Sulfanilamide diuretic activity

A considerable number of enzymes occupy a central and crucial role in the activity of drugs. Dihydrofolate reductase, an enzyme involved in purine and amino acid biosynthesis, is the target of antibacterial sulfanilamides, which act both as bacteriostatics and antimalarials. These drugs act on the enzyme in different ways, some being so-called antimetabolites (i.e., reversible enzyme inhibitors). Some diuretics act on carbonic... 

In 1940 sulfanilamide was shown to inhibit carbonic anhydrase. It was not useful as a diuretic because the doses required to produce diuresis were excessive. Investigation of some heterocyclic sulfonamides produced some clinically effective diuretics, for example ethoxzolamide (188), but the first really useful sulfonamide diuretic was acetazolamide (189). This compound also has anticonvulsant activity which is probably related to the presence of carbonic anhydrase in the CNS. Acetazolamide had the disadvantage of producing a metabolic acidosis through the excretion of HCO3- rather than Cl and it was found that some 1,3-disulfonamidobenzenes gave a more balanced diuresis. 

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 .

Inhibitors to the enzyme carbonic anhydrase. This enzyme is widely distributed in the body and has a fundamental role in the control of acid-base balance. In the 1920s it was noticed that the SULPHONAMIDE sulfanilamide had a weak diuretic action. Acetazolamide is a subsequent thiadiazole-sulphonamide derivative with potent carbonic anhydrase inhibitor activity. Clinically, it is used for antiglaucoma TREATMENT, is a weak diuretic and can be used to treat mountain sickness. Dichlorphenamide and dorzolamide are sulphonamide derivatives also used for antiglaucoma treatment. Methazolamide is used as a diuretic. Now that seven or more isoenzymes of carbonic anhydrase have been cloned. Isolated and mapped, some new initiatives are aimed at developing agents with more selective actions. 

Although the shrewd deductions of Schwartz from the accumulated observations were correct, and sulfanilamide proved to be a diuretic, the dose required was large and there were marked side effects. From this beginning, many laboratories set out to find other orally effective sulfonamides with greater potency and fewer unwanted actions. In 1950, Roblin and coworkers (43, 48) of the American Cyanamid Laboratories reported that heterocyclic sulfonamides show a high order of in vitro carbonic anhydrase inhibitory activity. Among the most active compounds was benzothiazole-2-sulfonamide, which had a potency several hundredfold (730 to 2500) that of sulfanilamide. 

An interesting sulfonamide diuretic that has little resemblance structurally to the thiazides is chlorthalidone, a benzophenone derivative. On a dose basis, it has an activity comparable to hydrochlorothiazide but is a much stronger carbonic anhydrase inhibitor than the thiazides, approximately 40 times sulfanilamide. Physical data indicate this compound to have the isoindoline structure rather than the benzophenone structure, I. The outstanding feature of this drug is its long duration of action, up to 72 hours (22, 32, 66). 

It was soon learned that the sulfonamide portion of an active diuretic molecule could not be monosubstituted or disubstituted. It was reasoned that a more acidic sulfonamide would bind more tightly to the carbonic anhydrase enzyme. Synthesis of more acidic sulfonamides produced compounds more than 2,500-fold more active than sulfanilamide. Acetazolamide was Introduced In 1953 as an orally effective diuretic drug. Before that time, the organic mercurials, which commonly required Intramuscular Injection, were the principal diuretics available. 

One of the best known cases is that of the bacteriostatic sulfanilamides whose minor diuretic and antihyperglycemic activities have become of great practical use through structural modification. Sulfanilamide is a very useful, practical, and academic tool. Structural variations on sulfanilamide have broken new ground that has led to a number of drugs in a variety of therapeutic fields (Figure 8.8). 

Some of the synthetized compounds were found 2500 times more active than sulfanilamide. One of these, 2-acetylammo-l,3,4-thiadiazol-5-sulfonamide, acet-azolamide (Diamox ), was studied in detail and reported in 1954 by T. Maren, and became the first clinically effective carbonic anhydrase inhibitor-type diuretic [69]. 

The development of sulphonamide diuretics arose from early observations concerning the use of sulfanilamide as an antibacterial agent. Sulfanilamide was shown to be the active metabolite of prontosil (Fig. 12.20) when used... 

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