Discovery of Novel Thiosemicarbazides Containing 1,3,5-Triazines Derivatives as Potential Synergists against Fluconazole-Resistant <i>Candida albicans</i>

• Main Authors: Fei Xie (Author), Yumeng Hao (Author), Jiacun Liu (Author), Junhe Bao (Author), Tingjunhong Ni (Author), Yu Liu (Author), Xiaochen Chi (Author), Ting Wang (Author), Shichong Yu (Author), Yongsheng Jin (Author), Liping Li (Author), Dazhi Zhang (Author), Lan Yan (Author)
• Format: Book
• Published: MDPI AG, 2022-10-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

The clinical prevalence of antifungal drug resistance has been increasing over recent years, resulting in the failure of treatments. In an attempt to overcome this critical problem, we sought novel synergistic enhancers to restore the effectiveness of fluconazole against resistant <i>Candida albicans</i>. Based on the structural optimization of hit compound <b>8</b> from our in-house library, a series of novel 1,3,5-triazines derivatives was designed, synthesized, and biologically evaluated for synergistic activity in combination with fluconazole. Among them, compounds <b>10a</b>-<b>o</b>, which contain thiosemicarbazides side chains, exhibited excellent in vitro synergistic antifungal potency (MIC₈₀ = 0.125-2.0 μg/mL, FICI range from 0.127 to 0.25). Interestingly, compound <b>10l</b> exhibited moderate <i>C. albicans</i> activity as monotherapy with an MIC₈₀ value of 4.0 μg/mL, and also on several <i>Cryptococcus</i> strains (MIC₈₀ ranging from ≤ 0.125-0.5 μg/mL) and <i>C. glabrata</i> (MIC₈₀ ≤ 0.125 μg/mL). These effects were fungal-selective, with much lower levels of cytotoxicity towards human umbilical vein endothelial cells. Here, we report a series of thiosemicarbazides containing 1,3,5-triazines derivatives as potent synergists with fluconazole, and have preliminarily validated compound <b>10l</b> as a promising antifungal lead for further investigation.

Item Description

10.3390/pharmaceutics14112334
1999-4923