Sulphonamides
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
Sulfamethizole
• White
crystalline powder soluble 1:2,000 in water
• Plasma
half-life is 2.5 hours
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
Sulfamethazine
• Have
greater water solubility than sulfamerazine and sulfadiazine
• Its
pKa is 7.2
• More
soluble in acid urine- kidney damage is decreased
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
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
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
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
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
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
Activation of
sulfasalazine to 5-aminosalicylic acid
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
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
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
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
• 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
