68-35-9 Usage
Uses
Used in Clinical Medicine:
Sulfadiazine is used as an antibacterial agent for treating upper respiratory tract infections, Meningococcal meningitis, otitis media, boils carbuncle, puerperal fever, urinary tract infections, and acute dysentery. It is effective against infections caused by hemolytic streptococcus, pneumococcus, meningococcis, Neisseria gonorrhea, and E. coli.
Used in External Medicine:
Sulfadiazine is used in the form of silver salts (sulfadiazine silver) as an external antibacterial agent, primarily for treating burns. The presence of the silver ion in the molecule is believed to facilitate increased antimicrobial and wound-healing action.
Used in Pharmaceutical Industry:
Sulfadiazine is used as a sulfonamide antibacterial in the development of various pharmaceutical products to combat bacterial infections.
Used in Immunosuppressive Therapy:
Sulfadiazine is used as a potent immunosuppressant, neuroprotective, neuroregenerative agent, and in vitro T cell proliferation blocker. It disrupts calcineurin-mediated signal transduction in T lymphocytes, making it useful in the treatment of autoimmune diseases and transplantation.
Pharmacological effects
Sulfadiazine hemolytic has inhibitory effect on various kinds of microorganisms including streptococcus, staphylococcus, meningococcus, pneumococcus, Neisseria gonorrhoeae, Escherichia coli, Shigella and other sensitive bacteria as well as Chlamydia trachomatis, actinomycetes, Plasmodium, Toxoplasma gondii and Star Nocardia. The antibacterial activity of this product is similar as that of sulfasuccinamide. But in recent years, there are increased reports regarding the bacterial resistance to this product, especially in Streptococcus, Neisseria and Enterobacteriaceae. Sulfa-class belongs to broad-spectrum antibacterial agents. The molecular structure of sulfadiazine is similar as that of the amino benzoic acid (PABA), and can compete with PABA for acting on the dihydrofolate synthetase inside bacterial cells, thereby preventing the biosynthesis of folic acid (essential for bacteria) using PABA as the raw material and further reducing the amount of metabolically active folate, which is a indispensible material for bacterial synthesis of purines, thymidine and deoxyribonucleic acid (DNA) and thereby inhibiting the growth and reproduction of bacteria.
Pharmacokinetics
This product can be easily absorbed after oral administration (more than 70% of the administrated drug can be absorbed), but with the absorption rate being relative slow. After a single oral dose of 2g, the plasma concentration reaches peak after 3~6 hours with the peak of free plasma concentration being about 30~60μg/ml. After drug absorption, it widely distributed in body tissue and pleural fluid, peritoneal fluid, synovial fluid, aqueous humor, saliva, sweat, urine and bile. The drug is easy to penetrate through the blood-brain barrier as well as being able to enter into the breast milk and penetrate through the placental barrier. When there is no meningeal inflammation, cerebrospinal fluid drug concentration is about 50% of the plasma concentration. While the value can be 50% to 80% when there is meningeal inflammation.
The drug has a low plasma protein binding rate which is around 38% to 48%. The elimination life for patients of normal renal function is about 10 hours while it can be as long as 34 hours for patients with kidney failure. Sulfadiazine drug is mainly deactivated in the liver through acetylation metabolism, followed by deactivation upon binding to the glucuronide in the liver. The drug is primarily excreted through glomerular filtration. Within 48 to 72 hours after administration of the drug, around 60% to 85% of administrated drug is excreted form urine. In addition, there is still a small amount of drugs being able to be discharged through feces, milk, and bile. Hemodialysis can partially clear the drug. However, peritoneal dialysis can’t effectively remove the drugs.
Pharmacokinetics
Oral absorption： Very good
Cmax 3 g oral： c. 50 mg/L after 3–4 h
Plasma half-life ：7–12 h
Volume of distribution： 0.36 L/kg
Plasma protein binding： c. 40%
Absorption and distribution
Adequate blood concentrations are easily achieved and
maintained after oral administration. It is well distributed
and penetrates in therapeutic concentrations into
the CSF, but because of resistance it is no longer the
drug of choice in meningitis. It crosses the placenta and
enters breast milk to achieve concentrations around 20%
of plasma levels.
Metabolism and excretion
Sulfadiazine is subject to acetylation in the liver. The acetyl
derivative lacks antibacterial activity and is excreted more
slowly (half-life 8–18 h). Parent compound and metabolite
are both excreted mainly by glomerular filtration.
Indications
Sulfa drugs belong to broad-spectrum antibiotic. However, because of the resistance of many current clinical common pathogens to this class of drugs, it is only used for treating the infection caused by sensitive bacteria and other kinds of susceptible pathogens.
Sulfadiazine (not including the FDC of this drug together with trimethoprim) has its main indications as follows:
1. Used for prevention and treating the meningococcal meningitis caused by sensitive Meningococcal.
2. When being used in combination with trimethoprim, it can be used for treating the otitis media and other kinds of soft tissue infection caused sensitive Haemophilus influenzae, Streptococcus pneumoniae and other kinds of Streptococcus.
3. Used for treating disease related to star nocardia.
4. Used as the adjuvant drug assisting in the treatment of chloroquine-resistant falciparum malaria.
5. Used as the secondary-choice drug for treatment of Chlamydia trachomatis-induced urethritis and cervicitis.
6. Used as the secondary-choice drug for treatment of neonatal inclusion conjunctivitis caused by Chlamydia trachomatis.
Side effects
1. it can cause kidney damage. This product has a low acetylation ratio. This product and its acetylated compound has a low solubility in the urine and is easily subject to crystal precipitation upon a acidic urine, doing harm to the renal tubular as well as the epithelial cells of other urinary tract and causing crystallization of urine, hematuria, proteinuria, and even urine retention or uremia in severe cases.
2. hematopoietic system reactions include neutropenia, acute hemolytic anemia, aplastic anemia, and thrombocytopenia purpura.
3. gastrointestinal reactions include nausea and vomiting. Occasionally: jaundice, liver and spleen. For newborns, premature children, it can cause jaundice, and even kernicterus.
4. urinary system damage: As the prototype of sulfonamides and acesulfame are primarily subject to renal excretion and thus have higher concentrations in the urine. Upon acidic urine, its solubility decreases and can be crystallized and precipitated in renal tubules, renal pelvis, ureter or bladder, causing crystallization of urine, hematuria, proteinuria, dysuria, oliguria and even urine retention.
5. allergic reactions: commonly include rash, drug fever and even exfoliative dermatitis, erythema multiforme exudativum in severe cases. This often occurs during the 7 to 10 days after the medication. Photosensitive dermatitis has also been reported.
Side effects
In addition to side effects common to the group, sulfadiazine
inhibits the metabolism of phenytoin. The risk of crystalluria
can be reduced by high fluid intake and alkalization of
the urine.
Originator
Sulfadiazine,Lederle,US ,1941
Manufacturing Process
5.4 parts of 2-amino-pyrimidine were covered with 15 parts of anhydrous
pyridine. The reaction mixture was treated with 14 parts of pnitrobenzenesulfonyl
chloride and the whole heated briefly on the steam bath
and let stand 45 minutes at room temperature. To the reaction mixture were
added 80 parts of hot alcohol and the precipitate was filtered off and washed
with water. The solid was dissolved in dilute caustic solution and the solution
was filtered, cooled and acidified. The 2-(p-nitrobenzenesulfonamido)-
pyrimidine precipitated and was collected.The crude 2-(p-nitrobenzenesulfonamido)-pyrimidine from the preceding step
was suspended in 130 parts alcohol and 1.5 parts of concentrated hydrochloric
acid were added. The suspension was then heated to reflux and 30 parts of
iron powder were added with mechanical stirring. The mixture was refluxed
and stirred for 24 hours with occasional addition of concentrated hydrochloric
acid. The reaction mixture was then made slightly basic and filtered hot and
the residues were extracted with several portions of boiling alcohol. The filtrate and wash solutions were combined and evaporated. The 2-
(sulfanilamido)-pyrimidine was recrystallized from boiling water with
decolorizing charcoal added, according to US Patent 2,410,793.
Therapeutic Function
Antibacterial
Antimicrobial activity
Sulfadiazine is somewhat more active than other sulphonamides.
Pharmaceutical Applications
Sulfadiazine is almost insoluble in water and unstable on
exposure to light. It is administered orally or, as the sodium
salt, by intravenous injection. It is a component of several
multi-ingredient preparations. Its low solubility in urine led
to its general replacement by other compounds. The intravenous
solution is highly alkaline and should not be given by
any other route.
Biochem/physiol Actions
Sulfadiazine is a sulfonamide antibiotic that blocks the synthesis of dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase. Sulfadiazine is a competitive inhibitor of bacterial para-aminobenzoic acid (PABA), which is required for bacterial synthesis of folic acid. It is active against Gram positive bacteria, Gram negative bacteria and Chlamydia. Mode of resistance is via the alteration of dihydropteroate synthase or alternative pathway for folic acid synthesis.
Clinical Use
Urinary tract infection
Nocardiasis
Chancroid
Toxoplasmosis (in combination with pyrimethamine)
Meningococcal infections
Prophylaxis of rheumatic fever
Safety Profile
Poison by intravenous route. Moderately toxic by ingestion and intraperitoneal routes. Human systemic
effects by ingestion: hematuria, anuria, general anesthesia, gastrointestinal effects. Experimental teratogenic and reproductive effects. When heated to decomposition it emits very toxic fumes of NOx and SOx.
Synthesis
Sulfadiazine, N1
-2-pyrimidinylsulfanilamide (33.1.7), is synthesized by
reacting 4-acetylaminobenzenesulfonyl chloride with 2-aminopyrimidine, which gives an
acetanilide derivative (33.1.6). The subsequent hydrolysis of this product with a base leads
to the formation of the desired sulfadiazine.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: increased risk of crystalluria with
methenamine.
Anticoagulants: effect of coumarins enhanced;
metabolism of phenindione possibly inhibited.
Antiepileptics: antifolate effect and concentration of
phenytoin increased.
Antimalarials: increased risk of antifolate effect with
pyrimethamine.
Antipsychotics: avoid concomitant use with
clozapine (increased risk of agranulocytosis).
Ciclosporin: reduced levels of ciclosporin; increased
risk of nephrotoxicity.
Cytotoxics: increase risk of methotrexate toxicity
Metabolism
Sulfadiazine is metabolised in the liver to the acetylated
form, with elimination predominantly via the kidneys.
Urinary excretion of sulfadiazine and its acetyl derivative
is dependent on pH; when the urine is acidic about 30%
is excreted unchanged in both fast and slow acetylators,
whereas when the urine is alkaline about 75% is excreted
unchanged by slow acetylators.
Check Digit Verification of cas no
The CAS Registry Mumber 68-35-9 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 6 and 8 respectively; the second part has 2 digits, 3 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 68-35:
(4*6)+(3*8)+(2*3)+(1*5)=59
59 % 10 = 9
So 68-35-9 is a valid CAS Registry Number.
InChI:InChI=1/C10H10N4O2S/c11-8-2-4-9(5-3-8)17(15,16)14-10-12-6-1-7-13-10/h1-7H,11H2,(H-,12,13,14,15,16)
68-35-9Relevant articles and documents
Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27
Blavier, Jeremy,Charles, Ma?lle,Hanson, Julien,Kronenberger, Thales,Laschet, Céline,Müller, Christa E.,Pillaiyar, Thanigaimalai,Rosato, Francesca,Wozniak, Monika
, (2021/08/27)
GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called “Super-Conserved Receptors Expressed in the Brain” (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC50 6.34, Emax 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC50 6.85, Emax 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC50 6.04, Emax 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC50 5.99, Emax 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.
Synthesis method of sulfadiazine
-
Paragraph 0017-0032, (2021/03/13)
The invention discloses a synthesis method of sulfadiazine. The method is characterized in that 4-acetamidobenzenesulfonyl chloride and 2-aminopyrimidine are used as initial raw materials, powdered calcium carbonate is used as an acid-binding agent for condensation, and then hydrolysis and acidification are carried out to synthesize sulfadiazine. According to the invention, the defects that at present, anhydrous pyridine and other organic bases are adopted as acid-binding agents, wherein pyridine can seriously pollute the environment, is difficult to recover and causes great safety threats tothe body health of workers are overcome, and the method is easy and convenient to operate, environmentally friendly and suitable for industrial production.
Green synthesis method of sulfadiazine
-
Paragraph 0013; 0017; 0019; 0020-0027, (2020/07/02)
The invention discloses a green synthesis method of sulfadiazine. The green synthesis method comprises the following steps: (a) adding 3-alkoxy acrolein into a mixture of an organic alcohol solvent and sulfaguanidine, mixing, heating, and refluxing to perform cyclization reaction; (b) after the cyclization reaction is finished, cooling the mixed material to carry out solid-liquid separation to obtain a solid which is a sulfadiazine crude product, and recycling the obtained liquid; (c) adding the sulfadiazine crude product into liquid caustic soda, heating to carry out salifying reaction, thenstirring to decolorize, and filtering to obtain filtrate; and (d) dropwise adding a hydrochloric acid solution into the filtrate, carrying out acidification crystallization, separating crystals, and drying. Phosphorus-containing organic waste liquid is not generated, and the solid waste generation amount is low.
Synthesis of calix[4]azacrown substituted sulphonamides with antioxidant, acetylcholinesterase, butyrylcholinesterase, tyrosinase and carbonic anhydrase inhibitory action
Akocak, Suleyman,Boga, Mehmet,Kalay, Erbay,Lolak, Nebih,Nocentini, Alessio,Oguz, Mehmet,Supuran, Claudiu T.,Yilmaz, Mustafa
, p. 1215 - 1223 (2020/05/27)
A series of novel calix[4]azacrown substituted sulphonamide Schiff bases was synthesised by the reaction of calix[4]azacrown aldehydes with different substituted primary and secondary sulphonamides. The obtained novel compounds were investigated as inhibitors of six human (h) isoforms of carbonic anhydrases (CA, EC 4.2.1.1). Their antioxidant profile was assayed by various bioanalytical methods. The calix[4]azacrown substituted sulphonamide Schiff bases were also investigated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase enzymes, associated with several diseases such as Alzheimer, Parkinson, and pigmentation disorders. The new sulphonamides showed low to moderate inhibition against hCAs, AChE, BChE, and tyrosinase enzymes. However, some of them possessed relevant antioxidant activity, comparable with standard antioxidants used in the study.
3-PHOSPHOGLYCERATE DEHYDROGENASE INHIBITORS AND USES THEREOF
-
Paragraph 00244, (2017/10/06)
The present invention provides compounds, compositions thereof, and methods of using the same.
Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction
Wang, Lei,Li, Li,Zhou, Zi-Han,Jiang, Zheng-Yu,You, Qi-Dong,Xu, Xiao-Li
, p. 63 - 73 (2017/05/10)
Identification of novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 protein-protein interaction (PPI) could be an alternative strategy to achieve Hsp90 inhibition. In this paper, a series of small molecules targeting Hsp90-Cdc37 complex are addressed and characterized. The molecules' key characters are determined by utilizing a structure-based virtual screening workflow, derivatives synthesis, and biological evaluation. Structural optimization and structure–activity relationship (SAR) analysis were then carried out on the virtual hit of VS-8 with potent activity, which resulted in the discovery of compound 10 as a more potent regulator of Hsp90-Cdc37 interaction with a promising inhibitory effect (IC50?=?27?μM), a moderate binding capacity (KD?=?40?μM) and a preferable antiproliferative activity against several cancer lines including MCF-7, SKBR3 and A549?cell lines (IC50?=?26?μM, 15?μM and 38?μM respectively). All the data suggest that compound 10 exhibits moderate inhibitory effect on Hsp90-Cdc37 and could be regard as a first evidence of a non-natural compound targeting Hsp90-Cdc37 PPI.
Synthetic method for sulfadiazine
-
Paragraph 0015-0016, (2017/01/26)
The invention discloses a synthetic method for sulfadiazine. The sulfadiazine is synthesized with sulphaguanidine and malonaldehyde as raw materials. The synthetic method has the advantages of being mild in reaction condition, short in reaction time, high in conversion rate and beneficial to industrial production.
Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
Luci, Diane K.,Jameson, J. Brian,Yasgar, Adam,Diaz, Giovanni,Joshi, Netra,Kantz, Auric,Markham, Kate,Perry, Steve,Kuhn, Norine,Yeung, Jennifer,Kerns, Edward H.,Schultz, Lena,Holinstat, Michael,Nadler, Jerry L.,Taylor-Fishwick, David A.,Jadhav, Ajit,Simeonov, Anton,Holman, Theodore R.,Maloney, David J.
, p. 495 - 506 (2014/02/14)
Human lipoxygenases (LOXs) are a family of iron-containing enzymes which catalyze the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Our group has taken a particular interest in platelet-type 12-(S)-LOX (12-LOX) because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Herein, we report the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide-based scaffold. Top compounds, exemplified by 35 and 36, display nM potency against 12-LOX, excellent selectivity over related lipoxygenases and cyclooxygenases, and possess favorable ADME properties. In addition, both compounds inhibit PAR-4 induced aggregation and calcium mobilization in human platelets and reduce 12-HETE in β-cells.
Hydrolysis of Schiff bases promoted by UV light
Huang, Zhaohua,Wan, Decheng,Huang, Junlian
, p. 708 - 709 (2007/10/03)
The first hydrolysis of Schiff base under 365 nm UV light is reported. The reaction was affected markedly by the solvent used. It has been successfully applied to the synthesis of compound 2c which is a useful antitumor agent.
Process for formulating a synthetic drug for use in animal feed, and resulting formulation
-
, (2008/06/13)
A method of formulating a synthetic drug for use in animal feed, for the purpose of reducing carry-over of the synthetic drug to subsequent lots of animal feed in the feed mill.
