Sulphonamides are a group of synthetic antimicrobial agents that contain the sulfonamide group (-SO2NH2). These drugs were among the first antimicrobial agents to be widely used in clinical medicine, and they paved the way for the antibiotic revolution in the mid-20th century. Sulphonamides are primarily bacteriostatic, meaning they inhibit the growth and multiplication of bacteria rather than directly killing them.
1. Medicinal Chemistry-III
Sulphonamides
Department of Pharmacy, Indira Gandhi National Tribal
University, Lalpur, Amarkantak (M.P.)
Dr. Akhilesh Tiwari
Assistant Professor
Department of Pharmacy,
IGNTU, Amarkantak
4/25/2024 1
2. Sulphonamides
Sulphonamides are a group of synthetic antimicrobial agents that contain the sulfonamide group (-
SO2NH2). These drugs were among the first antimicrobial agents to be widely used in clinical medicine,
and they paved the way for the antibiotic revolution in the mid-20th century. Sulphonamides are
primarily bacteriostatic, meaning they inhibit the growth and multiplication of bacteria rather than
directly killing them.
Clinical Uses:
Sulphonamides are used to treat a variety of bacterial infections, including:
- Urinary tract infections (UTIs)
- Respiratory tract infections
- Specific types of meningitis
- Some gastrointestinal infections
- Certain protozoal infections like Toxoplasmosis when combined with pyrimethamine
3. 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 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
4. Nomenclature of the Sulfonamides
• The nomenclature of sulphonamides follows the general rules of organic chemistry naming,
specifically for sulfonamide compounds. The sulphonamide group, a sulfur atom double-
bonded to two oxygen atoms and bonded to a nitrogen atom that is in turn bonded to a
hydrogen atom or organic group, forms the basis of this class of compounds. Here's a more
detailed look at how these drugs are typically named:
5. Basic Structure
The basic structure of sulphonamides can be represented as R-SO2-NH2, where R represents an
aromatic or heterocyclic ring to which the sulfonamide group is attached. The naming can vary
depending on the complexity of the R group and any additional substitutions.
Generic Names
Most sulphonamides have generic names ending in "-sulf-" followed by a suffix. The names often
reflect the structure, particularly the nature of the aromatic or heterocyclic group attached to the
sulfonamide nitrogen. For example:
• Sulfamethoxazole contains a methoxy group attached to a benzene ring as part of its R group.
• Sulfisoxazole has an isoxazole ring attached.
6. Systematic Naming
The systematic name of a sulphonamide can be determined by identifying the base compound and any
substituents:
1. Identify the main sulfonamide structure: Determine the aromatic or heterocyclic component that the
SO2NH2 group is attached.
2. Apply standard IUPAC nomenclature rules:
- Name the base aromatic or heterocyclic compound.
- Indicate the presence of the SO2NH2 group by using the prefix "sulfonamido" or the term
"sulfonamide" attached to the name of the ring system.
- Number the ring system to show the position of the sulfonamide group and any other substituents.
3. Add substituents: Name and number any additional substituents on the aromatic or heterocyclic ring
using standard nomenclature rules.
7. Examples
Sulfadiazine: The systematic name is 4-amino-N-pyrimidin-2-ylbenzenesulfonamide.
Here, the sulfonamide is attached to a benzene ring which also contains a pyrimidin-
2-yl group and an amino group at positions 2 and 4, respectively.
Silver Sulfadiazine: Known chemically as silver 1-[(4-aminophenyl)sulfonyl]-2-
pyrimidinylazanide, indicating the presence of silver, a pyrimidinyl group, and a
sulfonamido linkage on an aniline (amino-benzene) ring.
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)
9. Mechanism of Action of the Sulfonamides
Mechanism of Action:
Sulphonamides act by inhibiting the synthesis of dihydrofolic acid, a precursor to folic
acid, which is necessary for bacterial growth and replication. They achieve this by
competitively inhibiting the enzyme dihydropteroate synthase (DHPS), which is
involved in incorporating para-aminobenzoic acid (PABA) into dihydrofolic acid.
Because humans and other mammals do not synthesize their own folic acid but instead
obtain it through their diet, this pathway of inhibition specifically targets bacteria,
which makes sulphonamides selective in their action.
Side Effects:
• Sulphonamides are generally well tolerated but can cause a range of side effects,
including:
• - Allergic reactions such as skin rash and Stevens-Johnson syndrome
• - Gastrointestinal disturbances like nausea and vomiting
• - Hematological changes such as hemolytic anemia, particularly in patients with
G6PD deficiency
10. Resistance:
Bacterial resistance to sulphonamides has increased significantly since their introduction.
Resistance mechanisms include altered bacterial dihydropteroate synthase, decreased
permeability to the drug, or increased production of PABA. As a result, their use has declined in
favor of other, more effective antibiotics with fewer resistance issues.
Despite their reduced role in current antibiotic therapy due to resistance and the development
of newer drugs, sulphonamides remain a critical part of the antimicrobial arsenal, especially in
combination treatments and specific niche uses.
11. Mechanism of Action of the Sulfonamides
• 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
12. 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, Salmonella 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
13. 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 (Hyaluronic acid) 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)
14. 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
• 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
15. Classification
• 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.
16. Classification
• 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.
17. 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
18. Structure–Activity Relationships
• 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
19. 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
• Used to treat ulcerative colitis and Crohn disease
21. Sulfisoxazole
• 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
22. Sulfamethazine
• Have greater water solubility than sulfamerazine and sulfadiazine
• Its pKa is 7.2
• More soluble in acid urine- kidney damage is decreased
23. Sulfacetamide
• 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
24. Sulfapyridine
• 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
25. Sulfamethoxazole
• 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
26. Sulfadiazine
• 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
27. 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
28. Sulfasalazine
• 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
30. Folate Reductase Inhibitors
• Trimethoprim
• 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
32. Folate Reductase Inhibitors
• 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
33. Sulfamethoxazole–Trimethoprim; Cotrimoxazole
• 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
34. Sulfones
• 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
35. Dapsone
• 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
36. Dapsone
• 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
37. Dapsone
• 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
39. Trimethoprim- Synthesis
ethyl ester of
3,4,5-trimethoxydehydrocinnamic acid
ethyl formate
3,4,5-trimethoxybenzylmalonic ester
guanidine
cyclization
reaction
Replacement of the hydroxyl group in the resulting product with chlorine using phosphorous
oxychloride and then with an amino group using ammonia gives the desired trimethoprim
40. Dapsone- Synthesis
4-chloronitrobenzene sodium sulfide 4,4-dinitrodiphenylthioester
oxidation of the
sulfur atom
Reduction of the nitro group in the resulting compound using tin dichloride in
hydrochloric acid makes the desired dapsone
