Analysis of structure-activity relationship of indol-3-yl-N-phenylcarbamic amides as potent STING inhibitors.

Abstract

A structure-activity relationship (SAR) study of stimulator of interferon gene (STING) inhibition was performed using a series of indol-3-yl-N-phenylcarbamic amides and indol-2-yl-N-phenylcarbamic amides. Among these analogs, compounds 10, 13, 15, 19, and 21 inhibited the phosphorylation of STING and interferon regulatory factor 3 (IRF3) to a greater extent than the reference compound, H-151. All five analogs showed stronger STING inhibition than H-151 on the 2',3'-cyclic GMP-AMP-induced expression of interferon regulatory factors (IRFs) in a STINGR232 knock-in THP-1 reporter cell line. The half-maximal inhibitory concentration of the most potent compound, 21, was 11.5 nM. The molecular docking analysis of compound 21 and STING combined with the SAR study suggested that the meta- and para-positions of the benzene ring of the phenylcarbamic amide moiety could be structurally modified by introducing halides or alkyl substituents.

• Authors: Po-Wei Chang, Jing-Ya Wang, Wan-Ping Wang, Wei-Cheng Huang, Mine-Hsine Wu, Jen-Shin Song, Liuh-Yow Chen, Chun-Wei Tung, Ya-Hui Chi, Shau-Hua Ueng
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 95 Pg. 117502 (11 15 2023) ISSN: 1464-3391 [Electronic] England
• PMID: 37866089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• Amides
• Nucleotidyltransferases

Topics

• Amides (pharmacology)
• Molecular Docking Simulation
• Phosphorylation
• Structure-Activity Relationship
• Nucleotidyltransferases (metabolism)