Chemistry:Diarylquinoline
Diarylquinolines (DARQs) are a chemical class of drugs that treat tuberculosis. They target subunit c of mycobacterial ATP synthase,[1] inhibiting the enzyme so mycobacterium tuberculosis cannot synthesise ATP. This effectively kills the bacteria.
Although ATP synthase in bacteria is similar to its eukaryotic analogue, diarylquinoline agents (such as TMC207) are very specific to the bacterial enzyme,[2] so were expected to be safe for use in humans and other eukaryotes. This also suggests that bacterial ATP synthase inhibition is an attractive therapeutic target.[2]
Examples
Bedaquiline
Bedaquiline (previously TMC207) is a 1,4-diaryl quinoline (phenyl and naphthyl). US FDA approval in 2012. As of 2014, the only licensed indication of the drug bedaquiline is in the treatment of multi-drug-resistant tuberculosis, primarily due to concerns about safety.[citation needed]
Sorfequiline
Sorfequiline (previously TBAJ876) is a next generation diarylquinoline mycobacterial ATP synthase inhibitor claimed to have greater potency and reduced cardiac QT prolongation.[3] It is currently in phase 2 clinical trials.[4][5]
Synthesis of 1,4-diarylquinolines
The reaction of aryl aldehyde, malonodinitrile, and 3‐arylamino‐5,5‐dimethylcyclohex‐2‐enone can produce 1,4-diarylquinolines.[6]
Synthesis of 2,4-diarylquinolines
The reaction of enamides and imines can produce hetero aromatic quinoline derivatives.[7]
References
- ↑ "Diarylquinolines target subunit c of mycobacterial ATP synthase". Nature Chemical Biology 3 (6): 323–324. June 2007. doi:10.1038/nchembio884. PMID 17496888.
- ↑ 2.0 2.1 "Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue". Antimicrobial Agents and Chemotherapy 53 (3): 1290–1292. March 2009. doi:10.1128/AAC.01393-08. PMID 19075053.
- ↑ "Sorfequiline Shows Promise in Shortened Tuberculosis Therapy". 25 November 2025. https://www.emjreviews.com/microbiology-infectious-diseases/news/sorfequiline-shows-promise-in-shortened-tuberculosis-therapy/.
- ↑ Clinical trial number NCT07672405 for "Sorfequiline-based Regimens in Adults With Newly Diagnosed Drug-sensitive Pulmonary TB" at ClinicalTrials.gov
- ↑ Clinical trial number NCT06058299 for "Phase 2 Trial Assessing TBAJ876 or Bedaquiline, With Pretomanid and Linezolid in Adults With Drug-sensitive Pulmonary Tuberculosis" at ClinicalTrials.gov
- ↑ "Uncatalyzed and Solvent-Free Process for the Synthesis of 1,4-Diarylquinoline Derivatives". Synthetic Communications 38 (9): 1355–1364. 2008. doi:10.1080/00397910801916397.
- ↑ "Metal free synthesis of 2, 4-diarylquinoline derivatives with enamides and imines.". RSC Advances 5 (107): 88214–88217. 2015. doi:10.1039/c5ra17823a.
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