Sulphonamides and Sulfones || B.Pharm VI Semester (3rd Year 2nd Sem.) || Medicinal Chemistry-III - PHARMA WISDOM

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Friday, 17 April 2020

Sulphonamides and Sulfones || B.Pharm VI Semester (3rd Year 2nd Sem.) || Medicinal Chemistry-III


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Historical development of Sulfonamides:
Building on Ehrlich’s early work, Gerhard Domagk, a medical doctor employed by a German dye manufacturer made a breakthrough discovery by finding that a dye known as prontosil, dosed orally, was effective in curing life threatening streptococci infections in humans. He made the discovery in a desperate, but successful attempt to save his daughter who was dying of a streptococci infection.


German bacteriologist and pathologist who was awarded the 1939 Nobel Prize for Physiology or Medicine for his discovery (announced in 1932) of the antibacterial effects of Prontosil, the first of the sulfonamide drugs.

Chemistry of Sulfonamides:

Recognized since 1932.
- In clinical usage since 1935.
First compounds found to be effective antibacterial agents in safe dose ranges.
- Chemically, it is a molecule containing the sulfonamido (sulfanilamide, SO2NH2) functional group attached to aniline.
- Structurally related to p-amino benzoic acid (PABA).
- Chemical Modification of the sulphonamide structure has given rise to several important groups of drugs.
- This group is also present in other non-antibacterial compounds like
    Oral Hypoglycemic – Sulphonyl ureas
    Diuretics – Thiazides (Furosemide)
    Anti Mycobacterial - Sulphones
    Glucoma -Acetazolamide
All sulfa are white crystalline powder except Sulfaquinoxaline (yellow).
- Sulfa generally are weak organic acid, insoluble in water but much more soluble in alkaline aqueous sol. than in neutral or acidic.
The spectrum of all sulfonamides is generally the same.
Sulfonamide inhibit both Gram-positive & Gram negative bacteria, Nocardia, Actinomyces spp, & some Protozoa as Coccidia & Toxoplasma spp.  &  Streptococcus, Staphylococcus, Salmonella, Pasteurella, & E. coli . 
Sulfa used to treat or prevent acute systemic or local infections.

Mechanism of Sulfonamides :


Sulfonamide molecular structure is similar to p-Amino benzoic acid (PABA) which is needed in bacteria organisms as a substrate of the enzyme dihydro pteroate synthetase for the synthesis of Tetra Hydro Folic acid (THFA).
- Folic acid - synthesized from PABA, pteridine and glutamate.
- All sulfonamides are analogs of PABA.
- All sulfa drugs are bacteriostatic.

SAR of Sulfonamides:

Structure of Sulphonamides could be divided in to four parts:
1.) Para amino group
2.) Aromatic Ring
3.) Sulphonamide group
4.) N1-Substitution

1. Para Amino Group:
- The para amino group is essential for the activity and must be unsubstituted.
- It should be always substituted on para position of aromatic ring other wise anti bacterial activity is lost.

2. Aromatic Ring:
- It is the minimal structural requirement for the antibacterial activity. 
- It should be always para substituted.
- Replacement of Aromatic ring by other ring systems or the introduction of additional substituents on it decreases or abolish activity.

3. Sulphonamide group:
- Sulphonamide group along with aromatic ring is essential for the antibacterial activity.
- Sulphur atom should be directly linked to aromatic ring.
- The amino & Sulphonyl groups on the benzene ring are essential & should be in 1,4-position.
- Exchange of the -SO2NH group by –CO-NH reduce the activity.

4. N1-Substitution:
- Sulphonamide nitrogen should be primary or secondary.
- R could be substituted with hydrogen, aromatic ring or heterocyclic ring.
- Substitution of Aromatic Heterocyclic nuclei at N1 - yields highly potent compounds.
- N1 –Di substitution in general leads to inactive.

Classification of Sulphonamides:



Sulfonamide Structures:


Synthesis of Sulfacetamide:


Synthesis of Sulfamethoxazole:


Adverse Effects:
Produce mild-to-moderate nausea, vomiting, headache and mental depression.
- Produce hypersensitivity reactions (rashes, fever, eosinophilia).
- Rarely cause Stevens-Johnson Syndrome, erythema multiforme associated with lesions of skin and mucous membranes.

- Produce Kernicterus (bilirubun-induced brain dysfunction) in neonates because of the displacements of bilirubin form serum albumin binding site.

- Sever  adverse effects includes hepatitis, bone marrow depression and crysalluria

Folate Reductase Inhibitors:

TRIMETHOPRIM:
- Trimethoprim is selective inhibitor of bacterial DHFR
- Individually they both are bacteriostatic but the combination is bactericidal

CO-TRIMOXAZOLE:
Fixed dose combination
SULPHAMETHAXAZOLE   :   TRIMETHOPRIM (5 : 1)
- SEQUENTIAL BLOCK.
- Broad spectrum bactericidal combination.
- Delays the development of bacterial resistance

Synthesis of Trimethoprim:


Sulfones:
sulfone is a chemical compound containing a sulfonyl functional group attached to two carbon atoms. The central hexavalent sulfur atom is double-bonded to each of two oxygen atoms and has a single bond to each of two carbon atoms, usually in two separate hydrocarbon substituents.
Dapsone (diamino diphenyl sulfone, DDS), It was discovered by German chemists Fromm and Wittmann in 1908,  Was not utilized as a treatment until decades later.

Dapsone is used to treat dermatitis herpetiformis (a skin condition) and leprosy.  
It is also used with other drugs to treat Hansen's disease.
Dapsone is commonly used in combination with rifampicin and clofazimine for the treatment of leprosy

Synthesis of Dapsone:


Note: All information copyright @ www.pharmawisdom.co.in

Prepared By:
S.Seetaramswamy, M.Pharm
Assoc. Prof.
Dept. Pharmaceutical Chemistry

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