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dc.contributor.authorAnagani, Bhavani
dc.contributor.authorSingh, Jagbir
dc.contributor.authorBassin, Jatinder
dc.contributor.authorBesra, Gurdyal
dc.contributor.authorBenham, Christopher
dc.contributor.authorReddy, Tummala Rama Krishna
dc.contributor.authorCox, Jonathan
dc.contributor.authorGoyal, Madhu
dc.date.accessioned2020-05-23T00:11:19Z
dc.date.available2020-05-23T00:11:19Z
dc.date.issued2020-05-18
dc.identifier.citationAnagani , B , Singh , J , Bassin , J , Besra , G , Benham , C , Reddy , T R K , Cox , J & Goyal , M 2020 , ' Identification and validation of the mode of action of the chalcone anti-mycobacterial compounds ' , The Cell Surface . https://doi.org/10.1016/j.tcsw.2020.100041
dc.identifier.issn2468-2330
dc.identifier.otherPURE: 21422411
dc.identifier.otherPURE UUID: cde42add-a540-4932-9167-1e46101af810
dc.identifier.urihttp://hdl.handle.net/2299/22748
dc.description© 2020 The Author(s). This is an open access article published under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) licence: https://creativecommons.org/licenses/by-nc-nd/4.0/.
dc.description.abstractObjectives: The search for new TB drugs has become one of the great challenges for modern medicinal chemistry. An improvement in the outcomes of TB chemotherapy can be achieved by the development of new, shorter, cheap, safe and effective anti-TB regimens. Methods: Chalcones (1a-1o) were synthesized and evaluated for their antimycobacterial activity against Mycobacterium bovis BCG using growth inhibition assays. Compound 1a was selected as a ‘hit’ compound. The mode of action of compound 1a, was identified by mycolic acid methyl esters (MAMEs) and fatty acid methyl esters (FAMEs) analysis using thin layer chromatography. Dose dependent experiments were conducted by over-expressing components of FAS-II in M. bovis BCG to confirm the target. Ligand binding using intrinsic tryptophan assay and molecular docking were used to further validate the target. Results: MAMEs and FAMEs analysis showed dose-dependent reduction of MAMEs with the overall abundance of FAMEs suggesting that compound 1a targets mycolic acid biosynthesis. Direct binding of 1a to InhA was observed using an intrinsic tryptophan fluorescence binding assay, and a 2-fold IC50 shift was observed with an InhA overexpressing strain confirming InhA as the cellular target. Conclusion: The chalcone 1a exhibits potent antimycobacterial activity, displays a good safety profile and is a direct inhibitor of InhA, a key component in mycolic acid synthesis, validating this series for further anti-TB drug developmenten
dc.language.isoeng
dc.relation.ispartofThe Cell Surface
dc.rightsOpen
dc.subjectChalcones, Tuberculosis, MIC, InhA, Mycolic Acids, Docking
dc.titleIdentification and validation of the mode of action of the chalcone anti-mycobacterial compoundsen
dc.contributor.institutionAgriculture, Veterinary and Food Sciences
dc.contributor.institutionGeography, Environment and Agriculture
dc.contributor.institutionVeterinary Science
dc.contributor.institutionMicrobiology and Biotechnology
dc.contributor.institutionDepartment of Biological and Environmental Sciences
dc.contributor.institutionBiosciences Research Group
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionDepartment of Clinical and Pharmaceutical Sciences
dc.contributor.institutionPsychopharmacology, Drug Misuse and Novel Psychoactive Substances Unit
dc.contributor.institutionCentre for Health Services and Clinical Research
dc.contributor.institutionBasic and Clinical Science Unit
dc.contributor.institutionTRP Ion channels
dc.description.statusPeer reviewed
dc.relation.schoolSchool of Life and Medical Sciences
dc.description.versiontypeFinal Accepted Version
dcterms.dateAccepted2020-05-18
rioxxterms.versionAM
rioxxterms.versionofrecordhttps://doi.org/10.1016/j.tcsw.2020.100041
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue
herts.rights.accesstypeOpen


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