389-08-2

Usage

Uses

Used in Pharmaceutical Industry:
Nalidixic acid is used as an antimicrobial agent for the treatment of urinary tract infections caused by susceptible gram-negative microorganisms. It is particularly effective against the majority of E. Coli, Enterobacter species, Klebsiella species, and Proteus species.
Additionally, it serves as an inhibitor of the A subunit of bacterial DNA gyrase, which plays a crucial role in the replication and transcription of bacterial DNA. This inhibition helps in preventing the growth and proliferation of the targeted bacteria, making it a valuable component in the development of antibiotics and other antimicrobial treatments.

Originator

Neggram,Winthrop,US,1964

Manufacturing Process

A warm solution containing 41 grams of 4-hydroxy-7-methyl-1,8- naphthyridine-3-carboxylic acid and 39 grams of potassium hydroxide in 1 liter of ethanol and 200 cc of water was treated with 50 cc of ethyl iodide and the resulting mixture was refluxed gently overnight, acidified with hydrochloric acid and cooled. The resulting precipitate was collected and recrystallized twice from acetonitrile to yield 26 grams (56% yield) of 1-ethyl-7-methyl-4- oxo-1,8-naphthyridine-3-carboxylic acid, MP 229° to 230°C.The starting material is prepared by reacting 2-amino-6-methylpyridine with ethoxymethylene-malonic acid diethyl ester and then reacting that product with sodium hydroxide.

Therapeutic Function

Antibacterial

Antimicrobial activity

It displays good activity in vitro against a wide range of Enterobacteriaceae.

Air & Water Reactions

Insoluble in water.

Health Hazard

SYMPTOMS: Ingestion of Nalidixic acid may cause nausea, vomiting, abdominal pain, allergic reactions and possible liver damage.

Fire Hazard

Flash point data for Nalidixic acid are not available, but Nalidixic acid is probably combustible.

Pharmaceutical Applications

A 1,8 naphthyridone derivative available for oral administration.

Pharmacokinetics

Oral absorption: >90%Cmax 1 g oral: c. 25 mg/L Plasma half-life:c.1.5h Volume of distribution :0.4 L/kg Plasma protein binding: 93%The plasma concentrations achieved after oral administration vary widely. In infants with acute shigellosis, absorption is much impaired by diarrhea. Administration with an alkaline compound leads to higher plasma concentrations, partly as the result of enhanced solubility (nalidixic acid is much more soluble at higher pH) and absorption and partly because of reduced tubular reabsorption. It is rapidly metabolized, principally to the hydroxy acid, which is bacteriologically active, and glucuronide conjugates, which are not. The entire administered dose appears in the urine over a 24 h period. Elimination is reduced by probenecid. In the presence of renal impairment there is little accumulation of the active compound because it continues to be metabolized. However, elimination of metabolites is progressively delayed as renal function declines. About 4% of a dose appears in the feces.

Clinical Use

1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (NegGram) occurs as a pale buff crystalline powder that is sparingly soluble in water and ether but solublein most polar organic solvents.Nalidixic acid is useful in the treatment of urinary tractinfections in which Gram-negative bacteria predominate.The activity against indole-positive Proteus spp. is particularlynoteworthy, and nalidixic acid and its congeners representimportant alternatives for the treatment of urinary tractinfections caused by strains of these bacteria resistant toother agents. Nalidixic acid is rapidly absorbed, extensivelymetabolized, and rapidly excreted after oral administration.The 7-hydroxymethyl metabolite is significantly more activethan the parent compound. Further metabolism of theactive metabolite to inactive glucuronide and 7-carboxylicacid metabolites also occurs. Nalidixic acid possesses at1/2elim of 6 to 7 hours. It is eliminated, in part, unchanged inthe urine and 80% as metabolites.

Side effects

Adverse reactions are generally those common to all quinolones: gastrointestinal tract and CNS disturbances and skin rashes, including eruptions related to photosensitivity. About half of the reported CNS reactions involve visual disturbances, hallucinations or disordered sensory perception. Severe excitatory states, including acute psychoses and convulsions, are usually observed in patients receiving high dosages. The drug should be avoided in patients with psychiatric disorders or epilepsy.Acute intracranial hypertension has been observed in children, some of whom have also manifested cranial nerve palsies. Hemorrhage has occurred in patients who were also receiving warfarin, presumably due to displacement of the anticoagulant from its protein binding sites by the nalidixic acid. Hemolytic anemia has been described several times in infants with or without glucose-6-phosphate dehydrogenase deficiency; in adults, death has occurred from autoimmune hemolytic anemia. Arthralgia and severe metabolic acidosis have rarely been reported.

Safety Profile

Poison by intravenous and intraperitoneal routes. Moderately toxic by ingestion and subcutaneous routes. An experimental teratogen. Human systemic effects: convulsions, hyperglycemia, sweating, and blood changes in children. Experimental reproductive effects.Questionable carcinogen with experimental carcinogenic and tumorigenic data. Human mutation data reported. Used as an antibacterial agent and urinary tract antiseptic. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Nalidixic acid, 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthiridin-3- carboxylic acid (33.2.4), is synthesized by the following scheme. In the first stage, the reaction of 2-amino-6-methylpyridine and diethyl ethoxymethylenemalonate forms the substituted product (33.2.1), which when heated cyclizes to ethyl ester of 4-hydroxy -7-methyl-1,8-napthiridin-3-carboxylic acid (33.2.2). Hydrolyzing the resulting product with a base gives the corresponding acid (33.2.3). Alkylating this with ethyl iodide in the presence of potassium hydroxide gives nalidixic acid.

Drug interactions

Potentially hazardous interactions with other drugs Aminophylline and theophylline: possibly increased risk of convulsions. Analgesics: increased risk of convulsions with NSAIDs. Antibacterials: possibly antagonised by nitrofurantoin. Anticoagulants: anticoagulant effect of coumarins enhanced. Antimalarials: manufacturer of artemether with lumefantrine advises avoid. Ciclosporin: increased risk of nephrotoxicity. Cytotoxics: increases risk of melphalan toxicity

Metabolism

Nalidixic acid is partially metabolised in the liver to hydroxynalidixic acid, which has antibacterial activity similar to that of nalidixic acid and accounts for about 30% of active drug in the blood. Both nalidixic acid and hydroxynalidixic acid are rapidly metabolised to inactive glucuronide and dicarboxylic acid derivatives; the major inactive metabolite 7-carboxynalidixic acid is usually only detected in urine.

Purification Methods

Nalidixic acid crystallises from H2O or EtOH as a pale buff powder. It is soluble at 23o in CHCl3 (3.5%), toluene (0.16%), MeOH (0.13%), EtOH (0.09%), H2O (0.01%) and Et2O (0.01%). It inhibits nucleic acid and protein synthesis in yeast. [Lesher et al. J Med & Pharm Chem 5 1063 1962.]

InChI:InChI=1/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)/p-1

Upstream product

• 934343-42-7 C₁₆H₁₉N₃O₅ 
• 1430212-98-8 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 3-butene ester 
• 1430212-99-9 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 4-pentene ester 
• 1430213-00-5 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 5-hexene ester 
• 1430213-01-6 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 2-butene ester 
• 1430213-02-7 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 9-decene ester 
• 944441-96-7 nalidixic acid 
• 774550-70-8 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 2-propen-1-ol ester 
• 34748-19-1 diethyl N-ethyl-N-(6-methyl-2-pyridyl)aminomethylenemalonate 
• 13250-96-9 ethyl 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate 
• 13250-95-8 diethyl 2-{[(6-methyl-2-pyridyl)amino]methylene}propane-1,3-dioate 
• 1824-81-3 2-Amino-6-methylpyridine 
• 33331-59-8 ethyl 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate 
• 174814-96-1 [(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carbonyl)-amino]-acetic acid ethyl ester 

Downstream Products

• 83165-74-6 diethyl N-<(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carbonyl)-L-alanyl>-1-aminoethylphosphonate 
• 52377-28-3 nalidixic acid chloride 
• 10299-49-7 1-ethyl-7-methyl-1,8-naphthyridin-4(1H)-one 
• 697226-46-3 1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid allyloxycarbonyl-(4-phenylacetoxy-phenyl)-methyl ester 
• 104571-81-5 Ethyl 4-N-(1-Ethyl-1,4-Dihydro-7-Methyl-4-Oxo-1,8-Naphthyridine-3-Carbonyl)Aminomethylcyclohexanecarboxylate 
• 1025716-76-0 1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid [4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide 
• 220502-38-5 C₁₉H₁₇N₅O₄ 
• 1207382-88-4 N'-(4-hydroxybenzylidene)-1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carbohydrazide 

Relevant academic research and scientific papers

Synthesis and release kinetics of polymerisable ester drug conjugates: Towards pH-responsive infection-resistant urinary biomaterials

Herein we report the synthesis, characterisation and hydrolytic release kinetics of a suite of novel, polymerisable ester quinolone conjugates with varying alkenyl chain lengths. Hydrolysis was shown to proceed up to 17-fold faster upon elevation of pH from neutral to pH 9.29, making these conjugates attractive for the development of 'designer' infection-resistant urinary biomaterials exploiting the increase in urine pH reported at the onset of catheter-associated infection to trigger drug release.

N-Alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of carboxylic acid containing drugs

Synthesis and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) and N-aryl-N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of carboxylic acid containing drugs were carried out. The hydrolysis follows a SN1 type mechanism and is dependent on the nucleofugacity of the leaving group. Topical delivery of the NANAOCAM derivative of naproxen from IPM across hairless mice skin was examined in in vitro diffusion cell experiments. The prodrug was 4.5-fold less lipid soluble, 2.4-fold less water soluble and 3.6-fold less permeable than the parent drug.

Synthesis of selected novel covalently linked flavoquinolones

The synthesis of novel covalently linked flavoquinolones via amide bond is described using mixed anhydride method and their spectroscopic studies have been done by UV/Vis and 1H NMR spectroscopic data. Georg Thieme Verlag Stuttgart.

Heterocyclic mutilin esters and their use as antibacterials

Pleuromutilin compounds of the formula: 1are of use in anti-bacterial therapy.

Method and composition for treatment of erectile dysfunction

Compositions and methods for treatment of impotence or erectile dysfunction employ prostaglandins that are selective EP2or EP4prostanoid receptor agonists. The compositions can be formulated for intracavernous injection, or for transurethral or transdermal application.

Synthesis and in vitro investigations of nalidixic acid amides of amino acid esters as prodrugs

For a new DDS of nalidixic acid (1) to overcome its therapeutic drawbacks, amides of glycine ethyl ester and the methyl esters of alanine, phenylalanine, leucine, isoleucine and valine, 2(a-f), were synthesized as prodrugs. The stability of the prepared prodrugs in pH 1.2, 7.4 and 80% human plasma was investigated and showed higher stability in the buffers than in the plasma. It was noticed that the reversion of the parent drug from the synthesized prodrugs occurred through two steps, the first was hydrolysis of the ester moiety with formation of nalidixic acid amides of the amino acids as intermediates. The second step was the hydrolysis of these intermediates to 1 and the corresponding amino acid. The prodrugs showed an increase in the lipophilicity compared with 1 as indicated from the log P values. The plasma protein binding potency was studied in vitro using BSA and revealed a decrease in the percentage bound in case of glycine and alanine derivatives (of low lipophilicity) and increase in the percentage bound of phenylalanine, leucine and isoleucine derivatives (of high lipophilicity). Lower binding potency and higher lipophilicity was observed in the case of valine derivative, that was suggested to be owed to some steric hindrance with the binding sites.

Pharmaceutical compositions endowed with an antibacterial activity and their use in the treatment of infections due to gram-positive and gram-negative pathogens

Pharmaceutical compositions consisting of an antibiotic (cephalosporins, tetracyclines, kanamycin) associated with a heterocyclicic β-ketoacid (nalidixic acid, oxolinic acid, cinoxacine, piromidic acid, pipemidic acid) are endowed with a marked synergism against Gram-positive and Gram-negative pathogens as well with a particularly relevant efficacy against antibiotic-resistant strains.

1,8-Naphthyridine compounds and process for preparing the same

1,8-Naphthyridine compounds and a process for preparing chelated 1,8-naphthyridine derivatives and 1,8-naphthyridine derivatives which are pharmacautically useful compounds. Chelated 1,8-naphthyridine derivatives of the general formula [I]: STR1 wherein X and Y are independently a lower alkyl group, are prepared by subjecting a compound of the general formula [II]: STR2 wherein X and Y are as defined above and R is a lower alkyl group, to ring-closing condensation in the presence of boron trifluoride and/or a boron trifluoride complex at an elevated temperature, and 1,8-naphthyridine derivatives of the general formula [III]: STR3 wherein X and Y are as defined above, are prepared by treating the chelated 1,8-naphthyridine derivatives with water and/or an alcohol. The desired products can be readily obtained in high yields. The chelated compounds are novel compounds.

Ortho fused cycloalkano-4-quinolone-3-carboxylic acid derivatives

Cycloalkano-quinolone derivatives having anti-microbial activity characterized by the formula: SPC1 Wherein one of R1 and R2 designates hydrogen, halogen, nitro, amino, hydroxyl, acylamino, acyloxy, alkoxy or aryloxy and the other taken together with R3 forms an akylene bridge containing 2 to 6 carbon atoms, X is hydrogen, lower alkyl, which may be substituted by a member of the group consisting of halogen, hydroxyl, acyloxy, alkoxy, aryloxy, aralkyloxy, mercapto, alkylmercapto, arylmercapto, arylsulfonyl, and alkylsulfonyl, or X is unsubstituted alkenyl including alkadienyl, or alkynyl and Y is hydroxyl, amino or lower alkoxy, and the pharmaceutically acceptable salts thereof.

3-Imino-1,2,4-benzotriazine-1-oxides

New 3-Imino-1,2,4-benzotriazine-1-oxides of formula I SPC1 wherein R represents an alkyl, alkenyl or haloalkyl radical, a phenyl or aralkyl radical optionally substituted by alkyl, alkoxy, haloalkyl, halogen or hydroxy, X and Y each independently represent hydrogen, halogen, an alkyl or alkoxy radical, or one of the two symbols represents a phenoxy or phenylsulphonyl radical optionally substituted by halogen, alkyl, haloalkyl and/or alkoxy which are active against harmful microorganisms are disclosed.