Sulphonamides - Medicinal Chemistry III B. Pharma 6th Semester


Historical Development

       First effective chemotherapeutic agents that could be used systemically for the cure of bacterial infections in humans

       Led to a sharp decline in the morbidity and mortality of infectious diseases

       Antibacterial properties of the sulfonamides were discovered in the mid-1930s

       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

       Analogous to the way that the Gram stain works, and thus serve as a selective poison to kill these cells

       Dye, indeed, proved active in vivo against streptococcal infections in mice

       Curiously, it was not active in vitro

       Trefouel and others soon showed that the urine of prontosil rubrum–treated animals was bioactive in vitro

       Fractionation led to identification of the active substance as p -aminobenzenesulfonic acid amide (sulfanilamide)

       Colorless cleavage product formed by reductive liver metabolism

       Today, we would call prontosil rubrum a prodrug

       Discovery of sulfanilamide’s in vivo antibacterial properties ushered in the modern anti-infective era, and Domagk was awarded a Nobel Prize for medicine in 1939

       Following the dramatic success of Prontosil, a host of sulfanilamide derivatives was synthesized and tested

       By 1948, more than 4,500 compounds had been evaluated

       Of these, only about two dozen have been used in clinical practice

       Late 1940s, broader experience with sulfonamides had begun to demonstrate toxicity in some patients, and resistance problems limited their use throughout world

       Penicillins were excellent alternatives to the sulfonamides, and replaced the latter in antimicrobial chemotherapy

Nomenclature of the Sulfonamides

       Sulfonamide is a generic term that denotes three different cases:

       1. Antibacterials that are aniline-substituted sulfonamides (the “sulfanilamides”)

       2. Prodrugs that react to generate active sulfanilamides (i.e., sulfasalazine)

       3. Nonaniline sulfonamides (i.e., mafenide acetate)

Mechanism of Action of the Sulfonamides

       Inhibit the enzyme dihydropteroate synthase, an important enzyme needed for the biosynthesis of folic acid derivatives and, ultimately, the thymidine required for DNA

       By competing at the active site with p -aminobenzoic acid (PABA), a normal structural component of folic acid derivatives

       Sulfonamides may also be classified as antimetabolites

       Antimicrobial efficacy of sulfonamides can be reversed by adding significant quantities of PABA into the diet

       Folates are essential intermediates for the biosynthesis of thymidine without which bacteria cannot multiply

       Inhibition of the dihydropteroate synthase is bacteriostatic

       Humans are unable to synthesize folates from component parts, lacking the necessary enzymes (including dihydropteroate synthase), and folic acid is supplied to humans in our diet

       Sulfonamides consequently have no similarly lethal effect on human cell growth, and the basis for the selective toxicity of sulfonamides is clear

       Trimethoprim is an inhibitor of dihydrofolate reductase, which is necessary to convert dihydrofolic acid (FAH2) into tetrahydrofolic acid (FAH4) in bacteria

       Doesn’t have high affinity for the malaria protozoan’s folate reductase, but it does have a high affinity for bacterial folate reductase

Spectrum of Action of the Sulfonamides

       Inhibit Gram-positive and Gram-negative bacteria, nocardia, Chlamydia trachomatis, and some protozoa

       Some enteric bacteria, such as E. coli and Klebsiella, Salmonella, Shigella, and Enterobacter spp. are inhibited

       Sulfonamides are infrequently used as single agents

       Many strains of once-susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci are now resistant

       However, useful in some urinary tract infections because of their high excretion fraction through the kidneys

Ionization of Sulfonamides

       Sulfonamide group, SO2NH2, tends to gain stability if it loses a proton, because the resulting negative charge is resonance stabilized

       Since the proton-donating form of the functional group is not charged, we can characterize it as an HA acid, along with carboxyl groups, phenols, and thiols

       Loss of a proton can be associated with a pKa

       pKa of sulfisoxazole (pKa 5.0) indicates that the sulfonamide is a slightly weaker acid than acetic acid (pKa 4.8)

Crystalluria and the pKa

       Cause severe renal damage by crystallizing in the kidneys

       Sulfanilamides and their metabolites are excreted almost entirely in the urine

       pKa of the sulfonamido group of sulfanilamide is 10.4

       Urine is usually about pH 6 (and potentially lower during bacterial infections)

       Essentially all of the sulfanilamide is in the relatively insoluble, non-ionized form in the kidneys

       Sulfanilamide coming out of solution in the urine and kidneys causes crystalluria

       Recommended to drink increased quantities of water to avoid crystalluria

       Or bicarbonate was administered before the initial dose of sulfanilamide and then prior to each successive dose

Classification of Sulphonamides

       Broadly on the basis of their site of action

       1. For General Infections- employed against the streptococcal, meningococcal, gonococcal, staphylococcal and pneumococcal infections

       Examples : sulfanilamide, sulfapyridine, sulfathiazole, sulfadiazine, sulfamerazine, sulfadimidine, sufalene, sulfamethizole etc.

       2. For Urinary Infections- have been used extensively for the prevention and cure of urinary tract infections over the past few decades

       Examples : sulfacetamide, sulfafurazole, sulfisoxazole acetyl, sulfacitine, etc.

       3. For Intestinal Infections- not readily absorbed from the gastrointestinal tract. Enables their application for intestinal infections and also for pre-operative preparation of the bowel for surgery

       Examples : sulfaguanidine, phthalylsulfathiazole, succinylsulfathiazole, phthalylsulfacetamide, salazosulfapyridine, etc.

       4. For Local Infection- used exclusively for certain local applications

       Examples : Sulfacetamide sodium, Mafenide, etc.

       5. Sulphonamide Related Compounds- essentially differ from the basic sulphonamide nucleus, but do possess anti-bacterial properties

       Examples : Nitrosulfathiazole, dapsone, silver sulfadiazine, etc.

Structure–Activity Relationships

       Aniline (N4) amino group is very important for activity

       Any modification of it other than to make prodrugs results in a loss of activity

       N4-acetylated metabolites of sulfonamide are inactive

       Maximal activity seems to be exhibited by sulfonamides between pKa 6.6 and 7.4

       Need for enough non-ionized (i.e., more lipid soluble) drug to be present at physiological pH to be able to pass through bacterial cell walls

       Strongly electron-withdrawing character of the aromatic SO2 group makes the nitrogen atom to which it is directly attached partially electropositive

       This increases the acidity of the hydrogen atoms attached to the nitrogen so that this functional group is slightly acidic (pKa = 10.4)

       It was soon found that replacement of one of the NH2 hydrogens by an electron-withdrawing heteroaromatic ring enhanced the acidity of the remaining hydrogen and dramatically enhanced potency

       Also dramatically increased the water solubility under physiologic conditions

Therapeutic Applications

       Often used in combination with other agents

       Sulfamethoxazole in combination with trimethoprim is more commonly seen

       Sulfadiazine in the form of its silver salt is used topically for treatment of burns and is effective against a range of bacteria and fungus

       Sulfacetamide is used ophthalmically for treatment of eye infections caused by susceptible organisms

       Sulfasalazine- prodrug- not absorbed in gut- so delivered to distal bowel- undergoes reductive metabolism by gut bacteria converting the drug into sulfapyridine and 5-aminosalicyclic acid

       Used to treat ulcerative colitis and Crohn disease


       White crystalline powder soluble 1:2,000 in water

       Plasma half-life is 2.5 hours


       White, odorless, slightly bitter, crystalline powder

       Its pKa is 5.0

       At pH 6, this sulfonamide has a water solubility of 350 mg in 100 mL

       Used for infections involving sulfonamide-sensitive bacteria

       Effective in the treatment of Gram-negative urinary infections


       Have greater water solubility than sulfamerazine and sulfadiazine

       Its pKa is 7.2

       More soluble in acid urine- kidney damage is decreased


       White crystalline powder, soluble in water (1:62.5 at 37°C) and in alcohol

       It is very soluble in hot water, and its water solution is acidic

       It has a pKa of 5.4


       White, crystalline, odorless, and tasteless substance

       It is stable in air but slowly darkens on exposure to light

       It is soluble in water (1:3,500), in alcohol (1:440), and in acetone (1:65) at 25°C

       It is freely soluble in dilute mineral acids and aqueous solutions of sodium and potassium hydroxide

       pKa is 8.4

       Adverse effects- kidney damage and severe nausea

       Because of its toxicity, it is used only for dermatitis herpetiformis

       First drug to have an outstanding curative action on pneumonia


       Sulfonamide drug closely related to sulfisoxazole in chemical structure and antimicrobial activity

       Occurs as a tasteless, odorless, almost white crystalline powder

       Solubility of sulfamethoxazole in the pH range of 5.5 to 7.4 is slightly lower than that of sulfisoxazole

       Not absorbed as completely or as rapidly as sulfisoxazole


       White, odorless crystalline powder soluble in water to the extent of 1:8,100 at 37°C and 1:13,000 at 25°C, in human serum to the extent of 1:620 at 37°C

       Sparingly soluble in alcohol and acetone

       It is readily soluble in dilute mineral acids and bases

       pKa is 6.3

Mafenide Acetate

       Homologue of the sulfanilamide molecule

       It is not a true sulfanilamide-type compound, as it is not inhibited by PABA

       Particularly effective against Clostridium welchii in topical application

       Used during World War II by the German army for prophylaxis of wounds

       It is not effective orally

       It is currently used alone or with antibiotics in the treatment of slow-healing, infected wounds


       Brownish yellow, odorless powder, slightly soluble in alcohol but practically insoluble in water, ether, and benzene

       Sulfasalazine is broken down by gut bacteria in the body to m-aminosalicylic acid (mesalamine- anti-infl ammatory agent) and sulfapyridine

       Produce an orange-yellow color when the urine is alkaline and no color when the urine is acid

       Used to treat ulcerative colitis and Crohn disease

       Direct administration of salicylates is otherwise irritating to the gastric mucosa

Activation of sulfasalazine to 5-aminosalicylic acid

Folate Reductase Inhibitors


       Closely related to several antimalarials but does not have good antimalarial activity

       Potent antibacterial

       Originally introduced in combination with sulfamethoxazole, it is now available as a single agent

       Approved by the FDA in 1980, trimethoprim as a single agent is used only for the treatment of uncomplicated urinary tract infections

Trimethoprim- Mechanism of action

Sulfamethoxazole–Trimethoprim; Cotrimoxazole

       Combination of sulfamethoxazole and trimethoprim has proven to be the most successful method for treatment and prophylaxis of pneumocystis in patients with AIDS

       This combination was first reported as being effective against PCP in 1975

       By 1980, it had become the preferred method of treatment, with a response rate of 65% to 94%

       Effective against both pneumocystic pneumonia and the extrapulmonary disease

       P. jirovecii appears to be especially susceptible to the sequential blocking action of cotrimoxazole, which inhibits both the incorporation of p-aminobenzoic acid (PABA) into folic acid as well as the reduction of dihydrofolic acid to tetrahydrofolic acid by dihydrofolate reductase (DHFR)

       Most frequent side effects of trimethoprim-sulfamethoxazole are rash, nausea, and vomiting


       Primarily of interest as antibacterial agents

       Less effective than the sulfonamides

       PABA partially antagonizes the action of many of the sulfones, suggesting that the mechanism of action is similar to that of the sulfonamides

       Sulfones are proved useful in the treatment of leprosy

       Only dapsone is clinically used today

       Search for antileprotic drugs has been hampered by the inability to cultivate M. leprae in artificial media and by the lack of experimental animals susceptible to human leprosy


       Occurs as an odorless, white crystalline powder that is very slightly soluble in water and sparingly soluble in alcohol

       Pure compound is light stable, but traces of impurities, including water, make it photosensitive and thus susceptible to discoloration in light

       No chemical change is detectable following discoloration, the drug should be protected from light

       Used in the treatment of both lepromatous and tuberculoid types of leprosy

       Dapsone is used widely for all forms of leprosy, often in combination with clofazimine and rifampin

       Initial treatment often includes rifampin with dapsone, followed by dapsone alone

       It is also used to prevent the occurrence of multibacillary leprosy when given prophylactically

       Also the drug of choice for dermatitis herpetiformis and is sometimes used with pyrimethamine for treatment of malaria and with trimethoprim for PCP

       Serious side effects can include hemolytic anemia, methemoglobinemia, and toxic hepatic effects

       Hemolytic effects can be pronounced in patients with glucose-6-phosphate dehydrogenase deficiency

       During therapy, all patients require frequent blood counts

Sulfacetamide- Synthesis

       Direct alkylation of acetamide with 4-aminobenzenesulfonyl chloride

Sulfamethoxazole- Synthesis

       Step-1: cyclization of 2-methylacetylacetonitrile with hydroxylamine gives 3-amino-5-methylisoxazole

       Step-2: 4-acetylaminobenzenesulfonyl chloride with 3-amino-5-methylisoxazole

       Step-3: acidic hydrolysis (hydrochloric acid) of the protective acetyl group gives sulfamethoxazole 

Trimethoprim- Synthesis

Dapsone- Synthesis

Post a Comment