Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors

Research output: Contribution to journalArticleResearchpeer review

Authors

  • Isabell Walter
  • Sebastian Adam
  • Maria Virginia Gentilini
  • Andreas M. Kany
  • Christian Brengel
  • Andreas Thomann
  • Tim Sparwasser
  • Jesko Köhnke
  • Rolf W. Hartmann

External Research Organisations

  • Saarland University
  • TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH
  • Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
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Details

Original languageEnglish
Pages (from-to)2786-2801
Number of pages16
JournalCHEMMEDCHEM
Volume16
Issue number18
Publication statusPublished - 16 Sept 2021
Externally publishedYes

Abstract

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.

Keywords

    biological activity, complex structures, CYP121, Mycobacterium tuberculosis, structure-activity relationships

ASJC Scopus subject areas

Sustainable Development Goals

Cite this

Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors. / Walter, Isabell; Adam, Sebastian; Gentilini, Maria Virginia et al.
In: CHEMMEDCHEM, Vol. 16, No. 18, 16.09.2021, p. 2786-2801.

Research output: Contribution to journalArticleResearchpeer review

Walter, I, Adam, S, Gentilini, MV, Kany, AM, Brengel, C, Thomann, A, Sparwasser, T, Köhnke, J & Hartmann, RW 2021, 'Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors', CHEMMEDCHEM, vol. 16, no. 18, pp. 2786-2801. https://doi.org/10.1002/cmdc.202100283
Walter, I., Adam, S., Gentilini, M. V., Kany, A. M., Brengel, C., Thomann, A., Sparwasser, T., Köhnke, J., & Hartmann, R. W. (2021). Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors. CHEMMEDCHEM, 16(18), 2786-2801. https://doi.org/10.1002/cmdc.202100283
Walter I, Adam S, Gentilini MV, Kany AM, Brengel C, Thomann A et al. Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors. CHEMMEDCHEM. 2021 Sept 16;16(18):2786-2801. doi: 10.1002/cmdc.202100283
Walter, Isabell ; Adam, Sebastian ; Gentilini, Maria Virginia et al. / Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors. In: CHEMMEDCHEM. 2021 ; Vol. 16, No. 18. pp. 2786-2801.
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abstract = "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.",
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AU - Gentilini, Maria Virginia

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AU - Hartmann, Rolf W.

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