158089-76-0 Usage
Chemical Description
Sulfonamides are organic compounds containing a sulfonamide functional group.
Uses
1. Used in the Pharmaceutical Industry:
Sulfonamides are used as systemic antibacterial agents for treating various bacterial infections. They are grouped into short-lasting (sulfacytine, sulfadiazin, sulfamerazine, sulfametazine, sulfametizole, sulfisoxazole), moderate-lasting (sulfamethoxazole, sulfapyridine), and long-lasting (sulfamethoxypiridazine, sulfamter) drugs. However, long-lasting sulfonamides are no longer used independently due to the risk of hypersensitivity reactions.
2. Used in Ophthalmology:
Sulfonamides, such as sulfacetamide and sulfozoxazol, are used as ophthalmological drugs for treating bacterial eye infections.
3. Used in Gynecology:
Sulfonamides, including sulfabenzamide, sulfacetamide, sulfathiazole, and sulfizoxazol, are used for vaginal applications to treat bacterial infections in the female reproductive system.
4. Used in External Medicine:
Mafenid and silver sulfadiazine are examples of sulfonamides used for external applications, such as treating skin infections and burns.
5. Used in Intestinal Therapy:
Sulfasalazine and phthalylsulfathiazole are sulfonamides that act in the lumen of the intestines. They are poorly absorbed from the gastrointestinal tract and are used to treat conditions like inflammatory bowel disease.
6. Used in Chemical Synthesis:
2-(4-Methoxybenzyl)isothiazolidine 1,1-Dioxide (CAS# 158089-76-0) is a sulfonamide derivative used as a reagent in palladium-catalyzed α-arylation of sultams with aryl and heteroaryl iodides, which is an important reaction in the synthesis of various organic compounds.
Inhibitor of Nucleic Acid Synthesis
Sulfonamides act in the pathway of folic acid synthesis and thus act indirectly on DNA synthesis, since the reduced form of folic acid, tetrahydrofolic acid, serves as an essential co-factor in the synthesis of thymidylic acid.
Sulfonamides are analogs of p-aminobenzoic acid. They competitively inhibit dihydropteroate synthetase, the enzyme that condenses p-aminobenzoic acid with dihydropteroic acid in the early stages of folic acid synthesis. Most bacteria need to synthesize folic acid and cannot use exogenous sources of the vitamin. Mammalian cells, in contrast, require preformed folate and this is the basis of the selective action of sulfonamides. The antileprotic sulfone dapsone, and the antituberculosis drug p-aminosalicylic acid, act in a similar way; the basis for their restricted spectrum may reside in differences of affinity for variant forms of dihydropteroate synthetase in the bacteria against which they act.
Antimicrobial activity
Sulfonamides exhibit broad-spectrum activity against common Gram-positive and Gram-negative pathogens, although the potency against many bacteria within the spectrum is modest by present standards. Meningococci are generally much more susceptible than gonococci. Other organisms commonly susceptible include Bordetella pertussis, Yersinia pestis, Actinomyces spp., Nocardia spp., Bacillus anthracis, Corynebacterium diphtheriae, Legionella pneumophila, Brucella spp. and several important causes of sexually transmitted diseases (Chlamydia trachomatis, Haemophilus ducreyi and Calymmatobacterium granulomatis). Activity against anaerobes is generally poor. Pseudomonas aeruginosa is usually resistant, as are Leptospira, Treponema and Borrelia spp., rickettsiae, Coxiella burnetii and mycoplasmas. Mycobacteria are resistant, although the related sulfone, dapsone, exhibits good activity against M. leprae and para-aminosalicylic acid, which is structurally similar, was formerly widely used in tuberculosis. Sulfonamides act synergistically with certain diaminopyrimidines against many bacteria and some protozoa, including plasmodia and Toxoplasma gondii.In-vitro tests are markedly influenced by the composition of the culture medium and the size of the inoculum. The
different derivatives vary somewhat in antibacterial activity . Among those that are still fairly widely available as antibacterial agents, sulfadimidine shows comparatively low activity, whereas sulfadiazine, sulfisoxazole (sulphafurazole) and sulfamethoxazole, the sulfonamide commonly combined with trimethoprim , are relatively more active.
Acquired resistance
Resistance is now widespread and there is complete crossresistance among sulfonamides. Plasmid-mediated resistance in all enterobacteria is common. Resistance is found in 25–40% of strains of Escherichia coli and other enterobacteria infecting the urinary tract. Many strains of meningococci and H. ducreyi are now resistant.
Pharmaceutical Applications
The original sulphonamide, sulphanilamide, is the active principle of Prontosil, which holds a special place in medicine as the first agent to exhibit broad-spectrum activity against systemic bacterial disease . Within a few years of the introduction of Prontosil, numerous sulfonamide derivatives were synthesized. Advances included increased antibacterial potency, decreased toxicity, and the introduction of compounds with special properties such as high or low solubility and prolonged duration of action. Most have since been discarded, as safer and more active antibacterial agents have overtaken them, but a few are still in use for particular purposes, often in combination with diaminopyrimidines . Some survive in topical preparations, often in multi-ingredient formulations. Discussion here is limited to the most important sulfonamides that are still widely available; a short description is included of some of the many other compounds that are of more restricted availability.
Mechanism of action
The sulfonamides are bacteriostatic when administered to humans in achievable doses. They inhibit the
enzyme dihydropteroate synthase, an important enzyme needed for the biosynthesis of folic acid derivatives
and, ultimately, the thymidine required for DNA. They do this by competing at the active site with p-aminobenzoic acid (PABA), a normal structural component of folic acid derivatives.
Pharmacokinetics
Most sulfonamides are well absorbed after oral administration,
reaching a peak concentration in the blood of 50–100 mg/L
2–4 h after a dose of 2 g. After absorption, the behavior of the
individual compounds varies widely, depending on the extent
of protein-binding and metabolization. The main metabolic
pathway is conjugation by acetylation in the liver, although
glucuronidation and oxidation also occur. Sulfonamide acetylation
shows a bimodal distribution in the population, rapid
and slow inactivators corresponding with rapid and slow inactivators
of isoniazid. The conjugates are inactive antibacterially
and the low solubility of the acetyl conjugates of
some of the earlier compounds may give rise to renal toxicity.
A proportion, varying considerably with different compounds,
is contained in the red cells, some is free in the
plasma and some is bound to plasma albumin. Protein binding
varies widely, the highest levels being seen with long-
acting sulfonamides
such as sulfadoxine. Sulfonamides can be displaced
from their protein binding sites by a variety of compounds,
the most important clinically being oral anticoagulant
drugs. Administration of these compounds with sulfonamides
potentiates the anticoagulant effect and produces higher concentrations
of diffusible sulfonamide. Competition for plasma
albumin binding sites causes sulfonamides to displace albumin-
bound bilirubin.
Sulfonamides are distributed throughout the body tissues.
Access to the cerebrospinal fluid (CSF) is normally limited to
the unbound drug, but with increasing capillary permeability
and the passage of protein into the CSF in inflammation,
protein-bound sulfonamide enters and the total concentration
of drug in the CSF rises. The concentration of shortacting
sulfonamides in CSF varies between 30% and 80% of
the corresponding plasma concentration. Sulfonamides also
enter other body fluids, including the eye. They pass readily
through the placenta into the fetal circulation and also reach
the infant via the breast milk.
Sulfonamides are excreted mainly in the urine, the free
drug and its conjugates being frequently excreted at different
rates and by different mechanisms. Excretion is partly
by glomerular filtration and partly by tubular secretion, during
which some of the drug is reabsorbed. Substances with
high clearances (e.g. sulfisoxazole) are rapidly eliminated
from the plasma and achieve high concentrations in the urine.
Substances with low clearances are slowly excreted, plasma
levels are maintained for long periods, and low concentrations
appear in the urine. If renal function is impaired, excretion
may be delayed still further and therapeutic levels may persist
for considerably longer： if the drugs are given repeatedly, high
and possibly toxic levels may develop. Less than 1% of the
dose of most sulfonamides is excreted in the bile, but the proportion
is 2.4–6.3% for the long-acting compounds.
Clinical Use
Sulfonamides were formerly much used, alone or in combination
with trimethoprim, for the treatment of urinary
tract infection, but are no longer recommended because of
potential adverse reactions. Use in the treatment of respiratory
infections is now confined to a few special problems,
notably nocardiasis (and also for cerebral nocardiasis) and,
in combination with trimethoprim, in the prevention and
treatment of Pneumocystis jirovecii pneumonia. The value of
sulfonamides in the prophylaxis and treatment of meningococcal
infection is now greatly reduced by bacterial resistance.
Sulfonamides are sometimes used for chlamydial
infections and chancroid but are unreliable. Some formulations
are used topically in eye infections and bacterial vaginosis.
Combined preparations with pyrimethamine are used
in the treatment of drug-resistant malaria and for toxoplasmosis.
Side effects
With proper attention to dosage, side effects are relatively
uncommon, but some are serious. Crystals of less soluble
compounds, such as sulfadiazine, or of less soluble conjugates
may deposit in the urine and block the renal tubules or
the upper orifice of the ureter. Hematuria is a common early
sign. However, renal damage during sulfonamide therapy is
often due to a hypersensitivity reaction, rather than to tubular
blockage, with changes of tubular necrosis or vasculitis. Renal
failure has been recorded in several patients after treatment
with sulfamethoxazole, as a component of co-trimoxazole.
Hypersensitivity reactions usually occur as moderate
fever with a rash on about the ninth day of a course of treatment.
Repetition after an interval elicits the reaction immediately.
Rashes are commonly erythematous, maculopapular
or urticarial, and recur if the drug is given again. Well documented,
but uncommon, is a severe serum-sickness-like
reaction with fever, urticarial rash, polyarthropathy and
eosinophilia. Eosinophilia may occur without other allergic
manifestations.
Stevens–Johnson syndrome is a rare but potentially fatal
complication (one estimate puts the risk at 1–2 cases per
10 million doses). The relative risks of different sulfonamides
are not known accurately, but there are many reports of this
complication following the use of long-acting sulfonamides.
The time of onset varies from 2 to 24 days, and sometimes
as long as 6 weeks after discontinuing the drug. Toxic epidermal
necrolysis (Lyell’s syndrome) has also been recorded after
administration of long-acting sulfonamides.
Drug fever without other features may occur. A special
problem of hypersensitivity to the sulfonamide component
of co-trimoxazole is its frequency in the treatment of AIDS. Sulfonamides are among the compounds reported to provoke
systemic lupus erythematosus. An intractable type of sensitization
may result from local applications.
In patients with inherited glucose-6-phosphate dehydrogenase
deficiency, intravascular hemolysis and hemoglobinuria
may occur. Hemolysis may also occur as part of a generalized
sensitivity reaction. Agranulocytosis, aplastic anemia and
thrombocytopenia have been occasionally reported, especially
with earlier sulfonamides. Liver injury is rare.
Interference with bilirubin transport in the fetus by sulfonamide
administered to the mother may increase the free
plasma bilirubin level and result in kernicterus. Many other
interactions arise as a result of competition for plasma albumin
binding sites. Those of greatest potential clinical importance
are increases in the actions of oral anticoagulants and
sulfonylureas (but not biguanides) and increased toxicity of
methotrexate.
Check Digit Verification of cas no
The CAS Registry Mumber 158089-76-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,8,0,8 and 9 respectively; the second part has 2 digits, 7 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 158089-76:
(8*1)+(7*5)+(6*8)+(5*0)+(4*8)+(3*9)+(2*7)+(1*6)=170
170 % 10 = 0
So 158089-76-0 is a valid CAS Registry Number.
158089-76-0Relevant academic research and scientific papers
PYRIMIDINYL-PYRIDYLOXY-NAPHTHYL COMPOUNDS AND METHODS OF TREATING IRE1-RELATED DISEASES AND DISORDERS
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Paragraph 0836; 0837, (2018/10/19)
Described herein are pyrimidinyl-pyridyloxy-naphthyl compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula (I) or (I') structure : or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula (I) or (I') compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.
