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 (previously TMC207)
A 1,4-diarylquinoline (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.

Synthesis of 1,4-diarylquinolines

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

Synthesis of 2,4-diarylquinolines

The reaction of enamides and imines can produce heteroaromatic quinoline derivatives.[4]

References

  1. ↑ Koul, Anil; Dendouga, Najoua; Vergauwen, Karen; Molenberghs, Brenda; Vranckx, Luc; Willebrords, Rudy; Ristic, Zorica; Lill, Holger; Dorange, Ismet; Guillemont, Jerome; Bald, Dirk; Andries, Koen (2007). "Diarylquinolines target subunit c of mycobacterial ATP synthase". Nature Chemical Biology. 3 (6): 323–324. doi:10.1038/nchembio884. ISSN 1552-4450. PMID 17496888.
  2. 1 2 Haagsma, A. C.; Abdillahi-Ibrahim, R.; Wagner, M. J.; Krab, K.; Vergauwen, K.; Guillemont, J.; Andries, K.; Lill, H.; Koul, A.; Bald, D. (2008). "Selectivity of TMC207 towards Mycobacterial ATP Synthase Compared with That towards the Eukaryotic Homologue" (PDF). Antimicrobial Agents and Chemotherapy. 53 (3): 1290–2. doi:10.1128/AAC.01393-08. PMC 2650532. PMID 19075053.
  3. ↑ Wang, Xiang-Shan; Zhang, Mei-Mei; Jiang, Hong; Yao, Chang-Sheng; Tu, Shu-Jiang (2008). "Uncatalyzed and Solvent‐Free Process for the Synthesis of 1,4‐Diarylquinoline Derivatives". Synthetic Communications. 38 (9): 1355–1364. doi:10.1080/00397910801916397.
  4. ↑ Metal free synthesis of 2,4-diarylquinoline derivatives with enamides and imines
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