Sulphonamides PDF / PPT

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Description

Medicinal Chemistry-III

 

Sulphonamides

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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

 

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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
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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
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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)

 

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Mechanism of Action of the Sulfonamides

 

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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
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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

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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

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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)
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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
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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.

 

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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.
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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
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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

 

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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
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Sulfamethizole
• White crystalline powder soluble 1:2,000 in water

• Plasma half-life is 2.5 hours

 

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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

 

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Sulfamethazine
• Have greater water solubility than sulfamerazine and sulfadiazine

• Its pKa is 7.2

• More soluble in acid urine- kidney damage is decreased

 

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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

 

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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
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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

 

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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

 

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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

 

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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

 

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Activation of sulfasalazine to 5-aminosalicylic acid

 

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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

 

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Trimethoprim- Mechanism of action

 

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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

 

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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

 

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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

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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

 

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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

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

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
guanidine cyclization
ethyl formate
reaction
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