Sulfonamide: An introduction, classification, mechanism, SAR, with its adverse effect.



Sulfonamide is synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positive and gram-negative organisms. The simplest of sulfonamides is an organic sulfur compound chemically it is p-amino benzenesulfonamide. The antimicrobial compound having sulfonamide group (-SO2NH4) is called sulfonamides.

History of sulfonamide

Sulfonamide is the first successfully synthesized drug. In Germany, the famous scientist “Paul Ehrlich” (1854-1915) highlighted the relationship between selective stanning by dyes and their protozoal activity. This stimulated the study of azo dye as antibacterial also.

“Domagk” (1895-1964) collaborated and examined the activity of these dyes. He started the study of the bright red sulfamoyl azo dye, later named “Prontosil” in 1932. The dye was found to be active in curing streptococcal infections in mice, through it was inactive in vitro.

The patient who received prontosil was Hildegarde Domagk, the daughter of its discoverer who was suffering from a severe streptococcal infection. Institute in Paris was also able to conclude that the azo linkage in prontosil is metabolically broken and the active entity sulfonamide is generated.



Inactive in vitro but active in vivo against streptococcal as well as styploccous.

IUPAC Name– 4-amino benzene sulfonamide

Molecular Formula- C6H8N2O2S

Molecular weight- 172.21 g/mol

Structure of sulfonamides


Classification of sulfonamide-

Short-acting (4-8 hours)- Sulfadiazine

Intermediate-acting (8-12 hours)- Sulfamethoxazole

Long-acting (7 days)- Sulfadoxine, Sulfamethopyrazine.

Special purpose sulfonamide- Sulfacetamide sod., Sulfasalazine, Mafenide, Silver sulfadiazine.


•          Cotrimoxazole- Trimethoprim + Sulfamethoxazole (in 1:5)

•          Cotrimazine- Trimethoprim + sulfadiazine (in 1:5)

You may read- anti microbial agents.

Mechanism of action of sulfonamide–

Para-aminobenzoic acid (PABA) is a precursor of folic acid which is essential for growth and multiplication of many bacteria. Sulfonamides, being structural analogs of PABA, competitively inhibit folate synthetase enzyme and prevent the formation of folic acid, thereby producing the bacteriostatic effect. Folic acid not formed.

Mechanism-of -Action-of-Sulfonamides

Folic acid required for the synthesis of-



-Amino acids

Sulfonamides competitively inhibit the union of PABA, with pteridine reduce to form dihydro pteroic acid which conjugates with glutamic acid to produce DHFA (Dihydro folic acid). Sulfonamide also being chemically similar to PABA, and the sulfonamide may itself get inclusive to form an altered folate which is metabolically harmful.

Folic acid is essential for bacterial growth. Humans do not synthesize folic acid but acquired it through diet. The sulfonamides selectively inhibit microbial growth by inhibiting folic acid synthesis.

Spectrum activity of sulfonamides –

These are primarily bacteriostatic and active against many gram-positive and gram-negative bacteria and used primarily in the urinary tract and Nocardia infections. The pattern of sensitivity among microorganisms have changed from time to time and place to place. These have a vitro activity against gram-positive and gram-negative organisms. The anaerobic type of bacteria is not susceptible.

Bacterial Resistance of sulfonamides –

Most of the bacteria are capable of developing resistance to sulfonamides. Main in these are gonococci, pneumococci, Staph. aureus, meningococci, E. coli, Shigella and some Strep. pyogenes, Strep. viridans and anaerobes.

The resistant mutants are may produce an increased amount of PABA and their folate synthase enzyme has low cohesion for sulfonamides. They adopt an alternative pathway in folate metabolism.

Resistance developed in vivo is quite stronger. Sensitivity patterns have changed depending on the extent of use. When an organism is resistant to one sulfonamide, it is resistant to them of all. No cross-resistance between sulfonamides and other antimicrobial agents has been noted. The development of resistance has markedly limited the clinical usefulness of this class of compounds.

Bacteria that obtain folate from their environment are naturally resistant to sulfa drugs. Acquired bacterial resistance for the sulfa drugs can arise from plasmid transfers or random mutations.         

Pharma co-kinetics of sulfonamides-

Absorption- After oral absorption, most sulfa drugs are well absorbed. An exception is sulfasalazine. It is not absorbed when administered orally or as a suppository and, therefore, is reserved for the treatment of chronic inflammatory bowel disease.

Intravenous sulfonamides are normally reserved for those patients who are unable to take oral preparations. Because of the risk of sensitization, sulfonamide drugs are not usually applied topically use.

However, in the case of burns units, the creams of silver sulfadiazine or mafenide acetate have been effective in reducing burn-associated sepsis. Because they prevent the colonization of bacteria.

Note– Silver sulfadiazine is as primary because mafenide produces pain when applied at the application and its absorption maybe contribute to the acid-base disorder.

Distribution- Sulfa drugs are bound to serum albumin in the circulation, where the extent of binding depends on the ionization constant (pKa) of the drugs. In general, the smaller the pKa value, the greater the binding. Sulfa drug distributes throughout the bodily fluids and penetrate well into cerebrospinal fluids even in the absence of inflammation. They can also pass the placental barrier and enter fetal tissues.

Metabolism– The sulfa drug is acetylated in the liver and conjugated primarily in it. The acetylated produced is develop of antimicrobial activity but remains the toxic potential to precipitate at neutral or acidic pH. This causes crystalluria (stone formation) therefore, potential damage to the kidney.

Excretion- sulfa drugs are eliminated by glomerular filtration and secretion and requires dose adjustment for renal dysfunction Sulfonamides may be eliminated in breast milk.

Structural activity relationship (SAR) of sulfonamides-


-Free -NH2 group is essential for antibacterial activity as ④, but in the case of diuretics (sulfonamides as diuretics) this group is no free.

-If H atom of ① nitrogen is replaced by Ar/HCL/open-chain then the activity is increasing. Example- Sulfacetamide, Sulfa guanidine.

-Any substitution on the aromatic ring decreases the activity of reaction.

 -If the H atom of ① nitrogen group is replaced by heterocyclic ring then most active -sulfonamides formed. This heterocyclic ring maybe five or six-membered or maybe one hetero or two heteroatoms.

-The substitution of the electron-donating group on the pyrimidine ring enhances the activity. Example- Sulfadimidine, Sulfamethoxydiazine, sulfadimethoxine, sulfadoxine.

Synthesis of sulfonamide-


Sulfonamide related drugs-

  • Sulfadiazine– Sulfadiazine is a prototype of sulfonamide for general purpose that is rapidly absorbed orally and rapidly excreted in the urine, plasma protein bending is 50%, and it is 20-40% acetylated. The acetylated derivate is less soluble in urine, crystalluria is likely, it has good penetrability in the brain and CSF, was the preferred compound for meningitis.

Dissolve the sample in water and hydrochloric acid. Titrate the mixture with sodium nitrite and determine the endpoint potentiometrically.

Properties and uses- Sulfadiazine is a white or yellowish-white or pinkish-white crystalline powder or crystals, insoluble in water, slightly soluble in acetone, very slightly soluble in alcohol. It is soluble in solutions of alkali hydroxides and in dilute mineral acids also.

It is used in the treatment of carcinoid and rheumatic fever.

Dose- 0.5 gm QID to 2 gm TDS

  • Sulfamethoxazole- Sulfamethoxazole has its slower oral absorption and urinary exertion resulting in an intermediate duration of action with t1/2 in adults average 10 hours. It is the preferred compound for combining with trimethoprim because the t1/2 of both is relatively insoluble- crystalluria can occur.

Properties and uses- Sulfamethoxazole is a white or almost white crystalline powder, practically insoluble in water, soluble in acetone, sparingly soluble in ethanol, dissolves in dilute solutions of sodium hydroxide and in dilute acids. Used in the treatment of bacterial infections.

Dissolve the sample in dilute hydrochloric acid and add potassium bromide. Cool in ice and titrate against 0.1N Sodium nitrate. Determine the end-point electrometrically.

Dose- 1mg BD for two days, then 0.5g BD

  • Sulfadoxine, sulfamethopyrazine- These are ultra-long acting compounds, long-lasting >one week because of high plasma protein binding and sloe renal excretion with t1/2 5-9 days. They attain low plasma concentration (of free from) and are not suitable for the treatment of acute pyogenic infections, but are used in combination with pyrimethamine in the treatment of malaria (especially chloroquine-resistant P. falciparum), Pneumocystis jiroveci pneumonia in AIDs patients and in toxoplasmosis. Because they have caused serious cutaneous reaction, large scale use of the combination of prophylaxis of malaria is not recommended.
  • Sulfacetamide sod. – It is a highly soluble compound yielding natural solution which is only mildly irritating to the eye in the concentration up to 30. It is typically used for ocular infections because of susceptible bacteria and chlamydia that including ophthalmia neonatorum caused by Ch. Oculogenitalis.

 It attains a high concentration in the anterior segment and aqueous humor after tropical installation. The incidence of sensitivity reaction with ocular use of sulfacetamide sod. Has been low, but it must promptly when they occur.

Dissolve the sample in water and hydrochloric acid. Titrate with sodium nitrite and determine the endpoint potentiometrically.

Properties and uses- It exists as a white crystalline powder, bitter in taste. Used in the treatment of bacterial infections of the urinary tract.

Dose- 10%, 20%, 30% eye drops, 6% eye ointment.

  • Mafenide- It is not a typical sulfonamide, because a -CH2- bride separates the benzene ring and the amino group. It is used only tropically- inhibits a verity of gram-positive and gram-negative bacteria. In resistance to typical sulfonamides that it is active in the presence of pus and against Pseudomonas. Clostridia which are not inhibited by typical sulfonamides. It has been mainly employed fir burn dressing to prevent infection, but not treat already infected cases.

The biggest limitation is that mafenide produces a burning sensation and severe pain when applied to the raw surface. It is rapidly absorbed from the raw surface; metabolite is the carbonic anhydrous inhibitor. Accordingly, they alkalinize the urine, which can cause acidosis and hyperventilation. Mafenide must not be applied over large areas. Allergic reaction, particularly rashes also occur.

Use- It is used in the treatment and cure of gas gangrene. It is also effective against Clostridium welchii on topical application.

Dose– 1% cream for surface application

  • Silver Sulfadiazine- It is used as tropically as 1% cream and it is active against a large number of bacteria and fungi, even those resistant to another sulfonamide, for example- Pseudomonas. It slowly releases silver ions which appears to be largely responsible for the antimicrobial action. It is considered to be one of the most effective drugs for preventing infection of burnt surface and chronic ulcer and is well tolerated. However, it is not good for treating established infection.

Properties and uses- It is an effective topical antimicrobial agent, especially, against Pseudomonas species and it finds extensive use in burn therapy.

Dose- 1% cream

  • Sulfasalazine- It undergoes reductive metabolism by gut bacteria, converting the drug into sulfa pyridine and 5-amino salicylic acid, which are active components. Dissolve and dilute the sample in 0.1 M sodium hydroxide and add 0.1 M acetic acid and measure the absorbance at the maxima of 359 nm using an ultraviolet spectrophotometer.

Properties and uses- Sulfasalazine is a bright yellow or brownish-yellow fine powder, very slightly soluble in alcohol, practically insoluble in methylene chloride. It dissolves in dilute solutions of alkali hydroxides.

These are used for the treatment of ulcerative colitis.

Physical properties of sulfonamide- 

-These are found in white powder and granules in solid crystal form.

-The melting point is 165.5˚C.

-These are soluble in glycerol, propylene glycol, hydrochloric acid and insoluble in chloroform, ether, benzene, and petroleum ether, slightly soluble in water.

-PH of 0.5% aqueous solution is 5.8-6.1 and converted in natural to litmus.

-These are sensitive in light.

– pKa value is 10.6 at 20˚C and dissociation constant is 10.58.

Method of manufacturing-

These are the action of ammonia on acetyl sulfanilyl chloride, that is followed by hydrolyzing. The resulting N- acetyl sulfanilamide to sulfonamide by boiling with dilute hydrochloric acid or alkali.

Adverse effects of sulfonamides-

-Nausea, vomiting, and diarrhea, which ARE USUALLY MILD.

-In crystalluria, nephrotoxicity may develop as a result of it. Adequate hydration and alkalization of urine can prevent the problem by reducing the concentration of drug and promoting its ionization.

-Hypersensitivity reaction may occur as rashes, angioedema or Stevens-Johnson (due to a long-acting agent). When a patient’s previous reports show sulfa allergies, it is paramount to acquire a description of the reaction to direct appropriate therapy.

-Hematopoietic disturbance can occur in glucose-6-phosphate (G6PD) deficiency with a high dose of sulfonamide. Granulocytopenia and thrombocytopenia can also occur. Fatel reactions have been reported from associated agranulocytosis, aplastic anemia, and other blood dyscrasias.

-Kernicterus is the disorder that may occur in newborns because sulfonamide drugs are displace bilirubin from mandatory sites on serum albumin. The bilirubin is then free to pass into the CNS because the blood-brain barrier is not fully developed.

-Transient potentiation of the anticoagulant effect of warfarin results from the displacement from binding sites of serum albumin. The level of serum methotrexate may also rise through its displacement.

-Due to the contradiction of kernicterus, sulfa drugs should be avoided in newborns and infants led than 2 months of age, as well as in pregnant women also. Sulfonamides should not give those receiving methenamine since they can crystalize in the presence of formaldehyde produced by this agent.

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