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 -