14698-29-4 Usage
Description
Oxolinic acid, a synthetic antimicrobial agent, belongs to the family of quinolone antibiotics developed in Japan in the 1970s. It is primarily aimed at gram-negative bacteria, particularly those responsible for urinary tract infections. Oxolinic acid works by targeting DNA gyrase or topoisomerase II, enzymes essential for DNA synthesis, ultimately inhibiting DNA synthesis and cell division. It is also used in clinical microbiological antimicrobial susceptibility tests against gram-negative microbial isolates, providing antibiotic treatment options for infected patients. Additionally, oxolinic acid can be applied in agriculture, proving effective against seed-borne pathogens like Burkholderia glumae, which causes grain rot, sheath rot, seedling rot, and bacterial panicle blight.
Uses
Used in Pharmaceutical Industry:
Oxolinic acid is used as a quinolone antibiotic for the treatment of bacterial infections, particularly in urinary tract infections caused by gram-negative bacteria. It is also used in clinical microbiological antimicrobial susceptibility tests against gram-negative microbial isolates, helping to determine appropriate antibiotic treatment options for infected patients.
Used in Agricultural Industry:
Oxolinic acid is used as an antimicrobial agent in agriculture, effective against seed-borne pathogens such as Burkholderia glumae, which causes various types of rot and blight in crops.
Used in Research and Development:
Oxolinic acid is used in studies on DNA winding and coiling, as well as in research on dopaminergic neurotransmission processes. It is also utilized to study new transmissible resistance mechanisms qnrA, qnrB, qnrS, and aac(6′)Ib-cr in Escherichia coli and Salmonella enterica. Furthermore, oxolinic acid is added to culture medium for the isolation of Gardnerella vaginalis.
Used in Veterinary Medicine:
Oxolinic acid is used as a synthetic antibiotic in veterinary medicine for the treatment of bacterial infections in cattle, pigs, and poultry. It is available under the brand name Utibid (ParkeDavis).
References
https://en.wikipedia.org/wiki/Oxolinic_acid
http://www.toku-e.com/product/oxolinic_acid/
https://www.goldbio.com/product/3027/oxolinic-acid
Originator
Prodoxol,Warner,UK,1974
Manufacturing Process
A mixture of 27 parts by weight of 3,4-methylenedioxyaniline and 43 parts by weight of diethyl ethoxymethylenemalonate is heated at 80° to 90°C for 3 hours. The mixture is then heated at 80° to 90°C for 1 hour under about 15 mm pressure to remove the byproduct ethyl alcohol formed. The residue is recrystallized from ligroin (BP 60° to 90°C) to give diethyl[(3,4methylenetlioxyanilino)methylene] malonate as a yellow solid melting at 100° to 102°C. The analytical sample from ligroin melts at 101° to 102°C.
A mixture of 48 parts by weight of diethyl[(3,4-methylenedioxyanilino) methylene] malonate and 500 parts by weight of diphenyl ether is refluxed for 1 hour. The mixture is allowed to cool to about 25°C with stirring and 500 parts by weight of petroleum ether are added. Filtration gives 3-carbethoxy6,7-methylenedioxy-4-hydroxy-quinoline as a brown solid, MP 276° to 281°C. Several recrystallizations from dimethylformamide gives almost colorless analytical material, MP 285° to 286°C, (decomposes).
A mixture of 26 parts of 3-carbethoxy-6,7-methylenedioxy-4-hydroxyquinoline,16 parts of sodium hydroxide and 50 parts of dimethylformamide is heated at 70° to 75°C for 2 hours, then 31 parts of ethyl iodide is added over 1 hour with continued heating and stirring. After an additional 3 to 4 hours of heating (at 70° to 75°C) and stirring, the mixture is diluted with 500 parts of water, refluxed for 3 to 4 hours, acidified with concentrated hydrochloric acid and filtered to yield 18 to 22 parts of 1-ethyl-1,4-dihydro-6,7-methylenedioxy-4-oxo-3-quinoline-carboxylic acid, MP 309° to 314°C (decomposes). The analytical sample from dimethylformamide melts at 314° to 316°C (decomposes).
Therapeutic Function
Antibacterial (urinary)
Antimicrobial activity
Like nalidixic acid, this drug is effective with respect to Gram-negative microorganisms
and is used for the same indications. Synonyms of this drug are nidantin, prodoxol, ocolin,
uroxol, and others.
Pharmaceutical Applications
An oral 4-quinolone with a tricyclic structure. Its antibacterial spectrum is very similar to that of nalidixic acid, but it is more active againstEnterobacteriaceae (MIC 0.25–2 mg/L). Grampositive bacteria, Ps. aeruginosa and anaerobes are resistant.After repeated doses of 750 mg twice daily, mean plasma concentrations are initially very low, but steady state is reached at the third day and Cmax is around 3.5 mg/L. Administration with food delays absorption. Binding to plasma protein is about 80%. It undergoes complex biotransformation, and an enterohepatic cycle may account for the increase in the apparent elimination half-life from 4 to 15 h over 7 days of treatment as well as for the 20% of dose which can be recovered from the feces. About 50% of the dose appears in the urine in the first 24 h, partly in the form of metabolites, some of which display antibacterial activity.Side effects common to the quinolones occur frequently. About one-quarter of patients treated with 750 mg every 12 h suffer nausea and vomiting or restlessness and insomnia. Its only use is in the treatment of lower urinary tract infections.
Biochem/physiol Actions
Oxolinic acid is a quinolone antibiotic. It is a DNA-gyrase (topoisomerase II) inhibitor used for studies on DNA winding and coiling and acts as a dopamine reuptake inhibitor for studies on dopaminergic neurotransmission processes.
Safety Profile
Moderately toxic by ingestion. Low toxicity by skin contact. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.
Synthesis
Oxolinic acid, 5-ethyl-5,8-dihydro-8-oxo-1-dioxolo[4,5-g]-quinolin-
7-carboxylic acid (33.2.9), is basically synthesized by the same synthetic scheme as
nalidixic acid, although it uses 3,4-methylendioxyanyline (33.2.6) as the starting aromatic
amine component, and not the 2-amino-6-methylpyridine used to make nalidixic acid. This
compound is obtained by hydrogenation to 3,4-methylendioxy-1-nitrobenzene (33.2.5),
which is in turn synthesized by nitrating 1,2-methylendioxybenzene with nitric acid. The
resulting 3,4-methylendioxyaniline (33.2.6) is then reacted with ethoxymethylenmalonic
ester to make the substitution product (33.2.7), which when heated cyclizes to ethyl ester
of 4-hydroxy-6,7-methylendioxyquinolin-3-carboxylic acid (33.2.8). Hydrolyzis of this
with a base in dimethylformamide and direct treating of the obtained product with ethyl
iodide gives the desired oxolinic acid.
in vitro
previous study found that both inhibitors of dna gyrase of oxolinic acid and coumermycin a1 could block the dna synthesis in e. coli. moreover, the rate of bacterial dna synthesis first rapidly declined but then increased gradually at low concentrations of oxolinic acid. in varoius dna mutants, oxolinic acid was able to cause a rapid decline, followed by a slow decrease in synthesis rate of dna [1].
in vivo
animal study showed that the i.p. injection of oxolinic acid in mice could induce a dose dependent increase in locomotor activity, and such stimulation culminated at the 32 mg/kg dose and was smaller for higher doses at 64-128 mg/kg. when compared with haloperidol (d2 dopamine receptor antagonist) at increasing doses (50-100-200 mg/kg), the stimulant locomotor effect of oxolinic acid at 32 mg/kg was not reversed significantly. in addition, oxolinic acid at 32 mg/kg did not reverse the reserpine caused akinesia and even opposed the reversion that was induced by dexamphetamine [2].
IC 50
4.3 μm for dopamine uptake
Purification Methods
Purify the acid by recrystallisation from aqueous Me2CO, 95% EtOH or dimethylformamide. It has UV 220, (255.5sh), max 259.5, 268, (298sh, 311sh), 321 and 326nm [ 14.8, (36.8sh), 38.4, 38.4, (6.4sh, 9.2sh), 10.8 and 11.2 x 103]. [Kaminsky & Mettzer J Med Chem 11 160 1968, Beilstein 17 H 6, 17 I 3, 17 II 202, 17 III/IV 13, 17/1 V 11.]
references
[1] e c engle,s h manes, and k drlica. differential effects of antibiotics inhibiting gyrase. j bacteriol. 1982 jan; 149(1): 92–98.[2] garcia de mateos-verchere j,vaugeois jm,naudin b,costentin j. behavioural and neurochemical evidence that the antimicrobial agent oxolinic acid is a dopamine uptake inhibitor. eur neuropsychopharmacol. 1998 dec;8(4):255-9.
Check Digit Verification of cas no
The CAS Registry Mumber 14698-29-4 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 1,4,6,9 and 8 respectively; the second part has 2 digits, 2 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 14698-29:
(7*1)+(6*4)+(5*6)+(4*9)+(3*8)+(2*2)+(1*9)=134
134 % 10 = 4
So 14698-29-4 is a valid CAS Registry Number.
InChI:InChI=1/C13H11NO5/c1-2-14-5-8(13(16)17)12(15)7-3-10-11(4-9(7)14)19-6-18-10/h3-5H,2,6H2,1H3,(H,16,17)
14698-29-4Relevant articles and documents
-
Frank et al.
, p. 4545 (1977)
-
Transamination with enamidines and a new method for the synthesis of oxolinic acid
Granik,Dozorova,Marchenko,Budanova,Kuzovkin,Glushkov
, p. 745 - 748 (1988)
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Copper-Catalyzed Synthesis of Substituted 4-Quinolones using Water as a Benign Reaction Media: Application for the Construction of Oxolinic Acid and BQCA
Gore, Babasaheb Sopan,Lee, Chein Chung,Lee, Jessica,Wang, Jeh-Jeng
, (2019/05/24)
A copper-catalyzed three-component synthetic method has been developed for the synthesis of substituted 4-quinolone derivatives from substituted 3-(2-halophenyl)-3-oxopropane, aldehydes and aq. NH3 using water as an environmentally benign reaction media. Moreover, the synthetic utility of the obtained products has been successfully applied for the synthesis of available oxolinic acid and BQCA drugs. The key features of this approach include commercially available starting materials, broad scope, and moderate to good reaction yields. Reaction with formaldehyde, and other functionalities such as ?CN, ?NO2, ?SO2Ar, and ?COAr were also successful. In addition, reaction with heterocyclic compounds such as 3-(3-bromothiophen-2-yl)-3-oxopropanenitrile proceeded smoothly to afford tetrahydrothieno[3,2-b]pyridine-6-carbonitrile analogues. The practicality of the designed protocol was confirmed by gram scale synthesis of two derivatives. (Figure presented.).
Rhodium-catalyzed ortho C-H bond activation of arylamines for the synthesis of quinoline carboxylates
Gadakh, Sunita K.,Dey, Soumen,Sudalai
, p. 2969 - 2977 (2016/03/12)
The rhodium catalyzed annulation of anilines with alkynic esters allowing for the high-yield synthesis of quinoline carboxylates with excellent regioselectivity is described. This unprecedented reaction employs either formic acid as the C1 source and reductant or copper(ii) as the oxidant and is proposed to proceed via rhodacycle of in situ generated amide and enamine ester followed by ortho C-H activation of arylamines with rhodium as the catalyst.
Synthesis of 5-ethyl-8-oxo-5.8-dihydro-1,3-dioxolo [4,5-g] quinolines and related compounds
Pednekar, Suhas,Pandey, Anil Kumar
, p. 357 - 360 (2011/12/16)
Condensation of N-ethyl-3,4-methylenedioxyaniline 1 with diethyl ethoxymethylenemalonate 2 gave the unsaturated ester 3 which on thermal cyclization in refluxing diphenyl oxide gave ester 4. The ester on basic hydrolysis formed free acid 5 which upon treatment with thionyl chloride gave the acid chloride 6. Treatment of 6 with o-phenylenediamine, hydrazine hydrate, ammonia, urea and thiourea gave the amides (7-11). CS2 treatment in presence of KOH on 8 gave 12. 7-12 were prepared by conventional as well as under microwave irradiation. These compounds have been characterized on the basis of elemental analysis, IR, NMR and MS data.