Discovery of Novel Thiosemicarbazides Containing 1,3,5-Triazines Derivatives as Potential Synergists against Fluconazole-Resistant <i>Candida albicans</i>
Fei Xie,
Yumeng Hao,
Jiacun Liu,
Junhe Bao,
Tingjunhong Ni,
Yu Liu,
Xiaochen Chi,
Ting Wang,
Shichong Yu,
Yongsheng Jin,
Liping Li,
Dazhi Zhang,
Lan Yan
Affiliations
Fei Xie
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Yumeng Hao
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Jiacun Liu
Center of New Drug Research, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Junhe Bao
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Tingjunhong Ni
Department of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, No. 1239 Siping Road, Shanghai 200092, China
Yu Liu
Center of New Drug Research, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Xiaochen Chi
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China
Ting Wang
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Shichong Yu
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Yongsheng Jin
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Liping Li
Department of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, No. 1239 Siping Road, Shanghai 200092, China
Dazhi Zhang
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
Lan Yan
Center of New Drug Research, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
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 Candida albicans. Based on the structural optimization of hit compound 8 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 10a–o, 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 10l exhibited moderate C. albicans activity as monotherapy with an MIC80 value of 4.0 μg/mL, and also on several Cryptococcus strains (MIC80 ranging from ≤ 0.125–0.5 μg/mL) and C. glabrata (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 10l as a promising antifungal lead for further investigation.
