Saluretic sulfonamides

Figure 2.5 In addition to its antibacterial activity, sulfanilamide 11 (Figure 2.4) inhibits the enzyme carbonic anhydrase. Acetazolamide 12 is much more potent as a carbonic anhydrase inhibitor but its clinical use as diuretic was impaired by some serious side effects. Hydrochlorothiazide 13 is the prototype of orally active saluretic sulfonamide diuretics. Furosemide (frusemide) 14 and bumetanide 15 are so-called loop diuretics .

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

Muzolimine (710), a 1-substituted 2-pyrazolin-5-one derivative, is a highly active diuretic, differing from the structures of other diuretics since it contains neither a sulfonamide nor a carboxyl group. It has a saluretic effect similar to furosemide and acts in the proximal tubule and in the medullary portion of the ascending limb of the loop of Henle. Pharmacokinetic studies in dogs, healthy volunteers and in patients with renal insufficiency show that the compound is readily absorbed after oral administration (B-80MI40406). 

Replacement or removal of the sulfonamide group at position 7 yields compounds with little or no diuretic activity. Saturation of the double bond to give a 3,4-dihydro derivative produces a diuretic that is 10-fold more active than the unsaturated derivative. Substitution with a lipophilic group at position 3 gives a marked increase in the diuretic potency. Haloalkyl, aralkyl, or thioether substitution increases the lipid solubility of the molecule and yields compounds with a longer duration of action. Alkyl substitution on the 2-N position also decreases the polarity and increases the duration of diuretic action. Although these compounds do have carbonic anhydrase activity, there is no correlation of this activity with their saluretic activity (excretion of sodium and chloride ions). 

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