Diuretics have been empirically developed. Inorganic mercury was used as diuretics from 16C. Guy's Hospital Pills (containing the equal part of Hg2Cl2, digitalis, and squill) was well known in the 19 C. Discovery of the diuresis of merbaphen has led to develop many organomercurial diuretics and to give suggestion of the drug design of ethacrynic acid. Diuresis in patients given sulfonamide was discovered in 1938. Inhibition of carbonic anhydrase by sulfonamide was related to its diuresis. Drug design aimed to enhance the inhibition of this enzyme has obtained acetazolamide, then chlorothazide. But, the discovery of remarkably enhanced diuretic activity (decreased inhibition on the enzyme) of hydrochlorothazide changed this drug design to rondom chemical modification of thiazide ring. Then, furosemide and other loop diuretics were obtained. The structure-activity relationship of thiazides using the electronic state and other physico-chemical indices was studied by us. A large hydrophobic center linked to a positive formal charge was assumed to the receptor of thiazide. Binding of thiazide to erythrocyte which gives mild and long acting diuretic property was found by us. Recently, shut down of the tubuloglomerular feedback by loop diuretics was reported. Loop diuretics are metabolized to loss their activity. Therapeutic drug monitoring is necessary to obtain a desirable diuresis. By wide clinical use of thiazides and loop diuretics, patients with hyponatremia with eu-or hypervolemic increased. I have proposed aquaretics since 1976. In 1992, nonpeptide selective vasopressin V2 receptor antagonist (OPC-31260) was first synthesized in Japan. This has been found to cause hypotonic diuresis and elevation of serum Na level in men. The combined use of loop diuretics and aquaretics should be considered.

1. Structure Activity Relationship of Diuretics
Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
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2. Diuretics (some info in brief)
Examples of CA Inhibitors
M Borhan Uddin; MPharm (DU), MS (Canada), Ph.D. (first year, Ryerson University,Toronto)

3. Acetazolamide
Acetazolamide, a thiadiazole derivative, was the first of the carbonic anhydrase inhibitors to be
introduced as an orally effective diuretic, with a therapeutic effect that lasts approximately 8 to
12 hours. As mentioned earlier, its diuretic action is limited because of the systemic acidosis it
produces. The dose is 250 mg to 1 g per day.
Loop Diuretics
SAR (Furosemide)
Furosemide is an example of a high-ceiling diuretic and may be regarded as a derivative of
anthranilic acid or o-aminobenzoic acid. Research on 5-sulfamoylanthranilic acids at the
Hoechst Laboratories in Germany showed them to be effective diuretics. The most active of a
series of variously substituted derivatives was furosemide.
The chlorine and sulfonamide substitutions are features also seen in previously discussed
diuretics. Because the molecule possesses a free carboxyl group, furosemide is a stronger acid
than the thiazide diuretics (pKa = 3.9). This drug is excreted primarily unchanged. A small
amount of metabolism, however, can take place on the furan ring, which is substituted on the
aromatic amino group.
M Borhan Uddin; MPharm (DU), MS (Canada), Ph.D. (first year, Ryerson University,Toronto)

4. SAR (Bumetanide)
For bumetanide, a phenoxy group has replaced the customary chloro or trifluoromethyl
substitutions seen in other diuretic molecules(17). The phenoxy group is an electron-withdrawing
group similar to the chloro or trifluoromethyl substitutions. The amine group customarily seen at
position 6 has been moved to position 5. These minor variations from furosemide produced a
compound with a mode of action similar to that of furosemide, but with a marked increase in
diuretic potency. The short duration of activity is similar, but the compound is approximately
50-fold more potent. Replacement of the phenoxy group at position 4 with a C6H5NH- or C6H5S-
group also gives compounds with a favorable activity. However, when the butyl group on the C-5
amine is replaced with a furanylmethyl group, such as in furosemide, the results are not
favorable.
Torsemide
Further modification of furosemide-like structures has led to the development of torsemide.
Instead of the sulfonamide group found in furosemide and bumetanide, torsemide contains a
sulfonylurea moiety.
M Borhan Uddin; MPharm (DU), MS (Canada), Ph.D. (first year, Ryerson University,Toronto)

5. Thiazide Diuretics
The thiazide diuretics are weakly acidic with a benzothiadiazine 1,1-dioxide nucleus. The
structure for the thiazide diuretics, relative activities, and pharmacokinetic properties for the
thiazides are shown in Table 22.3. Chlorothiazide is the simplest member of this series, having a
pKa of 6.7 and 9.5. The hydrogen atom at the 2-N is the most acidic because of the electron-
withdrawing effects of the neighboring sulfone group. The sulfonamide group that is substituted
at C-7 provides an additional point of acidity in the molecule but is less acidic than the 2-N
proton. These acidic protons make possible the formation of a water-soluble sodium salt that can
be used for intravenous administration of the diuretics.
M Borhan Uddin; MPharm (DU), MS (Canada), Ph.D. (first year, Ryerson University,Toronto)

6. An electron-withdrawing group is necessary at position 6 for diuretic activity. Little diuretic
activity is seen with a hydrogen atom at position 6, whereas compounds with a chloro or
trifluoromethyl substitution are highly active. The trifluoromethyl-substituted diuretics are more
lipid-soluble and have a longer duration of action than their chloro-substituted analogs. When
electron-releasing groups, such as methyl or methoxyl, are placed at position 6, the diuretic
activity is markedly reduced.
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 (Table 22.3). 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).
Source: Foye's Medicinal Chemistry (7th edition)
M Borhan Uddin; MPharm (DU), MS (Canada), Ph.D. (first year, Ryerson University,Toronto)