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

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 . Based on the structural optimization of hit compound 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 -, which contain thiosemicarbazides side chains, exhibited excellent in vitro synergistic antifungal potency (MIC = 0.125-2.0 μg/mL, FICI range from 0.127 to 0.25). Interestingly, compound exhibited moderate activity as monotherapy with an MIC value of 4.0 μg/mL, and also on several strains (MIC ranging from ≤ 0.125-0.5 μg/mL) and (MIC ≤ 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 as a promising antifungal lead for further investigation.