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Medicinal Chemistry-III


Sulphonamides 1
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


Historical Development
• 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 3
Historical Development
• 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 4
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) 5
Mechanism of Action of the Sulfonamides 6
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 7
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 8
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 9
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) 10
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 11
• 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. 12
• 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. 13
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 14
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 15
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 16
• White crystalline powder soluble 1:2,000 in water

• Plasma half-life is 2.5 hours 17
• 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 18
• Have greater water solubility than sulfamerazine and sulfadiazine

• Its pKa is 7.2

• More soluble in acid urine- kidney damage is decreased 19
• 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 20
• 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 21
• 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 22
• 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 23
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 24
• 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 25
Activation of sulfasalazine to 5-aminosalicylic acid 26
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 27
Trimethoprim- Mechanism of action 28
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

• 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 29
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 30
• 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 31
• 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 32
• 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

• 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

• Step-3: acidic hydrolysis (hydrochloric acid) of the
protective acetyl group gives sulfamethoxazole Trimethoprim- Synthesis
guanidine cyclization
ethyl formate
ethyl ester of 3,4,5-trimethoxybenzylmalonic ester
3,4,5-trimethoxydehydrocinnamic acid

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 Dapsone- Synthesis

oxidation of the
4-chloronitrobenzene sodium sulfide 4,4-dinitrodiphenylthioester sulfur atom

Reduction of the nitro group in the resulting compound using tin dichloride in
hydrochloric acid makes the desired dapsone