Medicinal Chemistry – Course Code 508

[Pharmaceutical Chemistry-IVB]

1. Sulphonamides
2. Antimalarial Drugs
3. Diuretics
4. Antibiotics
5. Anti-Tubercular Drugs
6. Immunosuppressant
7. Antiviral Drugs

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Chapter 1- Sulphonamides
Saba Razzak
Pharm.D, M.Phil. Pharmaceutical chemistry

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List of contents

▪ Introduction
▪ History & The modern Era
▪ Mechanism of action
▪ Classification
▪ SAR
▪ General properties
▪ Therapeutic applications
▪ Pharmacokinetic
▪ Toxicity and Side effects

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Introduction

▪ Sulfonamides, also known as Sulphonamides/sulfa drugs, are a group

of synthetic antimicrobial drugs that inhibit the growth and
replication of bacteria.
▪ They belong to the broader class of antibiotics known as sulfonamide
antibiotics, that contain the sulfonamide (-SO2NH-) functional
group.
▪ Sulfonamides were one of the first effective treatments for bacterial
infections and have been widely used since the 1930s.

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Introduction

▪ They are primarily bacteriostatic against most gram-positive and

many gram-negative bacteria.
▪ Some sulfonamides are also devoid of antibacterial activity.
▪ e.g., the anticonvulsant sultiame.
▪ The sulfonylureas and thiazide diuretics are newer drug groups
based upon the antibacterial sulfonamides.

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 History

▪ Paul Ehrlich(1854-1915) was a German Jewish physician and scientist known

for his work in hematology, immunology, and antimicrobial chemotherapy.
▪ He developed techniques for staining tissue, which enabled the identification
of different blood cells and the diagnosis of various blood diseases.
▪ Ehrlich's most notable contribution was the discovery of arsphenamine
(Salvarsan)(1908), the first effective treatment for syphilis.
▪ This breakthrough initiated the concept of chemotherapy.
▪ However, Salvarsan and related drugs were revolutionary in treating some
protozoan infections (trypanosomiasis) and syphilis but, not effective against
streptococcal and staphylococcal infections, which were major killers during
that time.
▪ In the 1920s and 1930s, bacterial infections, including pneumonia and
tuberculosis, were widespread and posed significant threats. Even minor
injuries could be deadly in such an environment.

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History

▪ Fritz Mietzsch and Joseph Klarer of Bayer laboratories began a systematic

synthesis of azo dyes as possible antimicrobials.
▪ Azo dyes:
Any of a large class of synthetic dyes whose molecules contain two adjacent
nitrogen atoms between carbon atoms.
C-N=N-C
R−N=N−R′
▪ Sulfonamide azo dyes were included because they were relatively easy to
synthesize and had improving staining properties.
▪ They had the characteristic -N=N- coupling of azo dyes, but one of the
hydrogens attached to nitrogen had been replaced by a sulfonamide group.

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History

▪ In 1931 the two chemists presented a compound (KL695) that, although it

proved inactive in vitro, was weakly active in laboratory mice infected with
streptococcus.
▪ The chemists made substitutions in the structure of this molecule and,
several months and 35 compounds later, produced (KL730), which showed
incredible antibacterial effects on diseased laboratory mice. It was named
prontosil rubrum and patented as Prontosil.
▪ Gerhard Domagk, a physician like Ehrlich, assessed the new Mietzsch-
Klarer dyes as a pathologist and bacteriologist.
▪ According to Domagk, a drug's purpose was to either enhance the immune
system's capabilities or weaken the infectious agent, making it easier for
the immune system to overcome the invader.

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History
▪ In 1932, Domagk began a study of bright red dye, named as Prontosil.
▪ He found that it caused remarkable cures of streptococcal infections in mice (in-
vivo). However, Prontosil was inactive on bacterial cultures (in-vitro).
▪ Domagk spent the next three years investigating the antibacterial properties of
Prontosil. He finally published the first report of his findings in 1935.
▪ In the intervening three years Prontosil had been successfully used to treat several
diseases in humans, of both streptococcal and staphylococcal origins.
▪ In 1933, the first of many human cures of severe staphylococcal septicemias was
reported.
▪ Domagk even saved the life of his own six-year old daughter which was threatened
by a streptococcal infection from an unsterilized needle.
▪ Domagk’s discovery of the antibacterial properties of Prontosil won him the 1939
Nobel Prize in Physiology or Medicine.
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 History

▪ In 1935, Trefouel and coworkers reported their conclusion from a structure-activity

relationship of sulfonamide azo-dyes, that the azo linkage was metabolically broken to
release the active ingredient, sulfanilamide(P-amino benzene sulfonic acid amide).
▪ There reported finding was confirmed in 1937 when Fuller isolated sulfanilamide from the
blood and urine of patients being treated with Prontosil.
▪ Sulfanilamide isolated from Prontosil possessed true antibacterial properties.
▪ Thus, Prontosil was a prodrug….

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THE MODERN ERA

▪ Following Prontosil’s dramatic success, a cascade of sulfanilamide derivatives

began to be synthesized and tested more than 4,500 times by 1948.
▪ From these, only about two dozen actually have been used in clinical practice
conditions like;
▪ Meningitis,
▪ Childbed fever,
▪ Pneumonia,
▪ Blood poisoning,
▪ Gonorrhea,
▪ Burns from gas warfare, and
▪ Other serious burns.
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THE MODERN ERA

▪ But the advent of penicillin during World War II (late 1940’s), followed by a host of other
antibiotics that were more effective against bacteria, shifted the focus away from
Prontosil and the sulfa drugs.
▪ This was largely because of the sulfanilamide toxicity for some patients and because
sulfanilamide-resistant bacterial strains were becoming an increasing problem.
▪ Today, a few sulfonamides and, especially sulfonamide – trimethoprim combinations
are used extensively for opportunistic infections in patients with;
▪ AIDS.
▪ Pneumocystis carinnii pneumonia treatment & prophylaxis.
▪ Cerebral toxoplasmosis treatment and prophylaxis.
▪ Urinary tract infections and
▪ Burn therapy.

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 MECHANISM OF ACTION

▪ Bacteria need various folate coenzymes to synthesize

folic acid which is required for their nutritioning and also
to produce nucleic acid (DNA) for their cell division.
▪ In many microorganisms, dihydrofolic acid (FAH2) is
synthesized from p-aminobenzoic acid (PABA).
▪ All the sulfonamides currently in clinical use are synthetic
analogs of PABA.
▪ Because of their structural similarity to PABA, the
sulphonamides compete with this substrate for the
bacterial enzyme, dihydropteroate synthetase (folate
synthetase). Thus, they inhibit the synthesis of bacterial
dihydrofolic acid.

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 Classification
▪ The term “sulfonamide” is commonly used to refer both antibacterial as well as non-antibacterial
sulfonamides.
▪ The antibacterial sulfonamides are further classified into three categories.
▪ 1. Aniline-substituted sulfonamides;
▪ (e.g. Sulfanilamide)
▪ 2. Prodrugs that produce sulfanilamide;
▪ (e.g. Sulfasalazine)
▪ 3. Non-aniline sulfonamides;
▪ (e.g. Mafenide)
▪ The non-antibacterial sulfonamides include;
▪ Tolbutamide (an oral diabetic drug)
▪ Furosemide (a potent Loop diuretic)
▪ Chlorthalidone (a thiazide diuretic) 14
Structures of some clinically Important
Sulphonamides

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STRUCTURE-ACTIVITY RELATIONSHIP
(SAR)

General structure can be divided

into four parts,
▪ P-amino group
▪ Aromatic ring
▪ Sulfanilamide group
▪ N1 substitution

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 STRUCTURE-ACTIVITY RELATIONSHIP
(SAR)

▪ In sulfonamides, the parent nucleus is sulfanilamide and any substitution/

addition may take place either at N1 or N4 positions.
▪ At N1 different radicles are attached to form different derivatives of
sulfonamides.
▪ Attachment of pyridine ring at N1 position form Sulfa-pyridine.
▪ Attachment of pyrimidine ring at N1 position form Sulfadiazine.
▪ Attachment of di-methyl pyrimidine at N1 position form Sulfadimidine.
▪ Attachment of methyl isoxazol ring at N1 position form Sulfamethoxazole.

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 STRUCTURE-ACTIVITY RELATIONSHIP
(SAR)

▪ Any modification at N4 position other than to make prodrug (prontosil)

results in loss of activity.
▪ E.g. all of the N4 -acetylated metabolites of sulfonamides are inactive
▪ Salt forms of sulfonamides are more active than free/ unionized form. But
the ionized form can not cross lipid membrane so for that purpose they
prepared the substituted forms of sulfonamides which first cross the lipid
membrane then become ionized and produce action.

sulfanilamide 18
GENERAL PROPERTIES OF SULFONAMIDES

▪ Sulfonamides are white crystalline solid compounds.

▪ They are insoluble in water but there salt form is soluble in water.

Q: How this salt is formed?

▪ Ans: Basically sulfonamides are acidic in nature,
▪ Sulfonamides possess an acidic hydrogen attached to their sulfonamide group(-
SO2NH2). This makes them weak acids.
▪ but when they come in body they react with base in G.I.T and converted into ionized
form which is soluble in water.
▪ The ionization process is essential for the bioavailability of sulfonamide
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 Pharmacokinetics

▪ Except poorly absorbed sulfonamides used for ulcerative colitis & topical
burn preparations (e.g. Mafenide), all other sulfonamides are readily
absorbed and well distributed.
▪ They can be found in urine within 30 minutes after oral ingestion.
▪ The sulfonamides vary widely in protein binding, for example;
▪ Sulfisoxazole – 76%
▪ Sulamethoxazole – 60%
▪ Sulfadiazine – 38%.
▪ The fraction that is protein-bound is not active as an antibacterial, but
because the binding is reversible, free, and therefore, active sulfonamide
eventually becomes available.
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Pharmacokinetics

▪ Sulfonamides are excreted primarily as mixtures of un-metabolized

drug and metabolites (N4 –acetates, glucuronides).
▪ For example;
▪ Sulfisoxazole is excreted about 80% unchanged.
▪ Sulfmethoxazole is excreted about 20% unchanged.
▪ Sulfadimethoxine is excreted about 80% as the glucuronide.

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THERAPEUTIC APPLICATIONS OF SULFONAMIDES

▪ SULFANILAMIDE:
▪ It was one of the first sulfonamides introduced but now largely replaced by
other more effective and safer compounds.
▪ Nowadays, It is not recommended for systemic therapeutic use. It is
commonly used for the treatment of certain vaginal infections.
▪ Sulfanilamide is primarily indicated in conditions like;
▪ Various fungal infections.
▪ Meningitis.
▪ Pneumonia.
▪ Vulvo-vaginal candidiasis.

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THERAPEUTIC APPLICATIONS OF SULFONAMIDES

▪ SULFAPYRIDINE:
▪ It is sulfa drug or sulfonamide antibiotic with a wide spectrum against gram +ve and
gram –ve organisms.
▪ Whereas, it is freely soluble in dilute mineral acids and aqueous solutions of sodium and
potassium hydroxide.
▪ It was the first drug to have an outstanding curative action on pneumonia, but because
of its relatively high toxicity it has been replaced by sulfadiazine and sulfamerazine for
pneumonia.
▪ Nowadays, it is only used externally in the treatment of Dermatitis herpetiformis,
Pyoderma gangrenosum.
▪ Sulfapyridine’s plasma half-life is 9 hours.
▪ Several cases of kidney damage (crystalurea) have resulted from acetylsulfapyridine
crystals deposited in the kidneys. It also cause severe nausea in most patients.

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THERAPEUTIC APPLICATIONS OF SULFONAMIDES

▪ SULFADIMIDINE:
▪ Sulfadimidine or sulfamethazine is an antibacterial agent,
belonging to sulfonamides.
▪ It has a broad spectrum of activity, mainly in the treatment of
dysentery, meningitis (drug of choice) and urinary tract infections.
▪ Its plasma half-life is about 7 hours.

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THERAPEUTIC APPLICATIONS OF SULFONAMIDES

▪ SULFAMETHOXAZOLE:
▪ It was approved by FDA in 1961 as an antibacterial agent.
▪ It is effective against gram positive, gram negative bacteria and
some protozoan.
▪ Today, clinical use of sulfamethoxazole occurs primarily in
combination with trimethoprim (co-trimoxazole).
▪ It is mainly indicated in conditions like; meningitis, urinary tract
infections, respiratory tract infections (streptococcal pharyngitis),
dysentery and blood poisoning, etc.
▪ It has a plasma half-life of about 11 hours.
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THERAPEUTIC APPLICATIONS OF SULFONAMIDES

▪ Sulfadiazine is an antibacterial agent,▪ Nocardiosis

belonging to sulfonamides.
▪ Pneumonia
▪ It has a broad spectrum of activity
against gram positive bacteria, gram ▪ Prevention of rheumatic fever
negative bacteria and some protozoan. recurrence
▪ It is primarily indicated in conditions ▪ Respiratory tract infections
like;
▪ Toxoplasmosis
▪ Chancroid
▪ Urinary tract infections
▪ GI infections
▪ Alternative drug of choice in Rheumatic
▪ Malaria fever

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THERAPEUTIC APPLICATIONS OF SULFONAMIDES

▪ SILVER SULFADIAZINE (SILVADENE):

▪ The silver salt of sulfadiazine is a topical anti-infective agent with the
antibacterial properties of both silver ion and sulfadiazine.
▪ It is applied in a water-miscible cream base & has proved to be an
effective topical antimicrobial agent against both gram-positive &
gram-negative organisms.
▪ This is of particular significance in burn therapy as compare to other
standard burn treatments.
▪ Silver sulfadiazine is primarily used to prevent and treat infections of
wounds caused by second and third degree burns.

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THERAPEUTIC APPLICATIONS OF SULFONAMIDES

▪ SULFISOXAZOLE (SULFAFURAZOLE):
▪ It is a sulfonamide antibacterial agent that has activity against both
gram-positive and gram-negative bacteria.
It is primarily indicated in conditions like;
▪ Pneumonia.
▪ Gram-negative urinary tract infections.
▪ As alternative drug of choice in eye infections.
▪ Its plasma half-life is about 6 hours.

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TOXICITY & SIDE EFFECTS

▪ A variety of serious toxicity and hypersensitivity problems have been

reported with sulfonamides and sulfonamide-trimethoprim
combinations.
▪ Hypersensitivity reactions may include;
▪ Drug fever, Stevens-Johnson syndrome, skin eruptions, allergic
myocarditis, photosensitization, etc.
▪ Hematological side effects also sometime occurs and include;
▪ Hemolytic anemia, agranulocytosis, aplastic anemia, etc.
▪ Crystalluria may still occur, and nausea and related GI side effects are
also sometimes noted

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