Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules
We previously reported a series of coumestans−a naturally occurring tetracyclic scaffold containing a δ-lactone−that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to th...
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| Format: | Journal Article |
| Language: | English |
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ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
2021
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| Online Access: | http://purl.org/au-research/grants/arc/DE160100482 http://hdl.handle.net/20.500.11937/90987 |
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| author | Zhang, W. Liu, L.L. Lun, S. Wang, S.S. Xiao, S. Gunosewoyo, Hendra Yang, F. Tang, J. Bishai, W.R. Yu, L.F. |
| author_facet | Zhang, W. Liu, L.L. Lun, S. Wang, S.S. Xiao, S. Gunosewoyo, Hendra Yang, F. Tang, J. Bishai, W.R. Yu, L.F. |
| author_sort | Zhang, W. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | We previously reported a series of coumestans−a naturally occurring tetracyclic scaffold containing a δ-lactone−that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to the corresponding ‘open-form’ ethyl benzofuran-3-carboxylates, the enhanced anti-TB effects seen with the conformationally restricted coumestan series could be attributed to the extra π-π stacking interactions between the benzene ring of coumestans and the phenyl ring of F1670 residue located in the Pks13-TE binding domain. To further probe this binding feature, novel tetracyclic analogues were synthesized and evaluated for their anti-TB activity against the Mtb strain H37Rv. Initial comparison of the ‘open-form’ analogueues against the tetracyclic counterparts again showed that the latter is superior in terms of anti-TB activity. In particular, the δ-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb H37Rv with MIC value between 0.0313 and 0.0625 μg/mL, with high selectivity to Vero cells (64–128 fold). The thermal stability analysis supports the notion that the tetracyclic compounds bind to the Pks13-TE domain as measured by nano DSF, consistent with the observed SAR trends. Compound 65 also showed excellent selectivity against actinobacteria and therefore unlikely to develop potential drug resistance to nonpathogenic bacteria. |
| first_indexed | 2025-11-14T11:35:53Z |
| format | Journal Article |
| id | curtin-20.500.11937-90987 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:35:53Z |
| publishDate | 2021 |
| publisher | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-909872023-05-24T01:07:52Z Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules Zhang, W. Liu, L.L. Lun, S. Wang, S.S. Xiao, S. Gunosewoyo, Hendra Yang, F. Tang, J. Bishai, W.R. Yu, L.F. Science & Technology Life Sciences & Biomedicine Chemistry, Medicinal Pharmacology & Pharmacy Polyketide synthase 13 conformationally rigid tetracyclics Antitubercular agents Antitubercular agents Polyketide synthase 13 conformationally rigid tetracyclics Antitubercular Agents Bacterial Proteins Dose-Response Relationship, Drug Drug Design Enzyme Inhibitors Microbial Sensitivity Tests Models, Molecular Molecular Structure Mycobacterium tuberculosis Polyketide Synthases Quinolones Structure-Activity Relationship Mycobacterium tuberculosis Quinolones Polyketide Synthases Bacterial Proteins Enzyme Inhibitors Antitubercular Agents Microbial Sensitivity Tests Molecular Structure Structure-Activity Relationship Dose-Response Relationship, Drug Drug Design Models, Molecular We previously reported a series of coumestans−a naturally occurring tetracyclic scaffold containing a δ-lactone−that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to the corresponding ‘open-form’ ethyl benzofuran-3-carboxylates, the enhanced anti-TB effects seen with the conformationally restricted coumestan series could be attributed to the extra π-π stacking interactions between the benzene ring of coumestans and the phenyl ring of F1670 residue located in the Pks13-TE binding domain. To further probe this binding feature, novel tetracyclic analogues were synthesized and evaluated for their anti-TB activity against the Mtb strain H37Rv. Initial comparison of the ‘open-form’ analogueues against the tetracyclic counterparts again showed that the latter is superior in terms of anti-TB activity. In particular, the δ-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb H37Rv with MIC value between 0.0313 and 0.0625 μg/mL, with high selectivity to Vero cells (64–128 fold). The thermal stability analysis supports the notion that the tetracyclic compounds bind to the Pks13-TE domain as measured by nano DSF, consistent with the observed SAR trends. Compound 65 also showed excellent selectivity against actinobacteria and therefore unlikely to develop potential drug resistance to nonpathogenic bacteria. 2021 Journal Article http://hdl.handle.net/20.500.11937/90987 10.1016/j.ejmech.2021.113202 English http://purl.org/au-research/grants/arc/DE160100482 http://creativecommons.org/licenses/by-nc-nd/4.0/ ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Chemistry, Medicinal Pharmacology & Pharmacy Polyketide synthase 13 conformationally rigid tetracyclics Antitubercular agents Antitubercular agents Polyketide synthase 13 conformationally rigid tetracyclics Antitubercular Agents Bacterial Proteins Dose-Response Relationship, Drug Drug Design Enzyme Inhibitors Microbial Sensitivity Tests Models, Molecular Molecular Structure Mycobacterium tuberculosis Polyketide Synthases Quinolones Structure-Activity Relationship Mycobacterium tuberculosis Quinolones Polyketide Synthases Bacterial Proteins Enzyme Inhibitors Antitubercular Agents Microbial Sensitivity Tests Molecular Structure Structure-Activity Relationship Dose-Response Relationship, Drug Drug Design Models, Molecular Zhang, W. Liu, L.L. Lun, S. Wang, S.S. Xiao, S. Gunosewoyo, Hendra Yang, F. Tang, J. Bishai, W.R. Yu, L.F. Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules |
| title | Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules |
| title_full | Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules |
| title_fullStr | Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules |
| title_full_unstemmed | Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules |
| title_short | Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules |
| title_sort | design and synthesis of mycobacterial pks13 inhibitors: conformationally rigid tetracyclic molecules |
| topic | Science & Technology Life Sciences & Biomedicine Chemistry, Medicinal Pharmacology & Pharmacy Polyketide synthase 13 conformationally rigid tetracyclics Antitubercular agents Antitubercular agents Polyketide synthase 13 conformationally rigid tetracyclics Antitubercular Agents Bacterial Proteins Dose-Response Relationship, Drug Drug Design Enzyme Inhibitors Microbial Sensitivity Tests Models, Molecular Molecular Structure Mycobacterium tuberculosis Polyketide Synthases Quinolones Structure-Activity Relationship Mycobacterium tuberculosis Quinolones Polyketide Synthases Bacterial Proteins Enzyme Inhibitors Antitubercular Agents Microbial Sensitivity Tests Molecular Structure Structure-Activity Relationship Dose-Response Relationship, Drug Drug Design Models, Molecular |
| url | http://purl.org/au-research/grants/arc/DE160100482 http://hdl.handle.net/20.500.11937/90987 |