Medicinal Chemistry-2 - Sulfonamide (sulfa drugs)

Sulfonamides

·Prototype is Sulfanilamide [from prontosil prodrug].

·Bacteriostatic NOT bactericidial

·Act by competitive inhibition of dihydropteroate synthetase enzyme à inhibit folic acid synthesis à inhibit DNA synthesis.

·Structurally similar to PABA à as structure more similar to PABA, it becomes more active.

·Crystalluria g sulpha & acetyl metabolites are sparingly soluble in water.

·á pH or urine or â pka of drug à â risk of crystalluria.

·â pka à á solubility à â risk of crystalluria à UTI.

·Assay: depend on acidity [non-aqueous/argentometry], basicity [diazotization] / bromometry.

·Sulfacetamide Na salt is less alkaline than Na salts of other sulfa drugs à due to higher acidity à eye drops.

·á methyl groups on pyrimidine à á solubility.

·Methoxy group à bind to plasma proteins à long duration.

·To overcome bitter taste of sulfa drugs à acetyl prodrug on N1.

·Ag sulfadiazine [act on external cell structure] & mafenide acetate [NOT true sulfa] à used topically for burns.

·Additional basic or acidic moiety à intestinal sulfa.

·Sulfasalazine à only pyridine derivative à only used in ulcerative colitits.

·Best combination à sulfamethoxazole [DHPS inhibitor] + Trimethoprim [DHFR inhibitor]