1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity
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 agent...
| Main Authors: | , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2020
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| Online Access: | https://hdl.handle.net/10356/142311 |
| _version_ | 1824456079791095808 |
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| author | Yang, Xuan Wedajo, Wassihun Yamada, Yoshiyuki Dahlroth, Sue-Li Neo, Jason Jun-Long Dick, Thomas Chui, Wai-Keung |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Yang, Xuan Wedajo, Wassihun Yamada, Yoshiyuki Dahlroth, Sue-Li Neo, Jason Jun-Long Dick, Thomas Chui, Wai-Keung |
| author_sort | Yang, Xuan |
| collection | NTU |
| description | 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. |
| first_indexed | 2025-02-19T03:48:24Z |
| format | Journal Article |
| id | ntu-10356/142311 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:48:24Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | ntu-10356/1423112020-06-19T01:41:15Z 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity Yang, Xuan Wedajo, Wassihun Yamada, Yoshiyuki Dahlroth, Sue-Li Neo, Jason Jun-Long Dick, Thomas Chui, Wai-Keung School of Biological Sciences Science::Biological sciences Dihydrofolate Reductase Antimycobacterial Agent 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. NMRC (Natl Medical Research Council, S’pore) 2020-06-19T01:41:15Z 2020-06-19T01:41:15Z 2018 Journal Article Yang, X., Wedajo, W., Yamada, Y., Dahlroth, S.-L., Neo, J. J.-L., Dick, T., & Chui, W.-K. (2018). 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity. European journal of medicinal chemistry, 144, 262-276. doi:10.1016/j.ejmech.2017.12.017 0223-5234 https://hdl.handle.net/10356/142311 10.1016/j.ejmech.2017.12.017 29274493 2-s2.0-85038867624 144 262 276 en European journal of medicinal chemistry © 2017 Elsevier Masson SAS. All rights reserved. |
| spellingShingle | Science::Biological sciences Dihydrofolate Reductase Antimycobacterial Agent Yang, Xuan Wedajo, Wassihun Yamada, Yoshiyuki Dahlroth, Sue-Li Neo, Jason Jun-Long Dick, Thomas Chui, Wai-Keung 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity |
| title | 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity |
| title_full | 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity |
| title_fullStr | 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity |
| title_full_unstemmed | 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity |
| title_short | 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity |
| title_sort | 1 3 5 triazaspiro 5 5 undeca 2 4 dienes as selective mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity |
| topic | Science::Biological sciences Dihydrofolate Reductase Antimycobacterial Agent |
| url | https://hdl.handle.net/10356/142311 |
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