Sulphonamides Part 1 PDF

Discovery of Sulfonamides : Folate reductase inhibitors : The discovery of sulfonamides is a significant milestone event in the human chemotherapeutic history....

Discovery of Sulfonamides : Folate reductase inhibitors : The discovery of sulfonamides is a significant milestone event in the human chemotherapeutic history. Prontosil (1932) causes remarkable cures of streptococcal infections in mice. Studies proved that it cures several Sulfonamides are synthetic compounds that have activity against both gram-positive and gram- negative staphylococcal septicemias. It is inactive in vitro, but with excellent activity in vivo. From the conclusion from SAR of bacteria. sulphonamido azo dyes that the azo linkage was metabolically broken to release the active ingredient sulphanilamide. This Originally, sulfonamides were synthesized in Germany as azodyes. In an attempt to expand on earlier was approved when they isolate sulphanilamide from the blood and urine of patients being treated with prontosil. Due to ideas of using dyes as antimicrobial agents, a man by the name of Domagk toxicity and rapid development of resistant strains, antibiotics replace them. Gerhard Domagk (1895-1964) 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 The process of discovery for sulfonamides : drugs. Lead Compound : Notes : Prontosil - red dye Antibacterial activity in vivo (1935) Inactive in vitro Metabolised to active sulfonamide Acts as a prodrug Sulfanilamide - first synthetic antibacterial agent acting on a wide range of infections.  Mechanism of action : Mechanism of Action (Wood-fields Theory) : Sulfonamides Competitive enzyme inhibitors Bacteriostatic agents Not ideal for patients with weakened immune systems Mimic the enzyme substrate - para-aminobenzoic acid (PABA) Bind to the active site and block access to PABA Reversible inhibition Resistant strains produce more PABA Sulfadrug – Antimetabolite : Both the size and distribution of charge of the sulfonamides and PABA molecule are very similar, so sulfa drug play a role of metabolism antagonist. Target enzyme Dihydropteroate synthetase - bacterial enzyme Antimetabolite Theory Not present in human cells Important in the biosynthesis of the tetrahydrofolate cofactor Antimetabolites are compounds that prevent the biosynthesis or use of normal cellular metabolites. The usually are Cofactor is crucial to pyrimidine and DNA biosynthesis closely related in structure to the metabolite that is antagonized. Many antimetabolites are enzyme inhibitors. They may Crucial to cell growth and division combine with active site as if they were the substrate or cofactor.  Basic structure : Metabolic differences between bacterial and mammalian cells Dihydropteroate synthetase is present only in bacterial cells Transport protein for folic acid is only present in mammalian cells Structure-Activity Relationships : para-Amino group is essential (R1=H) para-Amido groups (R1=acyl) are allowed inactive in vitro, but active in vivo act as prodrugs Aromatic ring is essential The main characteristics of sulphonamides: para-Substitution is essential Sulfonamide group is essential Sulfonamide nitrogen must be primary or secondary R2 can be varied They are Amphoteric, they form salts with acids (N4) also they form salts with bases (N1). Sulphonamides are weak acids, at pKa = 10.4 SO2NH2 tends to lose H+ to give anion which is stabilized by resonance. When pH = pKa (ionized form: unionized form will be 1 : 1).When pKa of acid decreases, the acid strength increases. Normal Activity is seen when %ionization almost 50% giving best compromise between activity and transport This occur when pKa= physiological pH Unionized form will penetrate the membrane while Ionized form will bind to the receptor How to decrease the pKa: By adding heterocyclic rings to N1 with electron withdrawing properties giving additional stability to salt formation and decrease pKa, e.g: sulphadiazine Prodrugs of sulfonamides : Sulfonamides - Drug Metabolism ; Notes Amide group lowers the polarity of the sulfonamide Amide cannot ionize Alkyl group increases the hydrophobic character Crosses the gut wall more easily Notes Metabolised by enzymes (e.g. peptidases) in vivo Sulfonamides are metabolised by N-acetylation Metabolism generates the primary amine N-Acetylation increases hydrophobic character Primary amine ionizes and can form ionic interactions Reduces aqueous solubility Ionised primary amine also acts as a strong HBD May lead to toxic side effects Sulfanilamide analogues : Current uses Treatment of urinary tract infections Mechanism of resistance : Wide & unselective use of sulfonamides leads to development of resistant strains due to : 1. The increased production of PABA by m.o. Notes 2. The m.o develops an alternate route to synthesize folic acid R2 is variable N.B: Different aromatic and heteroaromatic rings are allowed Affects plasma protein binding.M.O resistant to one sulfonamide will be resistant to all Determines blood levels and lifetime of the drug Sulfonamide resistance can be transferred to sensitive species by transferring substance called (R factor ). Affects solubility {R-factor from resistant strains to sensitive strains to become resistant}. Affects pharmacokinetics rather than pharmacodynamics Sulfanilamides – applications : Notes Antibacterial drugs of choice prior to penicillins (1930s) Superseded by penicillins Eye lotions Treatment of gut infections Treatment of mucous membrane infections Side effects of sulphonamides: Sulphanilamide causes severe kidney damage by formation of crystals of sulphanilamide in the kidney. (also from N4 acetylated metabolite ) which form crystal urea. Sulphonamides are not very water soluble except in pH above the pKa (solubility product) that is above 10.4. The normal pH of the urine is 6 or lower during infection. So, most of sulphonamides will be in the insoluble form. At pH = pKa = 10.4 we have mixture 1:1 ionized:nonionized. To increase solubility of sulphonamide in the urine and decrease its side effects (crystal urea): 1. Drinking large amounts of water to increase the urine flow. 2. Raise pH of urine by oral NaHCO3 which increases the solubility of sulphonamide. 3. Using derivatives of sulphanilamides that have lower pKa (closer to pH of the urine). Example: sulphadiazine ( pKa=6.5) and sulphamerazine ( pKa=7.1). 4. Mixture of sulphonamides triple sulpha (S. diazine, S. merazine, S.methazine) leads to the same therapeutic level with much less danger of crystal uria as only 1/3 of the amount of any sulpha drug is present.