 Chemical Structure.png)
Nalidixic acid (formerly known as NSC-82174; NSC82174; Nevigramon, Neggram, Wintomylon, WIN 18,320), a synthetic 1,8-naphthyridine antimicrobial agent used to treat infections, is the first synthetic quinolone-based antibiotic with a narrow spectrum of bacteriocidal effects. It functions as an inhibitor of the bacterial DNA gyrase A subunit. With only a small amount of anti-gram-positive activity, nalidixic acid works best against gram-negative bacteria. It has bacteriostatic effects at lower concentrations and bactericidal effects at higher concentrations.
Physicochemical Properties
| Molecular Formula | C12H12N2O3 | |
| Molecular Weight | 232.24 | |
| Exact Mass | 232.084 | |
| Elemental Analysis | C, 62.06; H, 5.21; N, 12.06; O, 20.67 | |
| CAS # | 389-08-2 | |
| Related CAS # | 3374-05-8 | |
| PubChem CID | 4421 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 413.1±45.0 °C at 760 mmHg | |
| Melting Point | 227-229 °C(lit.) | |
| Flash Point | 203.6±28.7 °C | |
| Vapour Pressure | 0.0±1.0 mmHg at 25°C | |
| Index of Refraction | 1.605 | |
| LogP | 1.19 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 5 | |
| Rotatable Bond Count | 2 | |
| Heavy Atom Count | 17 | |
| Complexity | 378 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | O=C1C(C(=O)O[H])=C([H])N(C([H])([H])C([H])([H])[H])C2=C1C([H])=C([H])C(C([H])([H])[H])=N2 |
|
| InChi Key | MHWLWQUZZRMNGJ-UHFFFAOYSA-N | |
| InChi Code | 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) | |
| Chemical Name | 1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | DNA gyrase; topoisomerase IV; Quinolone antibiotic |
| ln Vitro | Nalidixic acid exhibits antimicrobial activity against a range of microorganisms, including Salmonella spp., Shigella spp., Brucella spp., Escherichia coli, Pasteurella spp., Klebsiella pneuiioniae, Aerobacter aeroyenes, Proteus spp., and 1.0-25.0 μg/ml. Its MIC values are 5.0-12.5 μg/ml, 0.5-2.5 μg/ml, 0.8-25.0 μg/ml, 1.25-30.0 μg/ml, 8-3.2 μg/ml, and 7.5-10.0 μg/ml, respectively[1]. |
| ln Vivo |
Gram-negative bacteria are the target of nalidixic acid's greatest in vivo activity, whereas Gram-positive organisms are typically more resilient. The ED50 values of E. coli, A. aerobacter, Proteus mirabilis, and Shigella fkxneri, which cause systemic infections, are 25 mg/kg, 60 mg/kg, 50 mg/kg, and 62 mg/kg, respectively, indicating maximum activity[1]. Nalidixic acid's oral, intravenous, and subcutaneous doses of 3300 mg/kg, 176 mg/kg, and 500 mg/kg, respectively, are the acute toxicity (LD50) in mice after parenteral and oral administration[1]. |
| Enzyme Assay | Fluoroquinolones are an important class of wide-spectrum antibacterial agents. The first quinolone described was nalidixic acid, which showed a narrow spectrum of activity. The evolution of quinolones to more potent molecules was based on changes at positions 1, 6, 7 and 8 of the chemical structure of nalidixic acid. Quinolones inhibit DNA gyrase and topoisomerase IV activities, two enzymes essential for bacteria viability. The acquisition of quinolone resistance is frequently related to (i) chromosomal mutations such as those in the genes encoding the A and B subunits of the protein targets (gyrA, gyrB, parC and parE), or mutations causing reduced drug accumulation, either by a decreased uptake or by an increased efflux, and (ii) quinolone resistance genes associated with plasmids have been also described, i.e. the qnr gene that encodes a pentapeptide, which blocks the action of quinolones on the DNA gyrase and topoisomerase IV; the aac(6')-Ib-cr gene that encodes an acetylase that modifies the amino group of the piperazin ring of the fluoroquinolones and efflux pump encoded by the qepA gene that decreases intracellular drug levels. These plasmid-mediated mechanisms of resistance confer low levels of resistance but provide a favourable background in which selection of additional chromosomally encoded quinolone resistance mechanisms can occur.[2] |
| Cell Assay | Effects of nalidixic acid and its derivatives were investigated on mouse cells transformed by methylcholanthrene or an activated c-Ha-ras oncogene. Our findings were as follows. Nalidixic acid preferentially suppressed growth in soft agar of transformed Balb/3T3 mouse cells induced by methylcholanthrene. The suppressive effect of nalidixic acid on growth in soft agar was reversible. Nalidixic acid reversibly reduced saturation density of these transformed cells. Oxolinic acid and pipemidic acid, which are derivatives of nalidixic acid, were less effective than nalidixic acid in suppressing growth in soft agar. Nalidixic acid suppressed growth in soft agar of NIH/3T3 mouse cells transformed by an activated c-Ha-ras, without affecting the amount of ras p21 proteins as detected by an immunoblotting analysis using a monoclonal antibody. These results show that nalidixic acid reversibly suppressed the expression of transformed phenotypes that were already being expressed.https://pubmed.ncbi.nlm.nih.gov/2690912/ |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Following oral administration, nalidixic acid is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 96%. Absorption may be delayed if taken with antacids. Following oral administration, NegGram is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Approximately four percent of NegGram is excreted in the feces. ABSORPTION & ELIMINATION RATES OF NALIDIXIC ACID WERE SHOWN TO BE LOW IN NEWBORN CHILDREN COMPARED WITH ADULTS, & ADULT VALUES WERE NOT OBTAINED UNTIL ABOUT THIRD YR OF LIFE. RELATIVE DISTRIBUTION VOL, HOWEVER, WERE SIMILAR IN BOTH AGE GROUPS. IN RATS & MICE ORAL DOSES ARE RAPIDLY ABSORBED WITH PEAK BLOOD CONCN ABOUT 1 HR LATER. ...ELIMINATION IS VIA KIDNEYS, PEAKING @ ABOUT 6TH HR. 80% OF ADMIN DOSE IS ELIMINATED IN 1ST 8 HR. IN DOGS HIGHLY EFFECTIVE CONCN APPEAR IN URINE WITHIN 2-3 HR AFTER ORAL ADMIN. ABSORPTION EFFICIENCY & RATE OF ELIMINATION OF...NALIDIXIC ACID...DECR IN PT WITH SHIGELLOSIS. POOR ABSORPTION WAS GENERALLY OBSERVED IN YOUNGER PT WITH MARKED DIARRHEA BUT THERE WAS NO READY EXPLANATION FOR DELAYED EXCRETION. Rapidly and almost completely absorbed from the gastrointestinal tract; bioavailability is approximately 96%. Absorption may be delayed if taken with antacids. For more Absorption, Distribution and Excretion (Complete) data for NALIDIXIC ACID (7 total), please visit the HSDB record page. Metabolism / Metabolites Hepatic. 30% of administered dose is metabolized to the active metabolite, hydroxynalidixic acid. Rapid conjugation of parent drug and active metabolite to inactive metabolites. Metabolism may vary widely among individuals. In the urine, hydroxynalidixic acid represents 80 to 85% of the antibacterial activity. WHEN NALIDIXIC ACID...IS INGESTED BY MAN, IT IS PARTLY EXCRETED AS FREE... /ACID/ BUT MUCH BIGGER PROPORTION IS EXCRETED AS MONOGLUCURONIDE...& CONSIDERABLE FRACTION AS 7-HYDROXYMETHYL METABOLITE...TOGETHER WITH SMALLER AMT OF LATTER IN CONJUGATED FORM. 3,7-DICARBOXYLIC ACID...IS MINOR METABOLITE. Nalidixic acid is partially metabolized in the liver to hydroxynalidixic acid and the glucuronic acid conjugates of nalidixic acid and hydroxynalidixic acid. The drug is also partially metabolized to the dicarboxylic acid derivative; there is some evidence suggesting that this metabolite is formed in the kidney. Biological Half-Life 1.1 to 2.5 hours in healthy adult patients, and up to 21 hours in patients with impaired renal function. APPROX 96% OF ORALLY ADMIN...IS ABSORBED. PLASMA CONCN OF 20-50 UG/ML MAY BE ACHIEVED, BUT ACID IS 93-97% BOUND TO PLASMA PROTEINS. IN BODY SOME... CONVERTED TO ACTIVE HYDROXYNALIDIXIC ACID, & BOTH ARE EXCRETED INTO URINE. MOST...IS CONJUGATED IN LIVER. PLASMA T/2 IS...8 HR...MAY BE...21 HR IN...RENAL FAILURE. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Limited information indicates that maternal doses of nalidixic acid up to 2 grams daily produce low levels in milk and would usually not be expected to cause any adverse effects in breastfed infants with monitoring of the infant for possible effects on the gastrointestinal flora, such as diarrhea or candidiasis (thrush, diaper rash). Nalidixic acid should be avoided while breastfeeding a glucose-6-phosphate dehydrogenase (G6PD) deficient infant. Other agents are preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Decreased weight gain, pallor, jaundice occurred in a 16-day-old infant probably caused by hemolytic anemia induced by maternal use of nalidixic acid orally 1 gram four times daily and amobarbital 65 mg orally three times daily. The infant developed jaundice, hyperbilirubinemia, reticulocytosis, eosinophilia, Heinz bodies and other signs of hemolysis 7 days after its mother was started on nalidixic acid. No G-6-PD deficiency or hemoglobin Zurich could be demonstrated. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Nalidixic acid is 93% bound to protein in the blood, and the active metabolite, hydroxynalidixic acid is 63% bound. Interactions ...AT PHYSIOLOGICAL CONCN...NALIDIXIC ACID...DISPLACED SUBSTANTIAL AMT OF WARFARIN FROM HUMAN ALBUMIN BY NON-COMPETITIVE MECHANISM. SYSTEMIC & URINARY ALKALINIZERS REDUCE ITS EFFECTIVENESS BY INCR ITS EXCRETION RATE. SYSTEMIC EFFECTIVENESS INCR IF URINE IS ACID. METABOLIC ACIDOSIS WAS INDUCED IN AN 18-YEAR-OLD MALE BY AN OVERDOSE OF NALIDIXIC ACID. SIMULTANEOUS INGESTION OF PROBENECID MAY HAVE ACCENTUATED EFFECT OF INGESTED NALIDIXIC ACID BY PROLONGING ITS SERUM T/2. Coumarin- or indandione-derivative anticoagulants, especially warfarin and dicumarol, may be displaced from protein-binding sites by nalidixic acid, resulting in increased anticoagulant effect; dosage adjustments may be necessary during and after nalidixic acid therapy. For more Interactions (Complete) data for NALIDIXIC ACID (6 total), please visit the HSDB record page. Non-Human Toxicity Values LD50 MOUSE ORAL 3.3 G/KG LD50 MOUSE SUBCUTANEOUS 0.5 G/KG LD50 MOUSE INTRAVENOUS 0.176 G/KG LD50 Rat oral 1160 mg/kg |
| References |
[1]. 1,8-NAPHTHYRIDINE DERIVATIVES. A NEW CLASS OF CHEMOTHERAPEUTIC AGENTS. J Med Pharm Chem. 1962 Sep:5:1063-5. [2]. Mechanism of Action of and Resistance to Quinolones. Microb Biotechnol.2009 Jan;2(1):40-61. |
| Additional Infomation |
Nalidixic Acid can cause cancer according to The National Toxicology Program. Nalidixic acid is a cream-colored powder. (NTP, 1992) Nalidixic acid is a monocarboxylic acid comprising 1,8-naphthyridin-4-one substituted by carboxylic acid, ethyl and methyl groups at positions 3, 1, and 7, respectively. An orally administered antibacterial, it is used in the treatment of lower urinary-tract infections due to Gram-negative bacteria, including the majority of E. coli, Enterobacter, Klebsiella, and Proteus species. It has a role as an antibacterial drug, a DNA synthesis inhibitor and an antimicrobial agent. It is a monocarboxylic acid, a 1,8-naphthyridine derivative and a quinolone antibiotic. It is a conjugate acid of a nalidixic acid anion. Nalidixic acid is a synthetic 1,8-naphthyridine antimicrobial agent with a limited bacteriocidal spectrum. It is an inhibitor of the A subunit of bacterial DNA gyrase. Nalidixic acid has been reported in Phaseolus vulgaris with data available. Nalidixic Acid is a synthetic quinolone and antibacterial agent with urinary tract antiseptic activity. Nalidixic acid concentrates in the renal tubules and bladder and exerts its local antibacterial actions by interference of DNA gyrase activity, thereby inhibiting DNA synthesis during bacterial replication in a dose-dependent manner. Nalidixic acid is active against most gram-negative organisms that cause urinary tract infections. A synthetic 1,8-naphthyridine antimicrobial agent with a limited bacteriocidal spectrum. It is an inhibitor of the A subunit of bacterial DNA GYRASE. Drug Indication For the treatment of urinary tract infections caused by susceptible gram-negative microorganisms, including the majority of E. Coli, Enterobacter species, Klebsiella species, and Proteus species. FDA Label Mechanism of Action Evidence exists for Nalidixic acid that its active metabolite, hydroxynalidixic acid, binds strongly, but reversibly, to DNA, interfering with synthesis of RNA and, consequently, with protein synthesis. IT APPEARS TO ACT BY INHIBITING DNA SYNTH. Therapeutic Uses Anti-Infective Agents, Quinolone /SRP: Antibacterial/ IN US, NALIDIXIC ACID IS APPROVED ONLY FOR TREATMENT OF URINARY TRACT INFECTIONS CAUSED BY SUSCEPTIBLE MICROORGANISMS. EFFECTIVENESS AGAINST INDOLE-POSITIVE PROTEUS IS ESP IMPORTANT. APPARENT CURES...IN 30-50% OF UNCOMPLICATED URINARY TRACT INFECTIONS. ...BRUCELLOSIS HAS BEEN SUCCESSFULLY MANAGED WITH ORAL NALIDIXIC ACID. DRUG HAS BEEN GIVEN IV TO TREAT GRAM-NEGATIVE SEPTICEMIAS. ...BACTERICIDAL TO MOST OF COMMON GRAM-NEGATIVE BACTERIA THAT CAUSE URINARY TRACT INFECTIONS. ...99% OF STRAINS OF E COLI, 98% OF PROTEUS MIRABILIS & 75-97% OF OTHER PROTEUS SPECIES, 92% OF KLEBSIELLA-ENTEROBACTER, & 80% OF OTHER COLIFORM BACTERIA ARE SENSITIVE TO DRUG. ... SOME STRAINS OF SALMONELLA & SHIGELLA...SENSITIVE. For more Therapeutic Uses (Complete) data for NALIDIXIC ACID (8 total), please visit the HSDB record page. Drug Warnings BECAUSE...MAY ACCUMULATE IN PT WITH RENAL OR HEPATIC INSUFFICIENCY, IT SHOULD BE USED VERY CAUTIOUSLY IN THESE PT, ESP IF NEUROLOGIC DAMAGE IS PRESENT. ... CAUTION IS INDICATED IF THIS DRUG IS USED DURING PREGNANCY, ALTHOUGH SOME... HAVE TAKEN IT DURING 2ND & 3RD TRIMESTERS WITHOUT ADVERSELY AFFECTING MOTHER OR FETUS. BY ORAL ROUTE IT IS DIFFICULT TO ACHIEVE EFFECTIVE PLASMA LEVELS. FUTHERMORE, BINDING TO PLASMA PROTEIN INHIBITS ACTIVITY. ... 4% THAT PASSES INTO BOWEL IS INSUFFICIENT TO BE EFFICACIOUS IN TREATMENT OF INTESTINAL SHIGELLOSIS... PSEUDOMONAS SPECIES ARE RESISTANT. ... ACQUIRED RESISTANCE TO DRUG OCCURS, BUT IT DOES NOT SEEM TO BE TRANSFERABLE. DETERMINATION OF URINARY LEVELS OF 17-KETOSTEROIDS & 17-KETOGENIC STEROIDS MAY BE FALSELY ELEVATED WHEN NALIDIXIC ACID HAS BEEN PRESCRIBED. For more Drug Warnings (Complete) data for NALIDIXIC ACID (19 total), please visit the HSDB record page. Pharmacodynamics Nalidixic acid is a quinolone antibacterial agent for oral administration. Nalidixic acid has marked antibacterial activity against gram-negative bacteria including Enterobacter species, Escherichia coli, Morganella Morganii; Proteus Mirabilis, Proteus vulgaris, and Providencia rettgeri. Pseudomonas species are generally resistant to the drug. Nalidixic acid is bactericidal and is effective over the entire urinary pH range. Conventional chromosomal resistance to nalidixic acid taken in full dosage has been reported to emerge in approximately 2 to 14 percent of patients during treatment; however, bacterial resistance to nalidixic acid has not been shown to be transferable via R factor. |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.5 mg/mL (2.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.3059 mL | 21.5295 mL | 43.0589 mL | |
| 5 mM | 0.8612 mL | 4.3059 mL | 8.6118 mL | |
| 10 mM | 0.4306 mL | 2.1529 mL | 4.3059 mL |