65-49-6 Usage
Description
4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS), is an antitubercular drug with multiple hydrogen-bonding functionality, including carboxylic acid, amine, and phenol groups. It is a model active pharmaceutical ingredient for studying salt and cocrystal formation. It is typically taken orally and has been used as a second-line agent to sulfasalazine in the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
Uses
Used in Medical Applications:
4-Aminosalicylic acid is used as an antimycobacterial and antitubercular agent for the treatment of tuberculosis. It is also used as an NF-kB inhibitor, which helps in managing inflammatory conditions.
Used in Diagnostic Procedures:
In the Sigma Periodic Acid Staining Procedure, 4-Aminosalicylic acid is used for staining glycoproteins in polyacrylamide gels. It is also used in conjunction with Schiff's reagent for dyeing organic tissues and detecting specific functional groups in chemical solutions.
Used in Pharmaceutical Research:
4-Aminosalicylic acid serves as a model compound for studying the formation of salts and cocrystals in molecules with multiple hydrogen-bonding functional groups, which is crucial for the development of new pharmaceutical formulations and drug delivery systems.
Originator
Pamisyl,Parke Davis,US,1948
Indications
p-Aminosalicylic acid is a bacteriostatic that inhibits most tuberculous mycobacteria. In
terms of tuberculostatic activity it is inferior to isoniazid and streptomycin. It is nephroand hepatotoxic, and is rarely used. A synonym of this drug is apacizin.
Manufacturing Process
As described in US Patent 427,564, aminosalicylic acid may be prepared from
m-aminophenol by heating with ammonium carbonate in solution under
pressure.
Alternatively, aminosalicylic acid may be made from sodium p-aminosalicylate
as described in US Patent 2,844,625 as follows: 196 grams of commercial
sodium para-aminosalicylate (18.5% H2O) was dissolved in 196 ml of water
and 150 ml of isopropanol. 6 grams of sodium bisulfite was dissolved in the
solution and the solution filtered. While stirring and keeping the temperature
between 25-31°C, seven grams of 85% formic acid and 27.5 grams of 95%
sulfuric acid in 150 ml of water was added during 1 ? hours. The mixture was
stripped 1 hour longer, cooled to 23°C and filtered. The filter cake was washed
with 100 cubic centimeters of water, further washed with 100 cc of 25%
isopropanol and 100 cc of water, and vacuum dried to constant weight at 45-
50°C. Weight of p-aminosalicylic acid was 76.5 grams (92.7% yield) exhibiting
a bulk density of 47 cc/oz.
Therapeutic Function
Antitubercular
Biological Activity
4-Aminosalicylic acid is an antimetabolite of p-aminobenzoic acid (PABA) that has antibacterial activity.It is active against streptomycin-sensitive and -resistant strains of M. tuberculosis (MICs = 0.78 and 0.39 μg/ml, respectively), an effect that can be reversed by PABA. 4-Aminosalicylic acid is an alternative substrate for mycobacterial dihydropteroate synthase (FolP1) and misincorporation into the folate pathway leads to accumulation of several folate-dependent metabolites including serine, homocysteine, dUMP, and AICAR, markers of folate pathway inhibition, in a concentration-dependent manner. It reverses manganese-induced increases in rat hippocampal levels of NOD-like receptor protein 3 (NLRP3), cleaved caspase-1, and phosphorylated p65, markers of NLRP3 inflammasome-dependent pyroptosis, when administered at a dose of 300 mg/kg. 4-Aminosalycilic acid is also a building block that has been used in the synthesis of luminescent lanthanide complexes. Formulations containing 4-aminosalicylic acid have been used in the treatment of tuberculosis.
Mechanism of action
p-aminosalicylic acid is thought to act as an antimetabolite interfering with the incorporation of
p-aminobenzoic acid into folic acid. When coadministered with INH, PAS is found to reduce the
acetylation of INH, itself being the substrate for acetylation, thus increasing the plasma levels of
INH. This action may be especially valuable in patients who are rapid acetylators.
Safety Profile
Moderately toxic ingestion andother routes. An eye irritant. Mutation data reported.When heated to decomposition it emits toxic fumes ofNOx.
Synthesis
p-Aminosalicylic acid, 5-amino-2-hydroxybenzoic acid (34.1.22),
is synthesized in a Kolbe reaction, which consists of direct interaction of m-aminophenol
with potassium bicarbonate and carbon dioxide while heating at a moderate pressure of
5–10 atm.
Metabolism
p-aminosalicylic acid is extensively metabolized by acetylation of the amino group and by conjugation with glucuronic acid and glycine at the carboxyl group. It is used primarily in cases of resistance, retreatment, and intolerance of other agents and is available from the CDC.
Purification Methods
Crystallise the acid from EtOH. [Beilstein 14 IV 1967.]
Check Digit Verification of cas no
The CAS Registry Mumber 65-49-6 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 6 and 5 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 65-49:
(4*6)+(3*5)+(2*4)+(1*9)=56
56 % 10 = 6
So 65-49-6 is a valid CAS Registry Number.
InChI:InChI=1/C7H7NO3/c8-4-1-2-5(7(10)11)6(9)3-4/h1-3,9H,8H2,(H,10,11)
65-49-6Relevant articles and documents
P-aminosalicylic acid production by enzymatic kolbeschmitt reaction using salicylic acid decarboxylases improved through site-directed mutagenesis
Ienaga, Saori,Kosaka, Sachiyo,Honda, Yuki,Ishii, Yoshitaka,Kirimura, Kohtaro
, p. 628 - 634 (2013)
A reversible salicylic acid decarboxylase (Sdc) catalyzes the carboxylation of m-aminophenol (m-AP) to paminosalicylic acid (PAS) as an antituberculous agent, through an enzymatic KolbeSchmitt reaction. To develop a highyield PAS production system through such an enzymatic reaction, we generated Sdc mutants by site-directed mutagenesis and succeeded in generating several mutants showing increased carboxylation specific activities. Among them, a Y64T-F195Y-Sdc mutant showed a 12-fold higher carboxylation specific activity toward m-AP than wild-type Sdc. By the whole-cell reaction of recombinant Escherichia coli BL21(DE3) expressing the gene encoding Y64T-F195Y-Sdc, 70mM PAS was produced from 100 mM m-AP within 2 h. This reaction time was shortened to one-twelfth that of the PAS production using E. coli BL21(DE3) expressing the gene encoding wild-type Sdc (24 h). Moreover, 140 mM PAS was produced from 200 mM m-AP within 9 h by the whole-cell reaction of recombinant E. coli BL21(DE3) expressing the gene encoding Y64T-F195Y-Sdc.
Production of p-aminosalicylic acid through enzymatic kolbeschmitt reaction catalyzed by reversible salicylic acid decarboxylase
Kirimura, Kohtaro,Yanaso, Satomi,Kosaka, Sachiyo,Koyama, Keiko,Hattori, Takasumi,Ishii, Yoshitaka
, p. 206 - 208 (2011)
A reversible salicylic acid decarboxylase (Sdc), found in the yeast Trichosporon moniliiforme WU-0401, is applicable for the production of p-aminosalicylic acid (PAS) from m-aminophenol (m-AP). For the high-yield production of PAS, used as an antituberculous agent, we developed F195Y, a genetically engineered Sdc mutant. We succeeded in selectively producing PAS from m-AP through an enzymatic KolbeSchmitt reaction in aqueous solution by using recombinant Escherichia coli cells expressing the gene encoding F195Y. We found that 70mM PAS was produced at 30 °C in 15h with a conversion yield of 70% (mol/mol).
For amino salicylic acid crystal form and its preparation method and application
-
Paragraph 0057-0059, (2017/08/25)
The invention relates to the field of pharmaceutical chemistry, in particular to a novel crystal form of p-aminosalicylic acid and a preparation method thereof. A crystal in the novel crystal form is subjected to X-ray powder diffraction, diffraction peak positions 2theta are used as spectrogram characteristic parameters, and 2theta are 7.36+/-0.2, 14.61+/-0.2, 17.01+/-0.2, 21.91+/-0.2 and 29.28+/-0.2 sequentially. The preparation of the crystal comprises steps of mixing p-aminosalicylic acid and an organic solvent, then utilizing a temperature differential method for crystallization, carrying out solid-liquid separation, drying solid, and obtaining the crystal in the novel crystal form. The invention further relates to preparations or compositions containing the novel crystal form, and applications of the novel crystal form to preparations of drugs for treating tuberculosis. The novel crystal form of p-aminosalicylic acid is good in stability, and not only has storage and transportation advantages, but also greatly facilitates industrial production.
4-aminosalicylic acid adducts
Cherukuvada, Suryanarayan,Bolla, Geetha,Sikligar, Kanishka,Nangia, Ashwini
, p. 1551 - 1557 (2013/05/21)
4-Aminosalicylic acid (p-aminosalicylic acid, PAS), an antituberculosis drug, is a model active pharmaceutical ingredient to study salt and cocrystal formation in a multiple hydrogen-bonding functionality molecule with carboxylic acid, amine, and phenol groups. A cytosine salt CYT+-PAS-, salt cocrystal hydrate CYT+-PAS--CYT-H2O, and nicotinamide cocrystal hydrate PAS-NAM-H2O, are described in this article. Furthermore, X-ray crystal structures of PAS sodium dihydrate, sulfate, and mesylate salts and dehydration/rehydration behavior of the sodium salt by powder X-ray diffraction are discussed.