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dc.contributor.authorZhang, W.
dc.contributor.authorLiu, L.L.
dc.contributor.authorLun, S.
dc.contributor.authorWang, S.S.
dc.contributor.authorXiao, S.
dc.contributor.authorGunosewoyo, Hendra
dc.contributor.authorYang, F.
dc.contributor.authorTang, J.
dc.contributor.authorBishai, W.R.
dc.contributor.authorYu, L.F.
dc.date.accessioned2023-03-15T06:52:52Z
dc.date.available2023-03-15T06:52:52Z
dc.date.issued2021
dc.identifier.citationZhang, W. and Liu, L.L. and Lun, S. and Wang, S.S. and Xiao, S. and Gunosewoyo, H. and Yang, F. et al. 2021. Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules. European Journal of Medicinal Chemistry. 213: ARTN 113202.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/90987
dc.identifier.doi10.1016/j.ejmech.2021.113202
dc.description.abstract

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.

dc.languageEnglish
dc.publisherELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
dc.relation.sponsoredbyhttp://purl.org/au-research/grants/arc/DE160100482
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectChemistry, Medicinal
dc.subjectPharmacology & Pharmacy
dc.subjectPolyketide synthase 13
dc.subjectconformationally rigid tetracyclics
dc.subjectAntitubercular agents
dc.subjectAntitubercular agents
dc.subjectPolyketide synthase 13
dc.subjectconformationally rigid tetracyclics
dc.subjectAntitubercular Agents
dc.subjectBacterial Proteins
dc.subjectDose-Response Relationship, Drug
dc.subjectDrug Design
dc.subjectEnzyme Inhibitors
dc.subjectMicrobial Sensitivity Tests
dc.subjectModels, Molecular
dc.subjectMolecular Structure
dc.subjectMycobacterium tuberculosis
dc.subjectPolyketide Synthases
dc.subjectQuinolones
dc.subjectStructure-Activity Relationship
dc.subjectMycobacterium tuberculosis
dc.subjectQuinolones
dc.subjectPolyketide Synthases
dc.subjectBacterial Proteins
dc.subjectEnzyme Inhibitors
dc.subjectAntitubercular Agents
dc.subjectMicrobial Sensitivity Tests
dc.subjectMolecular Structure
dc.subjectStructure-Activity Relationship
dc.subjectDose-Response Relationship, Drug
dc.subjectDrug Design
dc.subjectModels, Molecular
dc.titleDesign and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules
dc.typeJournal Article
dcterms.source.volume213
dcterms.source.issn0223-5234
dcterms.source.titleEuropean Journal of Medicinal Chemistry
dc.date.updated2023-03-15T06:52:52Z
curtin.departmentCurtin Medical School
curtin.accessStatusOpen access
curtin.facultyFaculty of Health Sciences
curtin.contributor.orcidGunosewoyo, Hendra [0000-0003-3897-1948]
curtin.identifier.article-numberARTN 113202
dcterms.source.eissn1768-3254
curtin.contributor.scopusauthoridGunosewoyo, Hendra [16480496000]
curtin.repositoryagreementV3


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