they are much weaker carbonic anhydrase inhibitors than acetazolamide, and may have
another mode of action in addition to carbonic anhydrase inhibition. They are widely
used in edema, hypertension, and cardiac insufficiency, in which a decrease in the
amount of tissue-bound or circulating water is imperative. Some newer derivatives, like
polythiazide (8.31), are three orders of magnitude more active and have a duration of
action of up to 24 hours. Furosemide (8.32) is formally a sulfanilamide but not a car-
bonic anhydrase inhibitor. It not only inhibits Na+reabsorption in the loop of Henle—
a part of the nephron—but probably also functions as an inhibitor of Na+–K+–ATPase,
which has a role in renal sodium transport as it does in other organs.
8.2.4.3 Miscellaneous Diuretic Drugs
Other diuretics do not act through carbonic anhydrase inhibition and are not sulfanyl-
amides. Ethacrynic acid (8.33) is based on some older Hg-containing diuretics, which
block enzymatic Na transport by binding to enzyme —SH groups. The unsaturated
ketone of ethacrynic acid can react in a similar way, binding —SH, whereas the car-
boxyl group ensures the concentration of the compound in the kidneys. The halogens
increase the electrophilic nature of the unsaturated ketone. Chloride ion elimination is
increased together with Na+excretion, but K+and HCO 3 elimination are low and the
urine pH stays at 6. Furosemide and ethracrynic acid are powerful drugs that are used
in patients resistant to other diuretics.
8.2.5 Enzyme Targets: Thymidylate SynthaseThymidylate synthase (E.C. 2.1.1.45) is the enzyme that methylates UMP to thymidine,
using methylene tetrahydrofolate as the carbon carrier. The enzyme can be inhibited
directly by analogues of uracil such as 5-fluorouracil (8.34, 5-FU). The antimetabolite
must be in the 5-fluorodeoxyuridine monophosphate (FdUMP) form to become active,
and the capability of cells to achieve this transformation is a major determinant of their
sensitivity to such drugs.
496 MEDICINAL CHEMISTRY