Sulfamethoxazole
- Iupac Name：4-amino-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide
- CAS No.: 723-46-6
- Molecular Weight：253.27
- Modify Date.: 2022-11-29 03:20
- Introduction: Like sulfisoxazole, this drug is effective in treating infections caused by streptococci,gonococci, pneumococci, staphylococci as well as colon bacillus. Unlike sulfisoxazole,only about 70% of it binds with proteins in the plasma after oral administration, and itdiffuses mostly to tissues and tissue fluids. However, since it is removed much slowerthan sulfisoxazole, it does not require frequent administration and is also the drug ofchoice for many systemic infections. Moreover, it is an ingredient of a combined drugnamed bactrim, biseptol, and so on (which will be examined later on), which has a fixedcorrelation with trimethoprim. Synonyms of this drug are gantanol, sinomin, sulfisomezole,and others.
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1. Names and Identifiers
- 1.1 Name
- Sulfamethoxazole
- 1.2 Synonyms
3-(p-aminophenylsulfonamido)-5-methylisoxazole 3-(para-Aminophenylsulphonamido)-5-methylisoxazole 3-Sulfanilamido-5-methylisoxazole 3-Sulphanilamido-5-methylisoxazole 4-Amino-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide 4-amino-n-(5-methyl-3-isoxazolyl)-benzenesulfonamid 5-Methyl-3-sulfanilamidoisoxazole 5-methyl-3-sulfanylamidoisoxazole 5-Methyl-3-sulfonylamidoisoxazole BACTRIM Benzenesulfonamide, 4-amino-N-(5-methyl-3-isoxazolyl)- EINECS 211-963-3 Gantanol MFCD00010546 N1-(5-methylisoxazol-3-yl)-4-aminobenzene-1-sulfonamide SEPTRA Septrin Sinomin Sulphamethoxazole
- 1.3 CAS No.
- 723-46-6
- 1.4 CID
- 5329
- 1.5 EINECS(EC#)
- 211-963-3
- 1.6 Molecular Formula
- C10H11N3O3S (isomer)
- 1.7 Inchi
- InChI=1S/C10H11N3O3S/c1-7-6-10(12-16-7)13-17(14,15)9-4-2-8(11)3-5-9/h2-6H,11H2,1H3,(H,12,13)
- 1.8 InChkey
- JLKIGFTWXXRPMT-UHFFFAOYSA-N
- 1.9 Canonical Smiles
- CC1=CC(=NO1)NS(=O)(=O)C2=CC=C(C=C2)N
- 1.10 Isomers Smiles
- CC1=CC(=NO1)NS(=O)(=O)C2=CC=C(C=C2)N
2. Properties
- 2.1 Density
- 1.462
- 2.1 Melting point
- 166-169℃
- 2.1 Boiling point
- 482.1 °C at 760 mmHg
- 2.1 Refractive index
- 1.6630 (estimate)
- 2.1 Flash Point
- 245.4 °C
- 2.1 Precise Quality
- 253.05200
- 2.1 PSA
- 106.60000
- 2.1 logP
- 3.10100
- 2.1 Appearance
- Crystals or white powder. (NTP, 1992)
- 2.2 Storage
- Store at -20°C.
- 2.3 Color/Form
- Powder
- 2.4 Decomposition
- When heated to decomposition it emits very toxic fumes of nitroxides and sulfoxides.
- 2.5 Odor
- Odorless
- 2.6 pKa
- pKa 5.60±0.05 (Uncertain)
- 2.7 Water Solubility
- Soluble in ethanol or acetone. Very slightly soluble in water
- 2.8 Stability
- Stable, but light sensitive. Incompatible with strong oxidizing agents.
- 2.9 StorageTemp
- Keep in dark place,Inert atmosphere,Room temperature
3. Use and Manufacturing
- 3.1 Definition
- ChEBI: An isoxazole (1,2-oxazole) compound having a methyl substituent at the 5-position and a 4-aminobenzenesulfonamido group at the 3-position.
- 3.2 Methods of Manufacturing
- 4-Amino-N- (5-methvl-isoxazol-3-vl)-benzenesulphonamide (STX608, XDS01099); The solution of N- (5-methylisoxazol-3-yl)-4-acetamidobenzenesulphonamid (3.4 g, 11.5 mmol) in 10percent NaOH solution (15 mL) was stirred at 80°C for 1h, cooled to rt and neutralized to pH 6 with acetic acid. The precipitate was washed with water, dried in vacuo to yield off-white solid (2, 8 g, 96percent). Mp167-169°C (lit [29], 168-171°C) ; TLC single spot at Rf 0.39 (6percent methanol-DCM) ; HPLC purity > 99percent (tR 1.6 min in 4percent water- methanol) ;'H NMR (400 MHz, CD30D) : S 7.54 (2H, m, ArH), 6.63 (2H, m, ArH), 6.08 (1H, s, ArH), 2.30 (3H, s, CH3) ; FAB-MS 254 (MH+) ; FAB-HRMS calcd for C10H12N303S (MH+) 254.0599, found 254.0605.To the intermediate 2 (2.53 mmol) suspended in water (15 mL)was added NaOH (31.7 mmol) and refluxed for 4 h to generate a yellow solution. This was acidified to pH 5.5 at 70-80 °C with 2 MHCl. After cooling it to room temperature precipitates formed werecollected, washed with H2O and dried to obtain the compound 3. 4.3.1
- 3.3 Usage
- As an antimicrobial agent, it is particularly effective in treating Staphylococcus aureus and E. coli. It is mainly used for the treatment of fowl cholera. It can be used as anti-infective drug and can be used for the treatment and prevention of acute and chronic urinary tract infections, respiratory infections, intestinal infections, Salmonella infections, children acute otitis media, and meningitis.
4. Safety and Handling
- 4.1 Symbol
- GHS07;
- 4.1 Hazard Codes
- Xn
- 4.1 Signal Word
- Warning
- 4.1 Risk Statements
- R22;R36/37/38
- 4.1 Safety Statements
- S22;S26;S36/37/39
- 4.1 Fire Hazard
- Flash point data for Sulfamethoxazole are not available but Sulfamethoxazole is probably non-flammable.
- 4.2 Hazard Class
- IRRITANT
- 4.2 Hazard Declaration
- H315; H317; H319; H335
- 4.2 RIDADR
- NONH for all modes of transport
- 4.2 Safety Profile
- Moderately toxic by ingestion and intraperitoneal routes. Questionable carcinogen with experimental tumorigenic data. When heated to decomposition it emits very toxic fumes of NOx and SOx.
- 4.3 Caution Statement
- P261-P280-P305 + P351 + P338
- 4.3 WGK Germany
- 2
- 4.3 RTECS
- WP0700000
- 4.3 Safety
-
Hazard Codes:?
Xi,Xn
Risk Statements: 36/37/38-43-22
R22: Harmful if swallowed.?
R43: May cause sensitization by skin contact.?
R36/37/38: Irritating to eyes, respiratory system and skin.
Safety Statements: 26-36/37/39-22
S22: Do not breathe dust.?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.?
S36/37/39: Wear suitable protective clothing, gloves and eye/face protection.
WGK Germany: 2
RTECS: WP0700000
Hazard Note: Irritant
HazardClass: IRRITANT
- 4.4 Specification
-
Side effects of Sulfamethoxazole (CAS NO.723-46-6):
The most common side effect of Sulfamethoxazole is gastrointestinal upset. Allergies to sulfa-based medications typically cause skin rashes, hives, or trouble breathing or swallowing and warrant immediate discontinuation of the medication and contact with doctor immediately.?In addition?Sulfamethoxazole/trimethoprim is also known to increase blood concentrations of the drug warfarin and can cause an unexpected increase in clotting time and uncontrolled bleeding. Sulfamethoxazole can also bring adverse effects?Neutropenia and thrombocytopenia if a patient is placed on long-term therapy.
- 4.5 Toxicity
- LD50 orally in mice: 3662 mg/kg (Yamamoto)
5. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
Not classified.
2.2 GHS label elements, including precautionary statements
| Pictogram(s) | No symbol. |
| Signal word | No signal word. |
| Hazard statement(s) | none |
| Precautionary statement(s) | |
| Prevention | none |
| Response | none |
| Storage | none |
| Disposal | none |
2.3 Other hazards which do not result in classification
none
7. Synthesis Route
723-46-6Total: 10 Synthesis Route
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Literatures:
Brimacombe, Kyle R.; Walsh, Martin J.; Liu, Li; Vasquez-Valdivieso, Montserrat G.; Morgan, Hugh P.; McNae, Iain; Fothergill-Gilmore, Linda A.; Michels, Paul A. M.; Auld, Douglas S.; Simeonov, Anton; Walkinshaw, Malcolm D.; Shen, Min; Boxer, Matthew B.
ACS Medicinal Chemistry Letters, 2014 , vol. 5, # 1 p. 12 - 17
Yield: ~99%
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9. Other Information
- 9.0 Merck
- 14,8918
- 9.1 BRN
- 6732984
- 9.2 Brand Name(s) in US
- Gantanol
- 9.3 Sulfonamide drugs
- Sulfa drugs have a relative broad antimicrobial spectrum and have certain inhibitory effect against most Gram-positive bacteria and gram-negative bacteria. However, different sulfonamide drugs have different extent of antibacterial efficacy. With the wide application of sulfonamide drugs, it will also be easy to lead to resistant strains; in particular the opportunity of resistant Staphylococcus aureus will be even higher than other kinds of resistant strains.
According to the absorption situations after oral administration, the sulfonamide drugs can be classified into two categories, the first category is easily absorbed sulfonamide drugs, which is characterized by rapid absorption. Generally, their plasma concentrations can reach peak at 2-4 hours after the administration (5 hour for long-acting drugs). This kind of sulfonamide drugs are mainly used for systemic infections. Another kind of drugs is hardly or poorly absorbed after oral administration with most of them being excreted through the intestinal tract and is mainly used for treating intestinal infections.
Sulfamethoxazole is a broad-spectrum antibiotic with particularly strong efficacy on Staphylococcus aureus and Escherichia coli and can be used for the treatment of urinary tract infections and fowl cholera. Sulfamethoxazole belongs to a systemic, moderate sulfonamide drug. It can compete with PABA through taking effect on the bacterial in vivo dihydrofolate synthase, preventing the bacterial synthesis of dihydrofolate and thereby inhibiting the bacterial growth and reproduction. It, together with other three kinds of sulfonamide drugs: sulfadiazine, sulfisoxazole and trisulfapyrimidine are currently excellent drugs for the treatment of nocardiosis. It has a half-life of 10 to 12 hours and can be partially acetylated. This product, although has the number of required medication be less than sulfisoxazole (2 times per day instead of four times), but its acetylated metabolites has a low solubility in the urine so the likelihood of large crystals formation in urine is bit higher. Patients should maintain enough hydrated conditions (the daily adult urine output should be not less than 1,500ml). When being used in combination with the synergist trimethoprim, its antibacterial activity can get significantly enhanced. Sulfamethoxazole compound (sulfamethoxazole/trimethoprim namely SMZ/TMP) can often give better efficacy than monotherapy (see dihydrofolate reductase inhibitors). Clinically it is commonly used for the treatment of urinary tract infections, respiratory tract infections, typhoid, and salmonella infections, Pneumocystis carinii echinococcosis and nocardiosis. It can also be used for preventing meningococcal meningitis. Some clinicians advocate use minocycline, erythromycin or ampicillin in combination with sulfamethoxazole to treat such infections. However, there has been no clinical data for proving that combination therapy is superior to single administration of sulfonamide. Sulfamethoxazole compound (TMP/SMZ), minocycline (Minocin) and amikacin can also be used for the treatment of nocardia infection.
- 9.4 Mechanism of action
- It is known that bacterial can synthesize thymidine, purine and finally synthesize DNA and need folic acid derivatives, tetrahydrofolate as cofactors. Most bacterial cells can’t allow the penetration of folic acid and instead needs the synthesis through aminobenzoic acid (PABA). Sulfonamide has a similar structure to PABA and thus can competitively inhibit the synthesis of the direct precursor of dihydrofolate, dihy-dropteroic acid through the reaction between PABA and pteridine. Mammalian cells, instead, is not inhibited since they require preformed folate and is not capable of synthesizing this product.
Treatment concentration of sulfonamide drug sulfamethoxazole is primarily bacteriostatic agents. However, when the bacteria is grown in the medium containing purine, amino aicd but very low concentration of thymine, the sulfonamide drugs can produce a bactericidal effect, that is, "thymine lethal defect". This bactericidal effect has been demonstrated in human blood and urine (Then and Angehrn, 1973 A and B; see also Pratt and Fekety, 1986).
The effect of sulfonamide drug-induced inhibition of bacterial cell growth can be reversed upon supplement in vitro of some substances (such as thymidine, purines, methionine and serine) to the growth medium. This may have important clinical significance. Because the pus generated by cells destruction may contain a large amount of these substances. It is therefore, upon purulent infection, the effect of the drug may be inhibited probably due to the presence of such substances. Furthermore, for the in vitro susceptibility testing, the medium can’t contain PABA for which even in trace amount, the test results can be disturbed.
- 9.5 Chemical Properties
- It is white crystalline powder and is odorless with slightly bitter taste. It has a melting point of 168 ℃. It is very slightly soluble in water, soluble in dilute acid, dilute alkali or ammonia.
- 9.6 Uses
- As an antimicrobial agent, it is particularly effective in treating Staphylococcus aureus and E. coli. It is mainly used for the treatment of fowl cholera.
It can be used as anti-infective drug and can be used for the treatment and prevention of acute and chronic urinary tract infections, respiratory infections, intestinal infections, Salmonella infections, children acute otitis media, and meningitis.
- 9.7 Production method
- It can be produced from 5-methyl-isobutyl-3-carboxamide via degradation, condensation and hydrolysis successively.
Use 5-methyl-isobutyl-3-carboxamide as raw materials, it is degraded into 5-methyl-isoxazol-3 amine under the action of sodium hypochlorite solution, then condense with para-acetamidophenoxymethyl chloride to generate 3-(p-acetamide benzenesulfonamido)-5-methylisoxazole with further hydrolysis under alkaline conditions to give 3-(p-amino benzenesulfonamido)-5-methylisoxazole.
- 9.8 Description
- Like sulfisoxazole, this drug is effective in treating infections caused by streptococci, gonococci, pneumococci, staphylococci as well as colon bacillus. Unlike sulfisoxazole, only about 70% of it binds with proteins in the plasma after oral administration, and it diffuses mostly to tissues and tissue fluids. However, since it is removed much slower than sulfisoxazole, it does not require frequent administration and is also the drug of choice for many systemic infections. Moreover, it is an ingredient of a combined drug named bactrim, biseptol, and so on (which will be examined later on), which has a fixed correlation with trimethoprim. Synonyms of this drug are gantanol, sinomin, sulfisomezole, and others.
- 9.9 Chemical Properties
- solid
- 9.10 Uses
- An antibacterial drug. Sulfonamide antibiotic that blocks the synthesis of dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase.
- 9.11 Uses
- antibacterial, antipneumocystis
- 9.12 Uses
- An antibacterial drug. Sulfonamide antibiotic that blocks the synthesis of dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase.This compound is a contaminant of emerging concern (CECs).
- 9.13 Definition
- ChEBI: An isoxazole (1,2-oxazole) compound having a methyl substituent at the 5-position and a 4-aminobenzenesulfonamido group at the 3-position.
- 9.14 Brand name
- Gantanol (Roche); Urobak (Shionogi).
- 9.15 Usage
- A broad spectrum bacteriostatic sulfonamide antibiotic
- 9.16 Storage Conditions
- 4-Amino-N- (5-methvl-isoxazol-3-vl)-benzenesulphonamide (STX608, XDS01099); The solution of N- (5-methylisoxazol-3-yl)-4-acetamidobenzenesulphonamid (3.4 g, 11.5 mmol) in 10percent NaOH solution (15 mL) was stirred at 80°C for 1h, cooled to rt and neutralized to pH 6 with acetic acid. The precipitate was washed with water, dried in vacuo to yield off-white solid (2, 8 g, 96percent). Mp167-169°C (lit [29], 168-171°C) ; TLC single spot at Rf 0.39 (6percent methanol-DCM) ; HPLC purity > 99percent (tR 1.6 min in 4percent water- methanol) ;'H NMR (400 MHz, CD30D) : S 7.54 (2H, m, ArH), 6.63 (2H, m, ArH), 6.08 (1H, s, ArH), 2.30 (3H, s, CH3) ; FAB-MS 254 (MH+) ; FAB-HRMS calcd for C10H12N303S (MH+) 254.0599, found 254.0605.To the intermediate 2 (2.53 mmol) suspended in water (15 mL)was added NaOH (31.7 mmol) and refluxed for 4 h to generate a yellow solution. This was acidified to pH 5.5 at 70-80 °C with 2 MHCl. After cooling it to room temperature precipitates formed werecollected, washed with H2O and dried to obtain the compound 3. 4.3.1
- 9.17 Antimicrobial activity
- The intrinsic activity is similar to that of sulfadiazine.
- 9.18 General Description
- Sulfamethoxazole’s plasma half-life is 11 hours. Sulfamethoxazole is a sulfonamide drug closely relatedto sulfisoxazole in chemical structure and antimicrobial activity.It occurs as a tasteless, odorless, almost white crystallinepowder. The solubility of sulfamethoxazole in the pHrange of 5.5 to 7.4 is slightly lower than that of sulfisoxazole but higher than that of sulfadiazine, sulfamerazine, or sulfamethazine.Following oral administration, sulfamethoxazole is notabsorbed as completely or as rapidly as sulfisoxazole, andits peak blood level is only about 50% as high.
- 9.19 General Description
- Crystals or white powder.
- 9.20 Air & Water Reactions
- Insoluble in water.
- 9.21 Fire Hazard
- Flash point data for Sulfamethoxazole are not available but Sulfamethoxazole is probably non-flammable.
- 9.22 Pharmaceutical Applications
- This is the sulfonamide component of co-trimoxazole. It is slightly soluble in water.
- 9.23 Pharmacokinetics
- Oral absorption： 85%
Cmax 800 mg oral： c.50 mg/L after 3–6 h
Plasma half-life： 6–20 h
Volume of distribution： 12–18 L
Plasma protein binding： 65%
Penetration of extravascular sites, including the CSF, is good. It crosses the placenta and achieves levels in breast milk of about 10% of the simultaneous plasma concentration. It is extensively metabolized, but about 30% of the dose is excreted unchanged in urine so that high concentrations are achieved.
- 9.24 Clinical Use
- Sulfamethoxazole is used only in combination with the diaminopyrimidine trimethoprim.
- 9.25 Side effects
- Unwanted effects are those common to sulfonamides. In addition, benign intracranial hypertension has been reported in children. Most side effects of co-trimoxazole are thought to be attributable to the sulfonamide component.
- 9.26 Safety Profile
- Moderately toxic by ingestion and intraperitoneal routes. Questionable carcinogen with experimental tumorigenic data. When heated to decomposition it emits very toxic fumes of NOx and SOx.
- 9.27 Chemical Synthesis
- Sulfamethoxazole, N1 -(5-methyl-3-isoxazolyl)sulfanilamide (33.1.20), is synthesized by a completely analogous scheme, except by using 3-amino-5-methylisoxazol as the heterocyclic component.
10. Computational chemical data
- Molecular Weight: 253.27g/mol
- Molecular Formula: C10H11N3O3S
- Compound Is Canonicalized: True
- XLogP3-AA: null
- Exact Mass: 253.05211239
- Monoisotopic Mass: 253.05211239
- Complexity: 346
- Rotatable Bond Count: 3
- Hydrogen Bond Donor Count: 2
- Hydrogen Bond Acceptor Count: 6
- Topological Polar Surface Area: 107
- Heavy Atom Count: 17
- Defined Atom Stereocenter Count: 0
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADccBzMABAAAAAAAAAAAAAAAAAAWAAAAAwAAAAAAAAAAABwAAAHgQUQAAACAyB0gAz9ZBQAAKpAKZyYnDCABAkIgAomDk2bNoIJCqAkZGAIIBikAgIyEcQAAAAAAQAAAAAAAAACAAAAAAAAAAAAAAAAA==
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