2. Academic Validation
  3. Design, synthesis and evaluation of novel deferasirox derivatives with high antifungal potency in vitro and in vivo

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

  • Eur J Med Chem. 2023 Dec 4:264:116026. doi: 10.1016/j.ejmech.2023.116026.
Tingjunhong Ni 1,  Xiaochen Chi 2,  Hao Wu 1,  Fei Xie 3,  Junhe Bao 3,  Jiayin Wang 4,  Zhe Ji 1,  Liping Li 1,  Xiaobo Wang 5,  Lan Yan 3,  Yumeng Hao 6,  Dazhi Zhang 7,  Yuanying Jiang 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No.1239 Siping Road, Shanghai, 200092, China.
  • 2 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No.1239 Siping Road, Shanghai, 200092, China; School of Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, No.110016, China.
  • 3 School of Pharmacy, Naval Medical University, No.325 Guohe Road, Shanghai, No.200433, China.
  • 4 School of Pharmacy, Naval Medical University, No.325 Guohe Road, Shanghai, No.200433, China; School of Pharmacy, Fujian University of Traditional Chinese Medicine, 1 Qiuyang Road, Fuzhou, 350112, China.
  • 5 The 967th Hospital of The Joint Logistic Support Force of PLA, Dalian, 116000, Liaoning, China.
  • 6 School of Pharmacy, Naval Medical University, No.325 Guohe Road, Shanghai, No.200433, China. Electronic address: haoyumenggogo@163.com.
  • 7 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No.1239 Siping Road, Shanghai, 200092, China; School of Pharmacy, Naval Medical University, No.325 Guohe Road, Shanghai, No.200433, China. Electronic address: zdzhang_yjhx@smmu.edu.cn.
  • 8 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No.1239 Siping Road, Shanghai, 200092, China. Electronic address: 13761571578@163.com.
PMID: 38070429 DOI: 10.1016/j.ejmech.2023.116026
Abstract

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 μg/mL to 16 μg/mL, including ten compounds with MIC values less than 1 μg/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 μg/mL to 1 μg/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 μg/mL to 1 μg/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.

Keywords

Amidation; Antifungal; Deferasirox; Iron chelation; Structure-activity relationship.

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