Description
Sulfamethizole is a broad spectrum sulfonamide antibiotic (MIC
90s = 1.25-5,000 μg/ml against clinical isolates of
E. coli and
K. pneumoniae). It inhibits dihydropteroate synthase, an enzyme involved in folate biosynthesis. Formulations containing sulfamethizole have previously been used to treat urinary tract infections.
Originator
Thiosulfil,Ayerst,US,1953
Uses
Sulfamethizole is a sulfonamide based antibiotic that exhibit bactericidal activities towards gram-negative bacteria. Sulfamehizole was shown to be effective in treating gram-negative Bacillus AmpC en
zyme in elderly patients with lower respiratory tract infection and as well as against microbs responsible for tuberculosis.
Definition
ChEBI: Sulfamethizole is a sulfonamide consisting of a 1,3,4-thiadiazole nucleus with a methyl substituent at C-5 and a 4-aminobenzenesulfonamido group at C-2. It has a role as an antimicrobial agent, an antiinfective agent, an EC 2.5.1.15 (dihydropteroate synthase) inhibitor and a drug allergen. It is a sulfonamide, a member of thiadiazoles and a sulfonamide antibiotic.
Manufacturing Process
To 10 grams acetaldehyde-thiosemicarbazone in 80 grams pyridine gradually
20 grams p-acetaminobenzolsulfonyl chloride is added. The reaction mixture is
heated about 1 hour on a water bath and is then charged in 1 liter water, to
which some acetic acid is added. The bottom sediment is sucked off and
washed with water, after which it is crystallized by alcohol. 20 grams of the
condensation product thus obtained is cleared in 100 cc water at about 30°C,
after which 45 grams calcium ferricyanide dissolved in about 100 cc water is
added. The reaction mixture is made slightly alkaline and held at a
temperature of about 80°C for 2 to 3 hours. It is important that the reaction mixture during the whole period of 2 to 3 hours is steadily held alkaline.
After the said 2 to 3 hours the liquid is cooled and the bottom sediment,
which has a greenish color, is filtered off. The liquid sucked off eventually is
treated with active carbon, filtered and made slightly acid by means of acetic
acid, at which 2-amino-benzolsulfonamido-5-methyl-1,3,4-thiodiazol (melting
point 204° to 206°C) is precipitated.
brand name
Thiosulfil (Wyeth);3p methazol;Amer-azo;Azocline;Azotrex;Dorsec;Lucatyl;Methisul;Micturol ampicilina seda;Nicene;Orozl;Procijec;Proklar-m;Rp 2145;S-methizole;Spasmo-harnosal;Starisil;Suladyne;Sulfa gram;Thiosulfil a;Tiosulfan;Uratrac;Urolex;Uroluxcosil;Uro-nebactin;Uropeutic;Urotrex.
Therapeutic Function
Antibacterial
World Health Organization (WHO)
Sulfamethizole, a sulfonamide anti-infective agent, was
introduced in 1953 for the treatment of bacterial infections. The importance of
sulfonamides has subsequently decreased as a result of increasing bacterial
resistance and their replacement by antibiotics which are generally more active
and less toxic. However sulfamethizole, which is rapidly eliminated, retains a place
in the treatment of urinary infections in some countries whereas in others its use has been discontinued.
Antimicrobial activity
This drug has antibacterial activity with respect to streptococci, pneumococci, staphylococci, meningococci, gonococci, colon bacillus, pathogenic dysentery, and others. It is not very toxic. It is generally used for acute, uncomplicated infections of the urinary tract that are caused by sensitive organisms. Because it is removed quickly from the organism by the kidneys, the level of drug in the plasma remains low, and therefore it is not used for treating infections that are localized in the urinary tract. Sulfisoxazole is the more preferred drug. Synonyms of this drug are urosol, rufol, thiosulfil, and others.
General Description
Sulfamethizole’splasma half-life is 2.5 hours. This compound is a white crystallinepowder soluble 1:2,000 in water.
General Description
White powder.
Air & Water Reactions
Insoluble in water.
Fire Hazard
Flammability data is lacking for SULFAMETHIZOLE. SULFAMETHIZOLE is probably non-flammable.
Pharmaceutical Applications
2-Sulfanilamido-5-methyl-1,3,4-thiodiazole. A short-acting
sulfonamide (plasma half-life 2.5 h). Protein binding is c. 85%.
About 60% is excreted in the urine within 5 h. It was formerly
widely used in the treatment of urinary tract infection.
Synthesis
Sulfamethizole, N1-(5-methyl-1,3,4-thiadiazole-2-yl)sulfanilamide
(33.1.15), is synthesized in two ways. According to the first, 5-amino-2-methyl-1,3,4-
thiadiazole is reacted with 4-nitrobenzenesulfonyl chloride to make a nitro derivative
(33.1.14), which is then reduced using iron filings in acetic acid to give the desired sulfamethizole.
The second method of making sulfamethizole consists of reacting 4-acetylaminobenzene sulfonyl chloride with thiosemicarbazone of acetaldehyde, and subsequent oxidative
cyclization of the product (33.1.16) to the substituted 1,3,4-thiadiazole in the presence of
potassium ferricyanide in base, along with the simultaneous removal of the protective
acetyl group.
References
[1] Patent: WO2011/82400, 2011, A2. Location in patent: Page/Page column 52
[2] Wambaugh, Morgan A, et al. “High-Throughput Identification and Rational Design of Synergistic Small-Molecule Pairs for Combating and Bypassing Antibiotic Resistance.”
PLoS Biology, 15 6, 2017, p. e2001644,
https://doi.org/10.1371/journal.pbio.2001644.
[3] Kerrn, M B, et al. “Effects of Sulfamethizole and Amdinocillin against Escherichia Coli Strains (with Various Susceptibilities) in an Ascending Urinary Tract Infection Mouse Model.”
Antimicrobial Agents and Chemotherapy, 47 3, 2003, pp. 1002–09,
https://doi.org/10.1128/AAC.47.3.1002-1009.2003.
[4] Watanabe, Haruo, and J.W. Hastings. “Inhibition of Bioluminescence in Photobacterium Phosphoreum by Sulfamethizole and Its Stimulation by Thymine.”
Biochimica et Biophysica Acta-Bioenergetics, 1017 3, 1990, p. Pages 229-234,
https://doi.org/10.1016/0005-2728(90)90189-B.
