Sulfonamides Chemical Properties

Melting point:

>47°C (dec.)

Boiling point:

397.0±44.0 °C(Predicted)

Density 

1.279±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

Acetonitrile (Slightly), Chloroform (Slightly)

form 

Solid

pka

-4.81±0.20(Predicted)

color 

Light Orange to Orange

CAS DataBase Reference

158089-76-0

Sulfonamides Usage And Synthesis

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.

Description

The antibacterial properties of the sulfonamides were discovered in the mid-1930s following an incorrect hypothesis but after observing the results carefully and drawing correct conclusions. Prontosil rubrum, a red dye, was one of a series of dyes examined by Gerhard Domagk of Bayer of Germany in the belief that it might be taken up selectively by certain pathogenic bacteria and not by human cells, in a manner analogous to the way in which the Gram stain works, and, therefore, serve as a selective poison to kill these cells. The dye, indeed, proved to be active in vivo against streptococcal infections in mice. Curiously, it was not active in vitro.

Uses

Sulfanilamide drugs do not currently have a clear classification. However, they are grouped as systemic (absorptive action), and local. They are subdivided into short-lasting (sulfacytine, sulfadiazin, sulfamerazine, sulfametazine, sulfametizole, sulfisoxazole); moderate-lasting (sulfamethoxazole, sulfapyridine); and long-lasting (sulfamethoxypiridazine, sulfamter), which, however, are no longer used as independent drugs because of extremely rare, yet nonetheless occurring, hypersensitivity reactions. Drugs for local use include those for ophthalmological use (sulfacetamide, sulfozoxazol); vaginal use (sulfabenzamide, sulfacetamide, sulfathiazole, sulfizoxazol); and external use (maphenid, silver sulfadiazine). Finally, this group includes sulfasalazine and phthalylsulfathiazole, a drug that acts in the lumen of the intestines, but which is poorly absorbed from the gastrointestinal tract.

Uses

2-(4-Methoxybenzyl)isothiazolidine 1,1-Dioxide (cas# 158089-76-0) is a useful a reagent in palladium-catalyzed α-arylation of sultams with aryl and heteroaryl iodides.

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.

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