Diuretics

• For high blood pressure, diuretics, commonly known as

"water pills," help your body get rid of unneeded water and
salt through the urine. Getting rid of excess salt and fluid
helps lower blood pressure and can make it easier for your
heart to pump. Diuretics may be used to treat a number of
heart-related conditions, including high blood pressure, heart
failure, kidney and liver problems, and glaucoma.
Therapeutic classes of diuretics
 Carbonic anhydrase

Carbonic anhydrases are zinc-containing enzymes that

catalyse the reversible reaction between carbon dioxide
hydration and bicarbonate dehydration. Carbonic
anhydrases have been found in all kingdoms of life.
active site of human carbonic
Ribbon diagram of human
anhydrase II, showing three histidine
carbonic anhydrase II. Active site
residues and a hydroxide group
zinc ion visible at center.
coordinating (dashed lines) the zinc ion
at center.
From PDB: 1CA2​.
 Carbonic Anhydrase Inhibitors
• Discovered shortly after the introduction of sulphanilamide as
an antibacterial.

• It was observed that sulphanilamide also produced systemic

acidosis and an alkaline urine (HCO3− excretion).

• It was shown that this activity was a result of renal carbonic

anhydrase (CA) inhibition.
 Acetazolamide

N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
 Methazolamide

N-[(5-aminosulfamoyl)-3-methyl-1,3,4-thiadiazole-2-
yl]Acetamide
 SAR’s of CAI’s
• The free sulfamoyl nitrogen is important for diuretic
activity. The mono- and di- substituents at SO2NH2
abolish the activity.

• Substitution of the methyl group on one of the ring

nitrogens (Methazolamide) retains the activity.

• The heterocyclic sulphonamides having highest

lipid/water partition coefficient and lowest pKa values
have greatest CA inhibitory and diuretic activity.

• The benzene meta sulphonamide derivatives have

activity only when substituted with chlorine or methyl
groups.
Methazolamide
 Dichlorphenamide

4,5-Dichloro-1,3-benzenedisulfonamide
Synthesis of acetazolamide
Thiazide and thiazide like diuretics
• The compounds in this group are mostly
analogues of 1,2,4-benzothiadiazine-1,1-
dioxide.
Examples
Thiazide and thiazide like diuretics
• They reduce the reabsorption of electrolytes
from the renal tubules, thereby increasing the
excretion of sodium and chloride ions, and
consequently of water.

• They also reduce carbonic anhydrase activity

but this effect is small.

• The thiazides also have a hypotensive

(antihypertensive) action.
Structures of thiazides
Synthesis of chlorothiazide
Hydrochlorothiazide
Hydroflumethiazide
Methyclothiazide
 SARs of thiazides
• Thiazides having benzothiadiazine-1,1-dioxide with
weakly acidic character have good activity.
• Presence of electron withdrawing group at C-6 is
necessary for good diuretic activity. Substitution of
chlorine at C-6 has good activity.
• Substitution of CF3 group has more lipid soluble and
larger diuretic action than chloro- compound.
• Presence of electron releasing groups like methyl or
methoxy at C-6 reduces the diuretic activity.
 SARs of thiazides cont’d
• Removal or replacement of sulphonamide at C-7
reduces the diuretic activity.
• Saturation of double bond between 3&4 produces
compounds having up to 10 times more diuretic activity
than unsaturated analogues.
• Introduction of lipophilic groups such as aryl alkyl, halo
alkyl, thio ether enhances the diuretic activity and
increases the duration of action.
• Alkyl substitution at N2 lowers the polarity and
enhances the duration of action.