2447-57-6 Usage
Description
Sulfadoxine is a sulfonamide antibiotic that functions by inhibiting dihydropteroate synthetase (DHPS), an enzyme crucial for folic acid synthesis. It is characterized by its ability to compete with 4-aminobenzoate (PABA), the natural substrate of DHPS, thereby preventing PABA incorporation into folic acid. As folic acid is vital for the synthesis of purine and pyrimidine, Sulfadoxine exhibits antiproliferative activity, particularly against non-resistant P. falciparum. It is available under the brand names Fanasil (Hoffmann-LaRoche-International) and Fanzil (Hoffmann-LaRoche) and is a white crystalline solid.
Uses
1. Used in Pharmaceutical Industry:
Sulfadoxine is used as an antibacterial agent for treating bacterial infections. It is particularly effective against non-resistant P. falciparum, showcasing its antiproliferative activity.
2. Used in Antimalarial Applications:
Sulfadoxine is used in combination with the antiprotozoal pyrimethamine (ChEBI:8673) as an antimalarial agent. This combination enhances its efficacy against malaria-causing parasites.
3. Used in Research and Development:
Sulfadoxine's ability to inhibit growth of P. falciparum in vitro, with varying potency between non-resistant and resistant strains, makes it a valuable compound for research and development in the field of antimalarial drug discovery and resistance studies.
Pharmacology and mechanism of action
The efficacy of sulphadoxine for the treatment of human malaria was first reported in 1964 [1]. Soon thereafter it was found that potentiation took place when sulphadoxine was combined with pyrimethamine for treatment of malaria and monotherapy was abandoned.
Malaria parasites synthesize their folate co-factors and cannot use dietary folic acid as the human host can. Sulphadoxine competes with para-aminobenzoic acid (PABA) for binding to the enzyme dihydropteroate synthetase in the synthesis of dihydropteroate which is an essential substance for the formation of folic acid [2]. It is active against asexual blood forms of P. falciparum but less active against other species. The action is too slow to be used alone for malaria treatment [3].
Indications
Sulphadoxine is used only in combination with pyrimethamine for the treatment of falciparum malaria. It should generally not be used for malaria prophylaxis except perhaps in long-term travellers who have previously tolerated the combination.
Side effects
Sulphadoxine is usually well tolerated. Vomiting, skin rashes, pruritus and haematological reactions such as haemolysis and leucopenia occur [4]. Hypersensitivity pneumonitis is reported[5, 6]. Cases of liver injury alone (hepatitis of hepatocellular, mixed hepatocellular, or aggressive type) or as part of a generalized allergic syndrome are well known[4, 6], and one case of fatal hepatic failure has also been reported [7].
Severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis) have been reported in persons taking prophylactic doses of sulphadoxine/pyrimethamine[6, 8]. Sulphadoxine has been incriminated as the most probable cause of these reactions. They all occurred within 7 weeks after start of prophylaxis.
The reported incidence was 1/5,000–8,000 users in USA and approximately 1/10,000 users in Sweden with fatality rates of 1/11,000–25,000 and 1/50,000, respectively. In Mozambique, when sulphadoxine was given alone in a single dose for cholera prophylaxis to 149,000 inhabitants, a total of 22 cases of Stevens-Johnson syndrome was seen with 3 deaths [9].
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.
Contraindications and precautions
The drug or its combination should not be given to patients allergic to sulphonamides. It should not be used in persons with severe blood, kidney or liver diseases.
Interactions
Increased impairment of folic acid synthesis and consequent haematological adverse effects may occur if trimethoprim or its combination with sulphonamide is administered concurrently. Sulphadoxine potentiates the action of warfarin and thiopentone [10].
Preparations
Sulphadoxine combined with pyrimethamine.
?? Fansidar? (Roche). Tablets (sulphadoxine 500 mg+pyrimethamine 25 mg), solution for intramuscular injection (sulphadoxine 200 mg/ml+pyrimethamine 10 mg/ml).
References
1. Laing ABG (1964). Antimalarial effect of sulphorthodimethoxine (Fanasil). BMJ, 2, 1439–1440.
2. The biology of malaria parasites. Technical Report Series no. 743 (1987). (Geneva: World Health Organization).
3. Chemotherapy of Malaria. Monograph series No. 27, 2nd edn, (1986), (Geneva: World Health Organization).
4. Hoigné R, Malinverni R, Sonntag R (1992). Sulfonomides, other folic acid antagonists and miscellaneous antibacterial drugs. In: Meyler’s Side Effects of Drugs, 12th edn, edited by M.N.G.Dukes (Amsterdam: Elsevier), pp. 715–722.
5. Svanbom M, Rombo L, Gustafsson L (1984). Unusual pulmonary reaction during short term prophylaxis with pyrimethamine-sulphadoxine (Fansidar). BMJ, 1, 1876.
6. Hellgren U, Rombo L, Berg B, Carlson J, Wiholm B-E (1987). Adverse reactions to sulphadoxinepyrimethamine in Swedish travellers: implications for prophylaxis. BMJ, 295, 365–366.
7. Zitelli BJ, Alexander J, Taylor S (1987). Fatal hepatic necrosis due to pyrimethamine-sulphadoxine (Fansidar). Ann Intern Med, 106, 393–395. 25. Miller KD, Lobel HO, Satriale RF, Kirutsky JN, Stern R, Campell CC (1986). Severe cutaneous reactions among American travellers using pyrimethamine-sulphadoxine (Fansidar) for malaria prophylaxis. Am J Trop Hyg, 35, 451–458.
8. Hernberg A (1985). Stevens-Johnson syndrome after mass prophylaxis with sulphadoxine for cholera in Mozambique. Lancet, 2, 1072–1073.
9. Sulfadoxine. Therapeutic Drugs, edited by Sir Colin Dollery (1991), (London: Churchill Livingstone), pp. S115–S119.
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.
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—it 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.
Check Digit Verification of cas no
The CAS Registry Mumber 2447-57-6 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 2,4,4 and 7 respectively; the second part has 2 digits, 5 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 2447-57:
(6*2)+(5*4)+(4*4)+(3*7)+(2*5)+(1*7)=86
86 % 10 = 6
So 2447-57-6 is a valid CAS Registry Number.
InChI:InChI=1/C12H14N4O4S/c1-19-10-11(14-7-15-12(10)20-2)16-21(17,18)9-5-3-8(13)4-6-9/h3-7H,13H2,1-2H3,(H,14,15,16)
2447-57-6Relevant articles and documents
Preparation method of sulfadoxine
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Paragraph 0033-0047, (2021/03/11)
The invention provides a preparation method of sulfadoxine. The method is a preparation method of sulfadimethoxine, and the sulfadimethoxine product is prepared by directly taking 4-chloro-5, 6-dimethoxypyrimidine and sodium sulfanilamide as raw materials through a condensation reaction. The method is simple in process, free of special requirements on equipment, simple and convenient to operate, good in product quality and suitable for industrial production.
Use of 4 - (P-amino sulfonaide yl) - 5-methoxy -6 chloro pyrimidine preparing method sulfadoxine
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Paragraph 0002; 0003; 0017-0024, (2017/02/17)
The invention relates to a method used for preparing sulfadimoxine from 4-(p-anilinesulfonamide)-5-methoxy-6 chloropyrimidine. The method comprises following steps: (a) methanol, sodium hydroxide, and water are delivered into a reactor, a trichloro ethylene solution containing 4-(p-anilinesulfonamide)-5-methoxy-6 chloropyrimidine is added with stirring, an obtained mixed material is heated to 69 to 72 DEG C for 2 to 6 hours of reflux reaction so as to obtain a mixture; (b) at a temperature of 76 to 78 DEG C, the mixture is subjected to distillation so as to remove methanol, and then is heated to 105 to 115 DEG C so as to remove trichloro ethylene, hydrochloric acid is added so as to adjust pH value to 9.5 to 10.5, active carbon is added, and an obtained solution is subjected to stirring decolouring at a temperature of 80 to 85 DEG C for 0.5 to 2h so as to obtain a clear liquid; and (c) glacial acetic acid solution is added into the clear liquid dropwise until pH value reaches 5.1 to 5.4, and the clear liquid is subjected to precipitation and centrifuge dewatering. According to the method, water and trichloro ethylene are delivered into the reactor, and are used for dissolving sodium hydroxide and 4-(p-anilinesulfonamide)-5-methoxy-6 chloropyrimidine respectively, so that heat energy generated by reaction can be reduced effectively, smoothness of reaction is ensured, and uniform distribution of the reactor temperature is realized.
