Sulfadoxine

Description

Sulfadoxin is a sulfonamide antibiotic that inhibits dihydropteroate synthetase (DHPS), an enzyme involved in folic acid synthesis. Sulfadoxin competes with 4-aminobenzoate (PABA), the native substrate of DHPS, and inhibits PABA incorporation into folic acid. Folate is essential for purine and pyrimidine synthesis, therefore, sulfadoxin has antiproliferative activity in non-resistant P. falciparum. Sulfadoxin inhibits growth of P. falciparum in vitro, but potency varies between non-resistant (IC₅₀ = 4 ng/ml) and resistant strains (IC₅₀ = 3,970 ng/ml).

Chemical properties

White Crystalline Solid

Originator

Fanasil,Roche,Italy,1973

The Uses of Sulfadoxine

Used as an antibacterial

The Uses of Sulfadoxine

Used as an antibacterial.

What are the applications of Application

Sulfadoxine is an antibiotic inhibiting Plasmodium falciparum

Background

A long acting sulfonamide that is used, usually in combination with other drugs, for respiratory, urinary tract, and malarial infections.

Indications

Sulfadoxine is used in combination with pyrimethamine for the treatment or prevention of malaria. It can also be used to treat various infections in livestock as well. Sulfadoxine and pyrimethamine is indicated for the treatment of Plasmodium falciparum malaria in those patients in whom chloroquine resistance is suspected.

Definition

ChEBI: A sulfonamide consisting of pyrimidine having methoxy substituents at the 5- and 6-positions and a 4-aminobenzenesulfonamido group at the 4-position. In combination with the antiprotozoal pyrimethamine (CHEBI:8673) it is used as an antimalarial.

Manufacturing Process

(a) α-methoxy-cyanoacetic acid methyl ester is condensed with thiourea, in the presence of sodium methylate, to form 2-thio-4-amino-5-methoxy-6- hydroxy-pyrimidine.
(b) The product thus obtained is methylated in a sodium methylate solution with methyl iodide to form 2-methylthio-4-amino-5-methoxy-6-hydroxypyrimidine of MP 203°C, from water.
(c) The latter product is methylated with phenyltrimethylammoniumtoluenesulfonate to form 2-methylthio-4-amino-5,6-dimethoxy-pyrimidine of MP 112° to 115°C, from 20% methanol.
(d) 0.9 gram of 2-methylthio-4-amino-5,6-dimethoxy-pyrimidine are dissolved in 3 ml of absolute pyridine. At 0°C, 1.2 grams of pacetylaminobenzenesulfonyl chloride are added thereto and the mixture is shaken until all the material is dissolved. The solution is allowed to stand for 22 hours at 0°C and the pyridine eliminated in vacuo at 20°C. To the resulting product are added 20 ml of water and 3 ml of glacial acetic acid, whereupon the whole mixture is heated to the boil, thus causing crystallization. The crude product obtained is dissolved in 40 ml of 2.5% soda solution, and the solution obtained is filtered and supersaturated with gaseous carbon dioxide. There is thus obtained 1.5 grams (85%) of 2-methylthio-4-(N4-acetyl-sulfanilamido)- 5,6-dimethoxy-pyrimidine of MP 220° to 221°C, from 50% ethanol.
(e) 1.3 grams of 2-methylthio-4-(N4-acetyl-sulfanilamido)-5,6-dimethoxypyrimidineare dissolved in 25 ml of water and 0.4 gram of anhydrous sodium carbonate, then refluxed for 3 ? hours in the presence of 6 to 7 grams of Raney nickel. Then, a solution of 1 gram of sodium hydroxide in 3 ml of water is added thereto and heating continued for another hour. The catalyst is filtered off and the filtrate acidified to Congo red with hydrochloric acid. The pH is then brought to 5 by means of ammonia, thus causing crystallization. There is thus obtained 0.51 gram of 4-sulfanilamido-5,6-dimethoxy-pyrimidine of MP 190° to 194°C, from 50% ethanol.

brand name

Fanasil (Hoffmann-LaRoche-International); Fanzil (Hoffmann-LaRoche).

Therapeutic Function

Antibacterial

Antimicrobial activity

Its antibacterial activity is relatively poor. Used alone it has a slow and uncertain effect against malaria parasites. Resistance of malaria parasites to the combination with pyrimethamine is common in many endemic areas.

Pharmaceutical Applications

An ultra-long-acting sulfonamide. It is no longer prescribed alone, but is used in combination with pyrimethamine as the antimalarial agent Fansidar. It is poorly soluble in water.

Pharmacokinetics

Sulfadoxine helps inhibit the enzyme dihydropteroate synthetase which is an enzyme necessary in the conversion of PABA to folic acid. As folic acid is vital to the synthesis, repair, and methylation of DNA which is vital to cell growth in Plasmodium falciparum. With this vital nutrient lacking, the parasite has difficulty in reproducing.

Pharmacokinetics

Oral absorption ：Extensive
C_max 500 mg oral： c. 60 mg/L after 3–4 h
Plasma half-life：c.6 days
Volume of distribution：0.13 L/kg
Plasma protein binding：94%
The extremely long half-life allows administration at weekly intervals. The acetyl metabolite has a similarly long half-life, but sulfadoxine is less extensively metabolized than many other sulfonamides.

Pharmacology

In terms of antibacterial action, this drug is analogous to other sulfanilamides; however, it possesses very prolonged action. Its half-life is from 120 to 200 h. Sulfadoxine is used for infectious diseases caused by microorganisms that are sensitive to the sulfanilamide drugs, such as infections of respiratory organs, gastric and urinary tracts; purulent infections of various localization, osteomyelitis, sinusitis, and other infections. It is used in combination with antimalarial drugs. Synonyms of this drug are sulfarmethoxine, fanasil, and fansidar.

Clinical Use

Sulfadoxine is used only in combination with pyrimethamine.

Side Effects

Side effects are those common to the group. There have been many reports of Stevens–Johnson syndrome following its use and the combination with pyrimethamine is no longer recommended for the prophylaxis of malaria.

Synthesis

Sulfadoxine, 4,5-dimethoxy-6-sulfanilamidopyrimidine (33.1.33), is synthesized by the standard scheme from 4-acetylaminobenzenesulfonyl chloride and 4-amino-5,6-dimethoxypyrimidine. However, the synthesis of 4-amino-5,6- dimethoxypyrimidine (33.1.31) is itself curious?ait is synthesized from methyl ester of methoxyacetic acid. Interacting this with dimethyloxalate in the presence of sodium methoxide gives the methoxy derivative (33.1.25), and the pyrolysis of this compound gives the dimethyl ester of methoxymalonic acid (33.1.26). Reacting this with ammonia gives the diamide of methoxymalonic acid (33.1.27). Heterocyclization of the resulting product by a reaction with formamide in the presence of sodium ethoxide gives 4,6- dioxy-5-methoxypyrimidine (33.1.28), which is then transformed to 4,6-dichloro-5- methoxypyrimidine (33.1.29). The resulting 4,6-dichloro-5-methoxypyrimidine (33.1.29) undergoes a reaction with ammonia to make 4-amino-6-chloro-5-methoxypyrimidine (33.1.30), and the resulting compound is then reacted with sodium methoxide to make the desired 5,6-dimethoxy-5-aminopyrimidine (33.1.31). Reacting this with 4-acetylaminobenzenesulfonyl chloride and subsequent hydrolysis of the acetyl group in (33.1.32) gives sulfadoxine.

Metabolism

Not Available