Nalidixic acid

Nalidixic acid
Clinical data
Trade names	NegGram, Wintomylon, others
AHFS/Drugs.com	Consumer Drug Information
Routes of; administration	Oral
ATC code	J01MB02 (WHO) ;
Legal status
Legal status	US: Not FDA approved;
Pharmacokinetic data
Protein binding	90%
Metabolism	Partially Hepatic
Elimination half-life	6-7 hours, significantly longer in renal impairment
Identifiers
	IUPAC name 1-Ethyl-7-methyl-4-oxo-[1,8]naphthyridine-3-carboxylic acid;
CAS Number	389-08-2 ;
PubChem CID	4421;
DrugBank	DB00779 ;
ChemSpider	4268 ;
UNII	3B91HWA56M;
KEGG	D00183 ;
ChEBI	CHEBI:100147 ;
ChEMBL	ChEMBL5 ;
CompTox Dashboard (EPA)	DTXSID3020912 ;
ECHA InfoCard	100.006.241
Chemical and physical data
Formula	C12H12N2O3
Molar mass	232.239 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C\2c1c(nc(cc1)C)N(/C=C/2C(=O)O)CC;
	InChI InChI=1S/C12H12N2O3/c1-3-14-6-9(12(16)17)10(15)8-5-4-7(2)13-11(8)14/h4-6H,3H2,1-2H3,(H,16,17) ; Key:MHWLWQUZZRMNGJ-UHFFFAOYSA-N ;
	(verify)

Nalidixic acid (tradenames Nevigramon, NegGram, Wintomylon and WIN 18,320) is the first of the synthetic quinolone antibiotics.

In a technical sense, it is a naphthyridone, not a quinolone: its ring structure is a 1,8-naphthyridine nucleus that contains two nitrogen atoms, unlike quinoline, which has a single nitrogen atom.^[1]

Synthetic quinolone antibiotics were discovered by George Lesher and coworkers as a byproduct of chloroquine manufacture in the 1960s;^[2] nalidixic acid itself was used clinically, starting in 1967.

Nalidixic acid is effective primarily against Gram-negative bacteria, with minor anti-Gram-positive activity. In lower concentrations, it acts in a bacteriostatic manner; that is, it inhibits growth and reproduction. In higher concentrations, it is bactericidal, meaning that it kills bacteria instead of merely inhibiting their growth.

It has historically been used for treating urinary tract infections, caused, for example, by Escherichia coli, Proteus, Shigella, Enterobacter, and Klebsiella. It is no longer clinically used for this indication in the US as less toxic and more effective agents are available. The marketing authorization for nalidixic acid has been suspended throughout the EU.^[3]

It is also a tool in studies as a regulation of bacterial division. It selectively and reversibly blocks DNA replication in susceptible bacteria. Nalidixic acid and related antibiotics inhibit a subunit of DNA gyrase and topoisomerase IV and induce formation of cleavage complexes.^[4] It also inhibits the nicking-closing activity on the subunit of DNA gyrase that releases the positive binding stress on the supercoiled DNA.

^ Emmerson AM, Jones AM (May 2003). "The quinolones: decades of development and use". The Journal of Antimicrobial Chemotherapy. 51 (Suppl 1): 13–20. doi:10.1093/jac/dkg208. PMID 12702699.
^ Lesher GY, Froelich EJ, Gruett MD, Bailey JH, Brundage RP (September 1962). "1,8-Naphthyridine Derivatives. A New Class of Chemotherapeutic Agents". Journal of Medicinal and Pharmaceutical Chemistry. 5 (5): 1063–1065. doi:10.1021/jm01240a021. PMID 14056431.
^ "Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics". European Medicines Agency. 11 March 2019.
^ Pommier Y, Leo E, Zhang H, Marchand C (May 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chemistry & Biology. 17 (5): 421–433. doi:10.1016/j.chembiol.2010.04.012. PMC 7316379. PMID 20534341.

[jac2003-1] Emmerson AM, Jones AM (May 2003). "The quinolones: decades of development and use". The Journal of Antimicrobial Chemotherapy. 51 (Suppl 1): 13–20. doi:10.1093/jac/dkg208. PMID 12702699.

[2] Lesher GY, Froelich EJ, Gruett MD, Bailey JH, Brundage RP (September 1962). "1,8-Naphthyridine Derivatives. A New Class of Chemotherapeutic Agents". Journal of Medicinal and Pharmaceutical Chemistry. 5 (5): 1063–1065. doi:10.1021/jm01240a021. PMID 14056431.

[3] "Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics". European Medicines Agency. 11 March 2019.

[4] Pommier Y, Leo E, Zhang H, Marchand C (May 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chemistry & Biology. 17 (5): 421–433. doi:10.1016/j.chembiol.2010.04.012. PMC 7316379. PMID 20534341.

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