Structure-Activity Relationship and Mode-of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors.
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Authors
Walter, IsabellAdam, Sebastian
Gentilini, Maria Virginia
Kany, Andreas M
Brengel, Christian
Thomann, Andreas
Sparwasser, Tim
Köhnke, Jesko
Hartmann, Rolf W
Issue Date
2021-05-19
Metadata
Show full item recordAbstract
CYP121 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.Citation
ChemMedChem. 2021 May 19. doi: 10.1002/cmdc.202100283. Epub ahead of print.Affiliation
HIPS, 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.Publisher
Wiley-VCHJournal
ChemMedChemPubMed ID
34010508Type
ArticleLanguage
enEISSN
1860-7187ae974a485f413a2113503eed53cd6c53
10.1002/cmdc.202100283
Scopus Count
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- Creative Commons