Design, synthesis and evaluation of novel deferasirox derivatives with high antifungal potency in vitro and in vivo

被引:0
作者
Ni, Tingjunhong [1 ]
Chi, Xiaochen [1 ,3 ]
Wu, Hao [1 ]
Xie, Fei [2 ]
Bao, Junhe [2 ]
Wang, Jiayin [2 ,4 ]
Ji, Zhe [1 ]
Li, Liping [1 ]
Wang, Xiaobo [5 ]
Yan, Lan [2 ]
Hao, Yumeng [2 ]
Zhang, Dazhi [1 ,2 ]
Jiang, Yuanying [1 ]
机构
[1] Tongji Univ, Shanghai Peoples Hosp 10, Sch Med, Dept Pharm, 1239 Siping Rd, Shanghai 200092, Peoples R China
[2] Naval Med Univ, Sch Pharm, 325 Guohe Rd, Shanghai 200433, Peoples R China
[3] Shenyang Pharmaceut Univ, Sch Chinese Mat Med, Shenyang 110016, Peoples R China
[4] Fujian Univ Tradit Chinese Med, Sch Pharm, 1 Qiuyang Rd, Fuzhou 350112, Peoples R China
[5] 967th Hosp Joint Logist Support Force PLA, Dalian 116000, Liaoning, Peoples R China
基金
中国国家自然科学基金;
关键词
Deferasirox; Antifungal; Structure-activity relationship; Amidation; Iron chelation; THERAPY; MUCORMYCOSIS; CHELATION; FAILURE;
D O I
10.1016/j.ejmech.2023.116026
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Here we designed and synthesized 58 deferasirox derivatives with the aim of discovering novel antifungal agents. Most compounds exhibited moderate to excellent in vitro antifungal activities against Cryptococcus neoformans H99 with MIC values ranging from 0.25 mu g/mL to 16 mu g/mL, including ten compounds with MIC values less than 1 mu g/mL that were further screened against an additional six pathogenic fungi. This class of compounds showed high potency against Candida glabrata with MIC values ranging from <0.125 mu g/mL to 1 mu g/mL. We identified that compound 54 has high potency against 14 strains of Candida glabrata spp. and Cryptococcus spp. with MIC values ranging from <0.125 mu g/mL to 1 mu g/mL. In addition, compound 54 significantly reduced the CFU in a mouse model of disseminated infection with Cryptococcus neoformans H99 at a dose of 10 mg/kg, which is comparable to FLC. Further investigations on compound 54 are currently in progress.
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页数:14
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