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Rational design, synthesis, and biological evaluation of heterocyclic quinolones targeting the respiratory chain of Mycobacterium tuberculosis

2017-05Journal article Open access
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dc.contributor.authorHong, W. David
dc.contributor.authorGibbons, Peter D.
dc.contributor.authorLeung, Suet C.
dc.contributor.authorAmewu, Richard
dc.contributor.authorStocks, Paul A.
dc.contributor.authorStachulski, Andrew
dc.contributor.authorHorta, Pedro
dc.contributor.authorCristiano, Maria De Lurdes
dc.contributor.authorShone, Alison E.
dc.contributor.authorMoss, Darren
dc.contributor.authorArdrey, Alison
dc.contributor.authorSharma, Raman
dc.contributor.authorWarman, Ashley J.
dc.contributor.authorBedingfield, Paul T. P.
dc.contributor.authorFisher, Nicholas E.
dc.contributor.authorAljayyoussi, Ghaith
dc.contributor.authorMead, Sally
dc.contributor.authorCaws, Maxine
dc.contributor.authorBerry, Neil G.
dc.contributor.authorWard, Stephen A.
dc.contributor.authorBiagini, Giancarlo A.
dc.contributor.authorO'Neill, Paul M.
dc.contributor.authorNixon, Gemma L.
dc.date.accessioned2018-12-07T14:57:51Z
dc.date.available2018-12-07T14:57:51Z
dc.date.issued2017-05
dc.description.abstractA high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified similar to 100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further similar to 90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles.
dc.description.sponsorshipNational Institute of Health Research (NIHR, BRC Liverpool); Medical Research Council [MRC DPFS-G1002586]; Medical Research Council (MRC CiC)
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1021/acs.jmedchem.6b01718
dc.identifier.issn0022-2623
dc.identifier.issn1520-4804
dc.identifier.urihttp://hdl.handle.net/10400.1/11727
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAmerican Chemical Society
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectNadhquinone Oxidoreductase Pfndh2
dc.subjectMultidrug-resistant tuberculosis
dc.subjectCatalyzed N-Arylation
dc.subjectDrug discovery
dc.subjectPlasmodium-Falciparum
dc.subjectIn-Vitro
dc.subjectAtp Homeostasis
dc.subjectDna gyrase
dc.subjectDiarylquinolines
dc.subjectIdentification
dc.titleRational design, synthesis, and biological evaluation of heterocyclic quinolones targeting the respiratory chain of Mycobacterium tuberculosis
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage3726
oaire.citation.issue9
oaire.citation.startPage3703
oaire.citation.titleJournal of Medicinal Chemistry
oaire.citation.volume60
person.familyNameHorta
person.familyNameCristiano
person.givenNamePedro
person.givenNameMaria de Lurdes
person.identifier.ciencia-idFA1A-E8E4-9C24
person.identifier.ciencia-idE411-6006-5A01
person.identifier.orcid0000-0001-7313-338X
person.identifier.orcid0000-0002-9447-2855
person.identifier.ridG-2345-2012
person.identifier.scopus-author-id9238724800
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication8217e5b0-c7e4-43af-bc28-c8ca8b5adc1c
relation.isAuthorOfPublicationb16751a6-748e-44b0-9c59-058cbd5b2cc3
relation.isAuthorOfPublication.latestForDiscoveryb16751a6-748e-44b0-9c59-058cbd5b2cc3

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