Sulfanilamide diuretics

Slow release drugs, 143 Solifpertine, 342 Sotalol, 41 Soterenol, 40 Spirilene, 292 Spi2 onolactone, 172 Stenbolone acetate, 155 Strecker reaction, 119 Streptokinase, 377 Sudoxicam, 394 Sulazepam, 403 Sulfabenzamide, 112 Sulfacytine, 113 Sulfanilamide, 112 Sulfanitran, 115 Sulfapyridine, 114 Sulfasalazine, 114 Sulfazamet, 113 Sulfonamide diuretics,... 

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... 

The development of sulfonamide carbonic anhydrase inhibitors was based on the observation that antibacterial sulfanilamides produce alkaline urine. This discovery led to the development of acetazolamide (8.29), a thiadiazole derivative. It is not an ideal drug because it promotes K+ excretion and causes a very high urine pH. Since chloride ions are not excreted simultaneously, systemic acidosis also results. Much more useful are the chlorothiazide (8.30) derivatives, which are widely used as oral diuretic drugs. These compounds differ from one another mainly in the nature of the substituent on C3 ... 

It is noteworthy that sulfanilamide structural modifications have led to other valuable classes of drugs already discussed, including the hypoglycemic sulfonylureas and the diuretic carbonic anhydrase inhibitors. 

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 .

The lead compound in the discovery of diuretics was sulfanilamide. An important product was chlorothiazide (157) (Scheme 33), which became the model for the most important thiazide diuretic, furosemide, or frusemide, 4-chloro-A-furfuryl-5-sulfamoylanthranilic acid, or 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino] benzoic acid (158), used... 

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. 

Diuretics and Hypotensives. One of the side effects of sulfanilamide therapy recognized during the early development of the sulfa drugs as anti-infection agents was the loss of sodium in patients. This observation led to the discovery... 

In the last ten years, the sulfonamide type of diuretic has yielded spectacularly to intensive study. The recognition that certain sulfonamides could have a useful influence upon renal electrolyte excretion is scarcely 15 years old The basic observations for this diuretic development arose from the sulfa drug era, from observations on the side effects of the first sulfa drug, sulfanilamide. Tishler (62) gives a chart depicting the many new drug fields where valuable... 

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 also was observed that sulfanilamide rendered the urine of dogs alkaline because of the Inhibition of carbonic anhydrase. This Inhibition of carbonic anhydrase resulted In a lesser exchange of hydrogen Ions for sodium Ions In the kidney tubule. Sodium Ions, along with bicarbonate Ions, and associated water molecules were then excreted, and a diuretic effect was noted. The large doses required and the side effects of sulfanilamide prompted a search for more effective carbonic anhydrase Inhibitors as diuretic drugs. 

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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