Chemical Properties
White Crystalline Solid
Uses
Used as an antibacterial
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.
Description
Sulfadoxin is a sulfonamide antibiotic that inhibits dihydropteroate synthetase (DHPS), an enzyme involved in folic acid (Item No.
20515) synthesis.
1 Sulfadoxin competes with 4-aminobenzoate (PABA), the native substrate of DHPS, and inhibits PABA incorporation into folic acid.
2 Folate is essential for purine and pyrimidine synthesis, therefore, sulfadoxin has antiproliferative activity in non-resistant
P. falciparum.
2,3 Sulfadoxin inhibits growth of
P. falciparum in vitro, but potency varies between non-resistant (IC
50 = 4 ng/ml) and resistant strains (IC
50 = 3,970 ng/ml).
3
Originator
Fanasil,Roche,Italy,1973
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
Oral absorption ：Extensive
Cmax 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.
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.
