Details
| Original language | English |
|---|---|
| Pages (from-to) | 2786-2801 |
| Number of pages | 16 |
| Journal | CHEMMEDCHEM |
| Volume | 16 |
| Issue number | 18 |
| Publication status | Published - 16 Sept 2021 |
| Externally published | Yes |
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
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
- Pharmacology, Toxicology and Pharmaceutics(all)
- Chemistry(all)
- Organic Chemistry
Sustainable Development Goals
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In: CHEMMEDCHEM, Vol. 16, No. 18, 16.09.2021, p. 2786-2801.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors
AU - Walter, Isabell
AU - Adam, Sebastian
AU - Gentilini, Maria Virginia
AU - Kany, Andreas M.
AU - Brengel, Christian
AU - Thomann, Andreas
AU - Sparwasser, Tim
AU - Köhnke, Jesko
AU - Hartmann, Rolf W.
N1 - Funding Information: We acknowledge the use of ESRF Beamline ID 23–2 and SLS Beamlines X06DA and X10SA. Open Access funding enabled and organized by Projekt DEAL.
PY - 2021/9/16
Y1 - 2021/9/16
N2 - 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.
AB - 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.
KW - biological activity
KW - complex structures
KW - CYP121
KW - Mycobacterium tuberculosis
KW - structure-activity relationships
UR - http://www.scopus.com/inward/record.url?scp=85108328702&partnerID=8YFLogxK
U2 - 10.1002/cmdc.202100283
DO - 10.1002/cmdc.202100283
M3 - Article
C2 - 34010508
AN - SCOPUS:85108328702
VL - 16
SP - 2786
EP - 2801
JO - CHEMMEDCHEM
JF - CHEMMEDCHEM
SN - 1860-7179
IS - 18
ER -