1. sulfonamides and Antileprotics.pptx

The chemistry, SAR, MOA of sulfonamides

1. SULFONAMIDES & ANTILEPROTIC AGENTS DR. MANJOOR AHAMAD SYED ,                             M.Pharm,Ph.D Associate. Professor  Department of Medicinal Chemistry,  College of Public Health and Medical Sciences, Mettu University, Mettu Post Box No-318 Ethiopia.

2. SULFONAMIDES Sulfonamides (sulphonamides) are a group of man-made (synthetic) medicines that contain the sulfonamide chemical group. They may also be called sulfa drugs. Many people use the term sulfonamide imprecisely to refer only to antibiotics that have a sulfonamide functional group in their chemical structure. The original antibacterial sulfonamides are synthetic (nonantibiotic)  antimicrobial  agents that contain the  sulfonamide  group. Some sulfonamides are also devoid of antibacterial activity, e.g., the  anticonvulsant  ( sulthiame) . The  sulfonylureas  and  thiazide diuretics  are newer drug groups based upon the antibacterial sulfonamides.

3. HISTORY The first sulfonamide, trade-named Prontosil, was a prodrug. Experiments with Prontosil began in 1932 in the laboratories of Bayer AG, at that time a component of the huge German chemical trust IG Farben . The first official communication about the breakthrough discovery was not published until 1935, more than two years after the drug was patented by Klarer and his research partner Fritz Mietzsch . Notes Prontosil - red dye Antibacterial activity in vivo (1935) Metabolised to active sulfonamide Acts as a prodrug Sulfanilamide - first synthetic antibacterial agent acting on a wide range of infections

4. CHEMISTRY OF SULFONAMIDES: In 1935 , Domagk , a German scientist demonstrated the antibacterial therapeutic property of Prontosil-an azo dye possessing p-amino-benzene sulfonamide group. He was awarded Nobel Prize of Medicine in 1939 for his outstanding contribution. The antibacterial activity of the drug was due to its sulfanilamide component. Chemically sulfa drugs are amphoteric . They behave as weak organic acid with pKa 4.79 to 8.56. Though they are weakly soluble in water, their solubility is increased at alkaline pH. Sodium salts are however easily soluble in water. The sulfacetamide is neutral in pH and is used to combat eye infections .

5. The nitrogen of amino group at para position is designated as N4 while nitrogen of SO 2 NH 2 is designated as N1. Systemic sulfa drugs are evolved by substitution at N1 position whereas gut active sulfa drugs are produced by substituting N4 posi­tion. The basic structure of sulfanilamide and PABA

6. STRUCTURE ACTIVITY RELATIONS: Sulphanilamide skeleton is the minimum structural requirement for antibacterial activity. The amino- and sulphonyl-groups on the benzene ring are essential and should be in 1 and 4 position. The N-4 amino group could be modified to be prodrugs, which are converted to free amino function in vivo . Sulphur atom should be directly linked to the benzene ring. Replacement of benzene ring by other ring systems or the introduction of additional substituents on it decreases or abolishes its activity. Exchange of the –SO2NH group by –CONH reduces the activity.

7. STRUCTURE ACTIVITY RELATIONS: On N-1 -substituted sulphonamides, activity varies with the nature of the substituent at the amino group. With substituents imparting electron-rich characters to SO2 group , bacteriostatic activity increases . Heterocyclic substituents lead to highly potent derivatives, while sulphonamides, which contain a single benzene ring at N-1 position , are considerably more toxic than heterocyclic ring analogues. The free aromatic amino groups should reside para to the sulphonamide group. Its replacement at ortho or meta position results in compounds devoid of antibacterial activity. The active form of sulphonamide is the ionized, maximum activity that is observed between the pKa values 6.6– 7.4.

8. STRUCTURE ACTIVITY RELATIONS: Substitutions in the benzene ring of sulphonamides produced inactive compounds. Substitution of free sulphonic acid (–SO3H ) group for sulphonamido function destroys the activity, but replacement by a sulphinic acid group (–SO2H ) and acetylation of N-4 position retains back the activity. Meta-Sulphonamides bind to the basic centres of arginine, histidine, and lysine sites of proteins. The binding groups are alkyl, alkoxy, and halides. The binding affects the activity of sulphonamides; protein binding appears to modulate the availability of the drug and its half-life. The lipid solubility influences the pharmacokinetic and antibacterial activity, and so increases the half-life and antibacterial activity in vitro.

9. CLASSIFICATION OF SULFONAMIDES 1. BASED ON CHEMICAL STRUCTURE: ( i ) Both N1 and N4 substituted sulfonamides - Succinyl sulfathiazole, Phthalyl sulfathiazole (ii) N-4 substituted sulphonamides (prodrugs): Prontosil. (iii) N1 substituted sulfonamides - Sulfadimidine (sulfamethazine), sulfamerazine, sulfaphenazole (Orisul), sulfamethoxazole (Sulfuno), Sulfadimethoxine (Madribon), sulfacetamide, Sulfaquinoxaline, sulfaethoxypyridazine, Sulfamethoxypridazine, Sulfasomidine, sulfisoxazole (sulfafurazole), Silversulfadiazine, sulfamylon (Mafenide), Sulfasimazole, sulfaguanidine etc. (iv) Miscellaneous: Mefenide sodium.

10. 2. ON THE BASIS OF THE DURATION OF ACTION ( i ) Extra-long-acting sulphonamides (half-life greater than 50 h): Sulphasalazine , Sulphaclomide , Sulphalene . (ii) Long-acting sulphonamides (half-life greater than 24 h): Sulphadoxine , Sulphadimethoxine , Sulphamethoxy pyridazine, Sulphamethoxydiazine , Sulphaphenazole , Sulphamethoxine . (iii) Intermediate-acting sulphonamides (half-life between 10–24 h): Sulphasomizole , Sulphamethoxazole. (iv) Short-acting sulphonamides (half-life less than 20 h): Sulphamethiazole , sulphaisoxazole . (v) Injectable (soluble sulpha drugs): Sulphafurazole , Sulphadiazine, Sulphamethoxine .

11. MODE OF ACTION: Sulfonamides compete with para aminobenzoic acid (PABA) for the catalytic site of the enzyme dihydropteroate synthetase (Woods, 1940) thereby inhibiting conver­sion of PABA to folic acid in bacteria. This action of sulfonamide is selective over bacteria without interfering animal cells. Antibacterial action can however, be re­versed by removal of sulfonamide or addition of PABA. Bacterial growth is inhibited by bacteriostatic action. Inhibited bacteria can be eliminated by host defence system preferably by phagocytosis.

12. Active site Active site Binding interactions Mechanism of action Ionic bond H-Bond van der Waals interactions O C O H 2 N S O O N R H 2 N

13. GENERAL METHOD OF SYNTHESIS FOR SULFONAMIDES:

14. Side effects: - Sulfonamides have the potential to cause a variety of untoward reactions, including urinary tract disorders, haemopoietic disorders, and hypersensitivity reactions. - When used in large dose, it may develop a strong allergic reaction. One of the most serious is Stevens Johnson syndrome (or toxic epidermal necrolysis). - Some of the original sulfonamide drugs were derived from azo dyes and had the interesting effect of temporarily turning the patient red. - N.B- Stevens-Johnson syndrome (SJS) is a life-threatening condition affecting the skin, in which due to cell death the epidermis separates from the dermis . The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes.

15. Adverse reactions: i ) The most common manifestation of a hypersensitivity reaction to sulfa drugs are rash and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia , thrombocytopenia, and fulminant hepatic necrosis, among others ii) The sulfonamide antibiotic chemical structures are implicated in the hypersensitivity reactions associated with the class. - The first is the N1 heterocyclic ring , which causes a type I hypersensitivity reaction. - The second is the N4 amino nitrogen that, in a stereospecific process, forms reactive metabolites that cause either direct cytotoxicity or immunologic response.

16. SUCCINYL SULFATHIAZOLE 4-oxo-4-[4-(1,3-thiazol-2-ylsulfamoyl) anilino] butanoic acid USES: The drug is used for its antibacterial activity in the GIT. The dose is 10g - 20g daily in divided doses. About 95% of the drug remains in the intestine and only 5% is hydrolysed, slowly, to Sulfathiazole and is absorbed. The Succinyl group is attached to form a Prodrug for Controlled release of drug Sulphathiazole. PHTHALYL SULFATHIAZOLE USES: Phthalylsulfathiazole is a broad-spectrum antibiotic which is part of the drug class, sulfonamides. It was used as an antibiotic for bowel surgery, and for infections of the colon. 2-[({4-[(1,3-Thiazol-2-ylamino) sulfonyl] phenyl} amino) carbonyl] benzoic acid

17. Sulphamethoxazole USES : It is used to treat certain infections, such as: Acute exacerbations (worsening) of chronic bronchitis. Urinary tract and acute ear infections. Shigellosis. Diarrhea. Pneumocystis jirovecii pneumonia (PCP) Synthesis:

18. Sulphapyridine: USES: Sulfapyridine is a  sulfa medicine . It is used to help control dermatitis herpetiformis ( Duhring's disease), a skin problem. It may also be used for other problems as determined by your doctor. However, sulfapyridine will not work for any kind of  infection  as other  sulfa medicines  do. Synthesis:

19. Sulphapyrimidine: USES: Sulfapyrimidine is a  sulfa medicine . It is used to help control dermatitis herpetiformis ( Duhring's disease), a skin problem. It may also be used for other problems as determined by your doctor. However, it will not work for any kind of  infection  as other  sulfa medicines  do. Synthesis:

20. Sulphacetamide : USES: Ophthalmic sulfacetamide stops the growth of bacteria that cause certain  eye infections . It is used to treat  eye infections  and to prevent them after injuries. It is also used in the treatment of VAGINITIS caused by Gardnerella vaginalis in combination with other drugs. Synthesis:

21. SULFAMETHIAZOLE 4-amino-N-(5-methyl-1,3,4-thiadiazol-2-yl)- benzenesulfonamide USES: Sulfamethiazole is a drug which is used for the treatment of urinary tract infection. SULFAGUANIDINE USES: Sulfaguanidine is a guanidine derivative of sulfanilamide used in veterinary medicine. Sulfaguanidine is poorly absorbed from the gut but is well suited for the treatment of bacillary dysentery and other enteric infections.

22. SULFADIMIDINE ( sulfamethazine ) Synthesis : USES: As an aid in the treatment of the following conditions caused by bacteria sensitive to sulfamethazine: foot rot, shipping fever, bacterial enteritis/scours, metritis, mastitis and bacterial respiratory disease. As an aid in the treatment of coccidiosis in sheep.

23. SULFASALAZINE Synthesis : USES: Sulfadiazine is an antibacterial prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of certain types of bacterial infections, including the treatment of chancroid, Toxoplasma gondii encephalitis, urinary tract infections, and other infections.

24. SULFISOXAZOLE (SULFAFURAZOLE) Synthesis: USES: Sulfisoxazole is used to treat or prevent infections in many different parts of the body. It belongs to the group of medicines known as sulfonamide antibiotics. It works by preventing the growth of bacteria. However, this medicine will not work for colds, flu, or other virus infections.

25. SULFADIMETHOXINE (MADRIBON) USES: Sulfadimethoxine is a sulfonamide antibiotic. Sulfadimethoxine is used to treat many infections including treatment of respiratory, urinary tract, enteric, and soft tissue infections. It is most frequently used in veterinary medicine, although it is approved in some countries for use in humans. 4-Amino-N-(2,6-dimethoxypyrimidin-4-yl) benzenesulfonamide

26. SULFAMERAZINE 4-amino-N-(4-methylpyrimidin-2-yl) benzenesulfonamide Synthesis: USES: Sulfamerazine is a sulfonamide drug that inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA) for binding to dihydropteroate synthetase (dihydrofolate synthetase). Sulfamerazine is bacteriostatic in nature.

27. SULFAQUINOXALINE 4-Amino-N-2-quinoxalinylbenzenesulfonamide Synthesis: USES: Sulfaquinoxaline is aveterinary   medicine  which can be given to cattle and sheep to treat coccidiosis. It is available in Pakistan with Sanna Laboratories in combination with Amprolium and Vitamin K as potential treatment of coccidiosis.

28. SULFAETHOXYPYRIDAZINE USES: Sulfaethoxypyridazine is a sulfonamide consisting of 6-ethoxypyridazine with a 4-aminobenzenesulfonamido group at the 3-position. Generally licensed for veterinary use only against bacterial infections, such as fowl cholera and salmonella infection. It has a role as an antibacterial agent. SILVERSULFADIAZINE USES: Silver sulfadiazine cream is used to prevent and treat wound infections in patients with second- and third-degree burns. Patients with severe burns or burns over a large area of the body must be treated in a hospital. Silver sulfadiazine is an antibiotic. It works by killing the bacteria or preventing its growth.

29. SULFAMYLON (Mafenide) USES: This medication is used alone or with other medications to help prevent and treat wound infections in patients with severe burns. Mafenide is a drug applied to the skin that belongs to a class of drugs known as sulfa antibiotics. It works by killing bacteria that may infect an open wound. 4-( Aminomethyl ) benzenesulfonamide

30. CO-TRIMOXAZOLE Trimethoprim/sulfamethoxazole, also known as co-trimoxazole among other names, is an antibiotic used to treat a variety of bacterial infections. It consists of one-part trimethoprim to five parts sulfamethoxazole (1:5). Cotrimoxazole sequentially block the Dihydropteroate synthase(sulfamethoxazole) and DHFR (Trimethoprim), in combination they produce broad spectrum of activity and delays the development of bacterial resistance. Co-trimoxazole is used to treat certain bacterial infections, such as pneumonia (a lung infection), bronchitis (infection of the tubes leading to the lungs), and infections of the urinary tract, ears, and intestines. It also is used to treat ' travelers ' diarrhea.

31. TRIMETHOPRIM Synthesis: USES: Trimethoprim is an antibiotic. It's used to treat urinary tract infections (UTIs), such as cystitis. Occasionally, trimethoprim is used to treat other types of infections, such as chest infections and acne.

32. SULFAMETHOXAZOLE SYNTHESIS: USES: Sulfamethoxazole/trimethoprim is an antibacterial prescription medicine approved by the U.S. Food and Drug Administration (FDA) to treat certain infections, such as: Acute exacerbations (worsening) of chronic bronchitis, Urinary tract and acute ear infections, Shigellosis, Diarrhea, Pneumocystis jirovecii pneumonia (PCP).

33. CO-TRIMAZINE It is a combination of Trimethoprim and sulfadiazine ( 1:5 ). Trimethoprim is selective inhibitor of bacterial DHFR. Individually both are bacteriostati c but in the combination they are bactericidal .

34. SULFADIAZINE: Synthesis: USES: Sulfadiazine is an antibacterial prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of certain types of bacterial infections, including the treatment of chancroid, Toxoplasma gondi encephalitis, urinary tract infections, and other infections.

35. TRI –SULFAPYRIMIDINES OR TRIPLE SULFA It consists of sulfadiazine, sulfamerazine and sulfamethazine USES: Triple sulfa is an antibacterial medication. It fights bacteria in the body. Triple sulfa vaginal is used to treat vaginal infections caused by the bacteria Gardnerella vaginalis. Triple sulfa vaginal may also be used for purposes other than those listed in this medication guide.

36. Notes Amide group lowers the polarity of the sulfonamide Amide cannot ionise Alkyl group increases the hydrophobic character Crosses the gut wall more easily Metabolised by enzymes (e.g. peptidases) in vivo Metabolism generates the primary amine Primary amine ionizes and can form ionic interactions Ionised primary amine also acts as a strong HBD Prodrugs of sulfonamides Enzyme

37. Notes R 2 is variable Different aromatic and heteroaromatic rings are allowed Affects plasma protein binding Determines blood levels and lifetime of the drug Affects solubility Affects pharmacokinetics rather than pharmacodynamices Sulfanilamide analogues

38. Sulfonamides - Drug Metabolism Notes Sulfonamides are metabolised by N -acetylation N -Acetylation increases hydrophobic character Reduces aqueous solubility May lead to toxic side effects Sulfathiazole Insoluble metabolite N -Acetylation

39. Sulfonamides with reduced toxicity Notes Thiazole ring is replaced with a pyrimidine ring Pyrimidine ring is more electron-withdrawing Sulfonamide NH proton is more acidic and ionizable Sulfadiazine and its metabolite are more water soluble Reduced toxicity Silver sulfadiazine is used topically to prevent infection of burns Sulfathiazole Sulfadiazine

40. Examples of Sulfonamides Sulfadoxine Pyrimethamine Belongs to a new generation of sulfonamides Long lasting antibacterial agent Once weekly dosing regime Sulfadoxine + pyrimethamine = Fanisdar Used for the treatment of malaria

41. Examples of Sulfonamides Sulfathiazole Succinic acid Enzyme Succinyl sulfathiazole Succinyl sulfathiazole Notes Acts as a prodrug of sulfathiazole Ionized in the alkaline conditions of the intestine Too polar to cross the gut wall Concentrated in the gut Slowly hydrolysed by enzymes in the gut Used for gut infections

42. Examples of Sulfonamides Benzoyl prodrugs Benzoyl prodrug Sulfonamide Benzoic acid Too hydrophobic to cross gut wall Slowly hydrolyzed by enzymes in gut Used for gut infections

43. ANTILEPROTIC AGENTS

44. ANTILEPROTIC AGENTS Leprosy is caused by a slow-growing type of bacteria called Mycobacterium leprae ( M. leprae ) Also known as Hansen's disease , after the scientist ho discovered M. leprae in 1873 It primarily affects the skin and the peripheral nerves Long Incubation period (3 – 5 years). Antileprotic drugs are classified as follows: SULFONES – dapsone (DDS)-Diamino Diphenyl Sulfone PHENAZINE DERIVATIVE - Clofazimine ANTITUBERCULAR DRUGS - Rifampicin, Ethionamide ANTIBIOTICS : Ofloxacin, Moxifloxacin, Minocycline and Clarithromycin

45. SULFONES Sulfones are primarily used as antibacterial agents and they are less effective than sulphonamides Thought to inhibit dihydropteroate synthetase Used in the treatment of leprosy

46. DAPSONE Synthesis: USES: This medication is used to treat a certain type of  skin  disorder (dermatitis herpetiformis). It is also used with other drugs to treat Hansen's disease. Dapsone belongs to a class of drugs known as sulfones. It works by decreasing swelling (inflammation) and stopping the growth of bacteria.

47. PHENAZINE DERIVATIVE MOA: Interference with template function of DNA Alteration of membrane structure and transport Disruption of mitochondrial electron transport. ADRs: well tolerated Skin: Reddish-black discolouration of skin, discolouration of hair and body secretions, Dryness of skin and troublesome itching, phototoxicity, conjunctival pigmentation GIT: Nausea, anorexia, abdominal pain and loose stool (early and late) – dreaded enteritis. Contraindication: Early pregnancy, liver and kidney diseases. USES: Clofazimine is a drug used to treat  leprosy. It can slow down the growth and weakly kill Mycobacterium leprae, the bacteria that cause leprosy. It is used in combination with rifampicin and dapsone for the treatment of the many forms of leprosy. CLOFAZIMINE It is Phenazine dye used as antileprotic, anti-inflammatory and Bacteriostatic ag ent.