Nalidixic acid

Structural formula
General
Non-proprietary name	Nalidixic acid
other names	1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ( IUPAC )
Molecular formula	C 12 H 12 N 2 O 3
Brief description	white to pale yellow, monoclinic crystals
External identifiers / databases
EC number	206-864-7
ECHA InfoCard	100.006.241
PubChem	4421
ChemSpider	4268
DrugBank	DB00779
Wikidata	Q281082
Drug information
ATC code	J01 MB02
Drug class	Antibiotic , quinolone
Mechanism of action	Gyrase inhibitors
properties
Molar mass	232.24 g · mol -1
Melting point	229.5 ° C
pK s value	6.0
solubility	low in water (100 mg l −1 at 23 ° C)
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances Caution
H and P phrases	H: 302
	P: 301 + 312 + 330
Toxicological data	2040 mg kg −1 ( LD 50 , rat , oral ) ; 88.4 mg kg −1 ( LD 50 , rat , iv ) ; 572 mg kg −1 ( LD 50 , mouse , oral ) ; 101 mg kg −1 ( LD 50 , mouse , iv ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Nalidixic acid is a synthetically produced chemical compound from the group of diazanaphthalenes , which have a strong structural similarity to quinolones . Its action as a gyrase inhibitor made it the first compound in this class to be used as an antibiotic in 1962 .

Extraction and presentation

The four-step synthesis starts in the first step with the reaction of 2-amino-6-methylpyridine with ethoxymethylene malonic acid diethyl ester. The resulting intermediate is then cyclized to the 1,8-naphthyridine structure. After the ethyl ester group has been saponified with sodium hydroxide solution , the target compound is obtained by N -alkylation using ethyl iodide .

effect

The active ingredient inhibits the enzyme gyrase in bacteria. Nalidixic acid was discovered in 1962 as an antibiotic with low toxicity , mainly effective against Gram-negative bacteria ( LD ₅₀ for oral administration in mice of approx. 3 g · kg ⁻¹ ). Based on nalidixic acid, similar but more effective antibiotics were sought. It was subsequently supplanted by the much more potent fluoroquinolones . Nalidixic acid is effective against Gram-positive and Gram-negative bacteria . In low concentrations it has a bacteriostatic effect, i.e. it prevents the reproduction of bacteria, while in higher concentrations it has a bactericidal effect and kills them.

use

It is mainly used to treat urinary tract infections caused by Escherichia coli , Proteus , Shigella , Enterobacter or Klebsiella . Due to the rapid development of resistance and a narrow spectrum of activity in Europe, the active ingredient is no longer on the market. A better alternative to the quinolonecarboxylic acids of the first generation is pipemidic acid , which is also effective against gram-negative pathogens thanks to a 7-piperazinyl substituent .

Trade names

Wintomylon ( Brazil )

Web links

MedlinePlus: Nalidixic Acid
HealthDigest.org: Nalidixic acid

Individual evidence

↑ ^a ^b ^c Entry on nalidixic acid. In: Römpp Online . Georg Thieme Verlag, accessed on November 11, 2017.
↑ ^a ^b Entry on Nalidixic acid in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on November 10, 2017.
↑ ^a ^b data sheet Nalidixic acid from Sigma-Aldrich , accessed on May 14, 2017 ( PDF ).
^ ^A ^b ^c ^d ^e A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications , 4th edition (2000), Thieme-Verlag Stuttgart, ISBN 978-1-58890- 031-9 .
↑ ^a ^b G. Y. Lesher, EJ Froehlich, MD Gruett, JH Bailey, PR Brundage: 1,8-Naphthyridine Derivatives. A New Class of Chemotherapeutic Agents in J. Med. Chem. 5 (1962) 1063-1065, doi: 10.1021 / jm01240a021 .
↑ Patent US 3,149,104 (Sterling Drug, September 15, 1964).
↑ RK Hamatake, R. Mukai, M. Hayashi: Role of DNA gyrase subunits in synthesis of bacteriophage phi X174 viral DNA March 1981; PMID 6262812 ; PMC 319165 (free full text).
↑ Schubert-Zsilavecz, Manfred., Roth, Hermann J .: Medicinal Chemistry: Targets - Drugs - Chemical Biology; 191 tables . 2., completely reworked. and exp. Ed. Dt. Apotheker-Verl, Stuttgart 2010, ISBN 978-3-7692-5002-2 .

[roempp-1] Entry on nalidixic acid. In: Römpp Online . Georg Thieme Verlag, accessed on November 11, 2017.

[chemid-2] Entry on Nalidixic acid in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on November 10, 2017.

[Sigma-3] ta sheet Nalidixic acid from Sigma-Aldrich , accessed on May 14, 2017 ( PDF ).

[Kleemann-4] A ^b ^c ^d ^e A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications , 4th edition (2000), Thieme-Verlag Stuttgart, ISBN 978-1-58890- 031-9 .

[Lesher-5] G. Y. Lesher, EJ Froehlich, MD Gruett, JH Bailey, PR Brundage: 1,8-Naphthyridine Derivatives. A New Class of Chemotherapeutic Agents in J. Med. Chem. 5 (1962) 1063-1065, doi: 10.1021 / jm01240a021 .

[6] Patent US 3,149,104 (Sterling Drug, September 15, 1964).

[UNAIDS2006-7] RK Hamatake, R. Mukai, M. Hayashi: Role of DNA gyrase subunits in synthesis of bacteriophage phi X174 viral DNA March 1981; PMID 6262812 ; PMC 319165 (free full text).

[8] Schubert-Zsilavecz, Manfred., Roth, Hermann J .: Medicinal Chemistry: Targets - Drugs - Chemical Biology; 191 tables . 2., completely reworked. and exp. Ed. Dt. Apotheker-Verl, Stuttgart 2010, ISBN 978-3-7692-5002-2 .