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dc.contributor.authorWalter, Isabell
dc.contributor.authorAdam, Sebastian
dc.contributor.authorGentilini, Maria Virginia
dc.contributor.authorKany, Andreas M
dc.contributor.authorBrengel, Christian
dc.contributor.authorThomann, Andreas
dc.contributor.authorSparwasser, Tim
dc.contributor.authorKöhnke, Jesko
dc.contributor.authorHartmann, Rolf W
dc.date.accessioned2021-07-01T09:51:58Z
dc.date.available2021-07-01T09:51:58Z
dc.date.issued2021-05-19
dc.identifier.citationChemMedChem. 2021 May 19. doi: 10.1002/cmdc.202100283. Epub ahead of print.en_US
dc.identifier.pmid34010508
dc.identifier.doi10.1002/cmdc.202100283
dc.identifier.urihttp://hdl.handle.net/10033/622915
dc.description.abstractCYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with antimycobacterial activity. Herein, we report the screening of a similarity-oriented library based on the former hit compound, the evaluation of affinity toward CYP121, and activity against M. bovis BCG. The results enabled a comprehensive SAR study, which was extended through the synthesis of promising compounds and led to the identification of favorable features for affinity and/or activity and hit compounds with 2.7-fold improved potency. Mode of action studies show that the hit compounds inhibit substrate conversion and highlighted CYP121 as the main antimycobacterial target of our compounds. Exemplified complex crystal structures of CYP121 with three inhibitors reveal a common binding site. Engaging in both hydrophobic interactions as well as hydrogen bonding to the sixth iron ligand, our compounds block a solvent channel leading to the active site heme. Additionally, we report the first CYP inhibitors that are able to reduce the intracellular replication of M. bovis BCG in macrophages, emphasizing their potential as future drug candidates against TB.en_US
dc.language.isoenen_US
dc.publisherWiley-VCHen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectCYP121en_US
dc.subjectMycobacterium tuberculosisen_US
dc.subjectbiological activityen_US
dc.subjectcomplex structuresen_US
dc.subjectstructure-activity relationshipsen_US
dc.titleStructure-Activity Relationship and Mode-of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors.en_US
dc.typeArticleen_US
dc.identifier.eissn1860-7187
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.en_US
dc.identifier.journalChemMedChemen_US
refterms.dateFOA2021-07-01T09:51:59Z
dc.source.journaltitleChemMedChem
dc.source.countryGermany


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International