Diarylquinoline

Diarylquinoline
Drug class
Bedaquiline is the founding member of this class
Class identifiers
UseAnti-tuberculosis drug
Mechanism of actionInhibitor
Biological targetsubunit c of ATP synthase
Chemical classDiarylquinoline
External links
MeSHD064687
Legal status
In Wikidata

Diarylquinolines (DARQs) are a chemical class of drugs that treat tuberculosis. They target subunit c of mycobacterial ATP synthase, 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, 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.

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. It is currently in phase 2 clinical trials.

Synthesis of 1,4-diarylquinolines

The reaction of aryl aldehyde, malonodinitrile, and 3‐arylamino‐5,5‐dimethylcyclohex‐2‐enone can produce 1,4-diarylquinolines.

Synthesis of 2,4-diarylquinolines

The reaction of enamides and imines can produce hetero aromatic quinoline derivatives.

References

  1. ↑ Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, et al. (June 2007). "Diarylquinolines target subunit c of mycobacterial ATP synthase". Nature Chemical Biology. 3 (6): 323–324. doi:10.1038/nchembio884. PMID 17496888.
  2. 1 2 Haagsma AC, Abdillahi-Ibrahim R, Wagner MJ, Krab K, Vergauwen K, Guillemont J, et al. (March 2009). "Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue". Antimicrobial Agents and Chemotherapy. 53 (3): 1290–1292. doi:10.1128/AAC.01393-08. PMC 2650532. PMID 19075053.
  3. ↑ Enesco A (25 November 2025). "Sorfequiline Shows Promise in Shortened Tuberculosis Therapy". European Medical Journal.
  4. ↑ Clinical trial number NCT07672405 for "Sorfequiline-based Regimens in Adults With Newly Diagnosed Drug-sensitive Pulmonary TB" at ClinicalTrials.gov
  5. ↑ 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
  6. ↑ Wang XS, Zhang MM, Jiang H, Yao CS, Tu SJ (2008). "Uncatalyzed and Solvent-Free Process for the Synthesis of 1,4-Diarylquinoline Derivatives". Synthetic Communications. 38 (9): 1355–1364. doi:10.1080/00397910801916397.
  7. ↑ Li Y, Zhou X, Wu Z, Cao J, Ma C, He Y, et al. (2015). "Metal free synthesis of 2, 4-diarylquinoline derivatives with enamides and imines". RSC Advances. 5 (107): 88214–88217. doi:10.1039/c5ra17823a.