My watch list
my.chemeurope.com  
Login  

1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity

Publication date:

20 January 2018


Source:European Journal of Medicinal Chemistry, Volume 144

Author(s): Xuan Yang, Wassihun Wedajo, Yoshiyuki Yamada, Sue-Li Dahlroth, Jason Jun-Long Neo, Thomas Dick, Wai-Keung Chui

The emergence of multi- and extensively-drug resistant tubercular (MDR- and XDR-TB) strains of mycobacteria has limited the use of existing therapies, therefore new drugs are needed. Dihydrofolate reductase (DHFR) has recently attracted much attention as a target for the development of anti-TB agents. This study aimed to develop selective M. tuberculosis DHFR inhibitors using rationale scaffolding design and synthesis, phenotype-oriented screening, enzymatic inhibitory study, whole cell on-target validation, molecular modeling, and in vitro DMPK determination to derive new anti-TB agents. 2,4-diamino-1-phenyl-1,3,5-triazaspiro[5.5]undeca-2,4-dienes 20b and 20c were identified as selective M. tuberculosis DHFR inhibitors, showing promising antimycobacterial activities (MIC50: 0.01 μM and MIC90: 0.025 μM on M. tuberculosis H37Rv). This study provided compelling evidence that compound 20b and 20c exerted whole cell antimycobacterial activity through DHFR inhibition. In addition, these two compounds exhibited low cytotoxicity and low hemolytic activity. The in vitro DMPK and physiochemical properties suggested their potential in vivo efficacy.
Graphical abstract




Authors:   Author(s): Xuan Yang, Wassihun Wedajo, Yoshiyuki Yamada, Sue-Li Dahlroth, Jason Jun-Long Neo, Thomas Dick, Wai-Keung Chui
Journal:   European Journal of Medicinal Chemistry
Year:   2017
Publication date:   24-Dec-2017
Facts, background information, dossiers
  • tuberculosis
  • Mycobacterium tuberculosis
  • Yamada
  • mycobacteria
  • medicinal chemistry
  • drugs
More about Elsevier
Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE