2. Academic Validation
  3. Design, synthesis and antifungal evaluation of borrelidin derivatives

Design, synthesis and antifungal evaluation of borrelidin derivatives

  • Bioorg Med Chem. 2018 Dec 15;26(23-24):6035-6049. doi: 10.1016/j.bmc.2018.11.005.
Caijuan Hu 1,  Hao Su 1,  Jinghan Luo 2,  Li Han 3,  Qingyin Liu 1,  Wenxi Wu 1,  Yu Mu 1,  Peipei Guan 1,  Tiemin Sun 4,  Xueshi Huang 5
Affiliations

Affiliations

  • 1 College of Life and Health Sciences, Northeastern University, Shenyang 110819, China.
  • 2 Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 College of Life and Health Sciences, Northeastern University, Shenyang 110819, China. Electronic address: hanli@mail.neu.edu.cn.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: suntiemin@syphu.edu.cn.
  • 5 College of Life and Health Sciences, Northeastern University, Shenyang 110819, China. Electronic address: huangxs@mail.neu.edu.cn.
PMID: 30442507 DOI: 10.1016/j.bmc.2018.11.005
Abstract

Borrelidin, a nitrile containing 18-membered polyketide Macrolide, display potent Antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis. The Antifungal activity and cytotoxicity of these target compounds were evaluated by broth microdilution and 3-(4,5-dimethylthiazol-2-yl)-3,5-phenytetrazoliumromide (MTT) methods. Among forty-seven prepared analogues, compound 3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5 μg/mL, respectively). Furthermore, compounds 4n and 4r presented better Antifungal activity against Aspergillus fumigatus with 12.5 μg/mL MIC value, which were insensitive to borrelidin. Preliminary structure-activity relationships (SAR) revealed that the ester analogues containing fragment -OCH2CH2N- had an important effect on the Antifungal activity. Meanwhile, the molecular docking study indicated the carboxyl substituents in BN could provide extra interaction with pathogenic Fungal threonyl-tRNA synthetase (ThrRS).

Keywords

Antifungal activity; Borrelidin; Molecular docking; Structure-activity relationships; Synthesis.

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