylisoxazole methoxyl. The in vitro antifungal activities demonstrate the introduction of isoxazole methoxyl moiety bearing medium side chains is beneficial for retaining the novel compounds antifungal activities. [Display omitted] •Novel triazole analogues featuring isoxazole moieties were designed and synthesized.•All compounds showed potent activity against Candida spp. (MICs ≤ 0.5 μg/mL).•The single-crystal data of compound 2 was obtained.•Compound a6 showed excellent inhibitory activity against some Candida spp. (MICs = 0.0313 μg/mL). In order to develop novel antifungal agents, based on our previous work, a series of (2R,3R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (a1-a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC80 values of 0.0313 μg/mL. In addition, compounds a6, a9, a12, a13 and a14 exhibited moderate inhibitory activities against fluconazole-resistant isolates with MIC80 values ranging from 8 μg/mL to 16 μg/mL. Furthermore, compounds a6, a12 and a23 exhibited low inhibition profiles for CYP3A4. Clear SARs were analyzed, and the molecular docking experiment was carried out to further investigate the relationship between a6 and the target enzyme CYP51.