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Eur J Med Chem. 2018 Jan 20;144:262-276. doi: 10.1016/j.ejmech.2017.12.017. Epub 2017 Dec 7.

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

Author information

1
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, 117543, Singapore.
2
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, 117545, Singapore.
3
Protein Production Platform, School of Biological Sciences, Nanyang Technological University, 138673, Singapore.
4
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, 117545, Singapore; Public Health Research Institute, New Jersey Medical School, Rutgers University, 225 Warren Street, Newark, NJ07103, USA. Electronic address: td367@njms.rutgers.edu.
5
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, 117543, Singapore. Electronic address: phacwk@nus.edu.sg.

Abstract

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.

KEYWORDS:

1,3,5-triazaspiro[5.5]undeca-2,4-diene; Antimycobacterial agent; Dihydrofolate reductase (DHFR); Tuberculosis (TB)

PMID:
29274493
DOI:
10.1016/j.ejmech.2017.12.017
[Indexed for MEDLINE]

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