Diuretics 567

Synthesis
2 2
+126 +126
621+ 6
1+
+&+2

1
&O 1+ &O + 2
&KORURDQLOLQHGLVXOIRQDPLGH &+,
1D2+

2 2
2 2 +126
+126 6 &+
6 1
1+&+ $ONDOL
K\GURO\VLV
&O 1 2
&O 1+ +

)&&+6&+&+2

2 2
+126 6 &+
1

&O 1 &+6&+&)
+
3RO\WKLD]LGH

Dosage forms: Polythiazide tablets B.P.

SAR of Thiazide Diruretics

5 1 5
  

    1+
6
+126
2 2

• The 2nd position can tolerate the presence of small alkyl groups such as CH 3.
• Substituents with hydrophobic character in the 3rd position increases saluretic activity 1000 times.
Substituents include –CH2Cl, –CHCl2, –CH2C6H5, –CH2S, –CH2 –C6H5. The increase in saluretic
activity correlates with the lipid solubility.
• Saturation of double bond between the 3rd and 4th position of nucleus increases the diuretic activity
approximately 3-fold to 10-fold. Example— Hydrochlorthiazide.
• Hydrogen atom at the 2nd position is more acidic due to the presence of neighbouring electron with-
drawing the sulphone group.
568 Drugs Acting on Urinary System

• A free sulphamoyl or potentially free sulphamoyl group at 7th postion is essential for activity.
N7-caproyl chlorthiazide is excreted as chorothiazide, the loss of sulphamoyl group eliminates the
diuretic effect, but not the antihypertensive action, example, diazoxide.
• Direct substitution of the 4th, 5th, or 8th position with an ethyl group usually results in diminished
diuretic activity.
• Substitution of the 6th position with an activating group is essential for diuretic activity. The subs-
tiutents include Cl, Br, and CF3 groups.
• The acidic protons make positive the formation of water-soluble sodium salt that can be used for
intravenous administration of the diuretics.
1 1
 1D2+
1+ 1±1D
6 6
+126 +126
2 2 2 2

II. c. CAse inhibitors

Mode of action: CAse is an enzyme that is present in the PT that catalyses the reversible reaction, H2O +
CO2 ↔ H2CO3. Carbonic acid spontaneously ionizes as H2CO3 H++ HCO3 –. CAse inhibitors reversibly
inhibits CAse resulting in the slowing of hydration of CO2 and decrease the availability of H+ to exchange
with luminal Na+ through Na+ - H+ antiporter.
i. Acetazolamide (Acetamide, Diamox, Ana)
1 1

+&2&+1 621+
6
1 6XOSKRQDPLGRWKLDGLD]RO\O DFHWDPLGH

Synthesis
+1 1+

1+1+Â+2  1+6&1 +1 6

+\GUD]LQHK\GUDWH $PPRQLXP 6 +1
WKLRF\DQDWH ELV WKLRFDUEDPR\O K\GUD]LQH

3KRVJHQH &\FOL]DWLRQ

1 1 &+&2&O 1 1
+&2&+1 6+ $F\ODWLRQ 6+
6 +1 6
&O
$T 2[LGDWLRQ
1 1 1+ 1 1

+&2&+1 621+
+&2&+1 62&O 6
6
$FHWD]RODPLGH