Antifolate drugs Sulfonamides Trimethoprim Sulfamethoxazole mixture 2 Lead

Antifolate drugs • Sulfonamides • Trimethoprim & Sulfamethoxazole mixture 2

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 3

Sulfonamides: mechanism of action • Inhibition of dihydropetroate synthase 4

Mechanism of action para-Aminobenzoic acid Dihydropteroate synthetase _ Reversible inhibition Dihydropteroate Sulfonamides L-Glutamic acid Dihydrofolate reductase NADPH 5 Tetrahydrofolate (coenzyme F) _ Trimethoprim

Mechanism of action Binding interactions H 2 N C O H 2 N O Active site H-Bond van der Waals interactions Ionic bond 6 S O O NR

Synthesis of Sulfa drugs 7

Sulfonamides - Drug Metabolism N-Acetylation Sulfathiazole Notes • Sulfonamides are metabolised by N-acetylation • N-Acetylation increases hydrophobic character • Reduces aqueous solubility • May lead to toxic side effects 8 Insoluble metabolite

Structure-Activity Relationships para-Amino group Aromatic Sulfonamide • para-Amino group is essential (R 1=H) • para-Amido groups (R 1=acyl) are allowed • inactive in vitro, but active in vivo • act as prodrugs • Aromatic ring is essential • para-Substitution is essential • Sulfonamide group is essential • Sulfonamide nitrogen must be primary or secondary • R 2 can be varied 9

Sulfonamides: antimicrobial activity • • • Gram positive and negative bacteria Nocardia, chlamydia trachomatis Some protoza Some enteric bacteria Rickettisiae stimulated! 10

Sulfonamides: resistance • Overproduction of PABA • Low affinity dihydropetroate synthase • Loss of permeability to sulfonamides 11

Sulfonamides: pharmacokinetics • Oral absorbable – Short – Medium – Long • Serum protein bind – 20 ~ 90% • Excreted into urine • Oral, nonabsorbable • topical 12

Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim 13

Sulfonamides: chemistry 14

Sulfonamides: clinical uses • Oral absorbable agents – Sulfisoxazole, sulfamethoxazole • To treat urinary tract infection – Sulfadiazine: toxoplasmosis – Sulfadoxine: long acting, in a combination for treatment of malaria • Oral nonabsorbable agents – Ulcerative colitis, enteritis, other inflammatory bowel disease • Topical agents – Sulfacetamide: ophthalemic – Mafenide & silver sulfadiazine: topically ( Burn ) 15

Sulfonamides: adverse reactions • Cross allergenic sulfonamide drugs: – Thiazide, furosemide, diazoxide, sulfonylurea hypoglycemic agents, and others – Fever, skin rashes, exfoliative dermatitis, photosensivity, urticaria, nausea, vomiting, diarrhea – Stevens-Johnson syndrom • Urinary tract disturbances – Crystalluria, hemturia, obstruction • Hematopoietic disturbance – – Hemolytic or aplastic anemia Granulocytopenia, thrombocytopenia, leukmoid reaction Hemolysis in G-6 PDH deficient patients Kernicterus in newborn of mothers have taken near the end of pergnancy 16

Trimethoprim: chemistry 17

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Clinical use • Oral trimethoprim – Acute urinary infection • Oral trimethoprim-sulfamethoxazole – P jiroveci pneumonia, shigellosis, systemic salmonella infection, complicated urinary tract infection, – Active against many respiratory pathogens • Intravenous trimethoprim-sulfamethoxazole – Gram negative sepsis, pneumocystis pneumonia – Shigllosis, typhoid fever • Oral pryrimethamine with sulfanamide – With sulfadiazine in Leishmaniasis, toxoplasmosis – With sulfadoxine in malaria 19

Adverse effects • • Megaloblastic anemia Leukopenia, granulocytopenia Can be prevented by folinic acid The AIDS patients have high frequency of unwanted reactions Sulfones ( Dapson) • Thought to inhibit dihydropteroate synthetase • Used in the treatment of leprosy 20