Diuretic agents are drugs that increase renal excretion of water and electrolytes (mainly sodium salt). ❖ Purpose of diuretic therapy: • To decrease fluid volume of the body. • To adjust the water and electrolyte balance. ❖ Uses: • in the management of pathological conditions such as edema (e.g. in congestive heart failure and certain renal diseases) and hypertension. ❖ MOA • Most diuretics work by inhibiting Na+ transport at one or more of the four major anatomical sites of the nephron (proximal tubule, loop of henle, distal tubule and collecting duct) that regulate Na+ re-absorption. ❖ Most diuretics are weak organic acids (-COOH, - SONH2 ) or weak organic bases (amines) Classes of Diuretics Type Example Site of action Mechanism Carbonic anhydrase (CA) acetazolamide Proximal tubule inhibition of CA inhibitors Osmotic Mannitol Loop of Henle (DTL) Osmotic action Proximal tubule Loop diuretics furosemide Loop of Henle (TAL) inhibition of Na+ -K + - 2Clsymport Thiazides hydrochlorothiazide Distal convoluted inhibition of Na+ -Cltubule symport Potassium-sparing diuretics (1) Na+ channel triamterene, Cortical collecting tubule inhibition of Na+ inhibitors Amiloride channel (2) aldosterone spironolactone antagonists Cortical collecting tubule inhibition of aldosterone receptor

1. PCH 523
Medicinal Chemistry II
PART 1 - DIURETICS

2. ❖ Diuretic agents are drugs that increase renal excretion of
water and electrolytes (mainly sodium salt).
❖ Purpose of diuretic therapy:
• To decrease fluid volume of the body.
• To adjust the water and electrolyte balance.
❖ Uses:
• in the management of pathological conditions such as
edema (e.g. in congestive heart failure and certain renal
diseases) and hypertension.
❖ MOA
• Most diuretics work by inhibiting Na+ transport at one or
more of the four major anatomical sites of the nephron
(proximal tubule, loop of henle, distal tubule and collecting
duct) that regulate Na+ re-absorption.
❖ Most diuretics are weak organic acids (-COOH, - SONH2 ) or
weak organic bases (amines)

3. Classes of Diuretics
Type Example Site of action Mechanism
Carbonic anhydrase (CA) acetazolamide Proximal tubule inhibition of CA
inhibitors
Osmotic Mannitol Loop of Henle (DTL) Osmotic action
Proximal tubule
Loop diuretics furosemide Loop of Henle (TAL) inhibition of Na+-K+-
2Cl- symport
Thiazides hydrochlorothiazide Distal convoluted inhibition of Na+-Cl-
tubule symport
Potassium-sparing diuretics
(1) Na+ channel triamterene, Cortical collecting tubule inhibition of Na+
inhibitors
Amiloride
channel
(2) aldosterone spironolactone
antagonists Cortical collecting tubule
inhibition of aldosterone
receptor

4. Carbonic Anhydrase (CA) Inhibitors
Acetazolamide
S
N
N
SO2NH2
CH3CONH
Methazolamide Dichlorphenarmide
S
N N
C
H3
SO2NH2
CH3CON
SO2NH2
SO2NH2
Cl
Cl

5. Carbonic Anhydrase Inhibitors (CAIs)
❖ MOA
• CA catalyses the reversible reaction;
➢ Carbonic acid spontaneously ionizes as
➢ CAIs inhibit carbonic anhydrase in the membrane and
cytoplasm of the epithelial cells
• Inhibition of CA thus inhibits HCO3
- reabsorption.
• Accumulation of HCO3
- in the tubular lumen subsequently
inhibits Na+-H+ exchange and Na+ reabsorption.
• => prevention of NaHCO3
- re-absorption => diuresis occurs
H2O + CO2 H2CO3
H2CO3 H+ + HCO3
-

6. ❖Acetazolamide
➢Synthesis
N
H2 NH2 .H2O + NH4SCN NH
NH
S
H
N
H2
Cyclization
Phosgene
N
N
SH
N
H2
CH3COCl
N
N
SH
CH3COHN
Cl2
N
N
SOCl 2
CH3COHN
NH3
N
N
SO2NH2
CH3COHN
Acetazolamide

7. ➢Properties:
• white crystalline powder
• soluble in dilute alkali hydroxide solutions
• slightly soluble in water and in alcohol.
➢Uses: adjunctive treatment of oedema due to
congestive heart failure, drug induced oedema,
glaucoma and petitmal epilepsy.
➢Assay: Dissolve the sample in dimethylformamide
and titrate against 0.1 M ethanolic sodium
hydroxide. Determine the end point
potentiometrically.

8. SARs of CAIs
❖ Two groups of CAIs are;
• Heterocylic sulphonamides (acetazolamide and methazolamide)
• Meta-disulphamoyl benzene derivatives (dichlorphenarmide and
dorzolamide)
❖ Heterocylic sulphonamides:
• The C-2 sulphamoyl group is important for activity.
• The free sulphamolyl moiety is necessary to bind with Zn++ in the enzyme;
hence, substitution of sulphamoyl group gives inactive compound.
• The moiety to which the sulphamoyl group is attached must be heterocyclic
or aromatic in character.
• The heterocyclic sulphonamides with higher partition coefficient and lowest
Pka value have greatest CA inhibitory and diuretic activites. Example—
acetazolamide, methazolamide.
• N-alkylation with methyl group on ring N- of acetazolamide yields active
compound (methazolamide).
S
N
N
SO2NH2
CH3CONH

9. SARs of CAIs contd.
❖ m-Disulphamoyl benzene derivatives
• m-Disulphamoyl benzene do not have diuretic activity.
• Substituted m-sulphamoyl benzene exhibits diuretic activity.
• The unsubstituted sulphamoyl moiety is essential for the activity;
any substitution affects the potency of the compound.
• The sulphamoyl moiety can be replaced with similar electrophilic
groups (e.g. carboxyl, carbamoyl) that may increase the potency of
the compound.
• Maximum diuretic activity is obtained when 4th is substituted by Cl,
Br, CF3, or NO2 group.
• Substitution of amino group at 6th position decreases CA inhibitor
activity.
SO2NH2
H2NO2S 1
2
3
4
5
6

10. Thiazides and thiazide-like diuretics
❖ Thiazides
• Also called benzothiadiazides.
• They are sulfonamide derivatives.
❖ Some diuretics having similar pharmacological actions as thiazides but have the
following structures (different from thiazides) e.g., Chlorthalidone, Indapamide,
Metolazone and Quinethazone.
N
S
N
R2
R3
R6
O O
S
O
O
N
H2
1
2
3
4
5
6
7 8
Drugs Structure
Chlorothiazide R2= H, R3= H, R6= Cl
Hydrochlorothiazide R2= H, R3= H, R6= Cl
(Saturated between C3 and N4
Hydroflumethiazide R2= H, R3= H, R6= CF3
(Saturated between C3 and N4
NH
O
H
O
Cl
H2NO2S
Chlorthalidone

11. ❖ MOA
• Thiazides inhibit a Na+—Cl– symport in the luminal membrane
• Inhibit NaCl reabsorption
• Acts the distal convoluted tubule
• may have a small effect on the NaCl reabsorption in the proximal tubule
• Also enhance Ca++ reabsorption in the distal convoluted tubule by inhibiting Na+
entry
❖ SAR of thiazides
• H atom at N-2 is the most acidic due to the
electron-withdrawing effects of the neighbouring sulfone group.
• Sulfonamide group at C-7 provides an additional point of acidity in molecule but is
less acidic than N-2 proton.
• A free sulfamoyl group at position 7 is essential for diuretic activity.
• These acidic protons make possible the formation of a water-soluble sodium salt
that can be used for I.V. dosing.
• An electron-withdrawing group is essential at position 6.
• The diuretic activity is enhanced by substitution at position 3.
• Replacement of 6-Cl by 6-CF3 does not change potency but allters duration of
action.
N
S
N
R2
R3
R6
O O
S
O
O
N
H2
1
2
3
4
5
6
7 8

12. • Replacement of 6-Cl by electron-donating groups (e.g. CH3)
reduces diuretic activity.
• Saturation of thiadiazine ring to give 3, 4-dihydro derivative and
replacement replace or removal of sulfonamide group at position
C-7 yields compounds with little or no diuretic activity.
❖ Properties and uses of Hydrochlorthiazide: It’s a white crystalline
powder, which is soluble in acetone and dilute alkali hydroxide
solutions, but sparingly soluble in alcohol. It is similar to
chlorothiazide, but it is ten times more potent. Used in the
treatment of oedema associated with congestive heart failure,
renal, and hepatic disorders.
❖ Assay: Dissolve the sample in dimethyl sulphoxide and titrate
against 0.1 M tetrabutylammonium hydroxide in 2-propanol.
Determinine the end point potentiometrically.

13. Loop or high ceiling diuretics
➢ Produce peak diuresis than other diuretics
➢ Act distinctly on renal tubular function (at loop of Henle)
➢ There are two major classes:
• sulfonamide derivatives such as furosemide, bumetanide and torsemide;
• non-sulfonamide loop diuretic such as ethacrynic acid
• Bumetanide (Bumex®) is 40 to 50 X more potent than furosemide.
❖ MOA
• inhibit reabsorption of NaCl and KCl by inhibiting the Na+ —K+ —2Cl– symport in
the luminal membrane of the thick ascending limb (TAL) of loop of Henle.
NH
O
Cl
COOH
H2NO2S
Furosemide
O
C
H3
O
CH2 COOH
Cl
Cl
Ethacrynic acid
1
2
3
4
5 6

14. ❖ SAR of Ethacrynic acid
• Increased activity when a electron withdrawing group (i.e. Cl–)
is placed ortho to the unstaturated ketone.
• Ortho and meta positions substituted with chlorine produce
most active compound.
O
C
H3
O
CH2 COOH
Cl
Cl
Ethacrynic acid
1
2
3
4
5 6

15. OSMOTIC DIURETICS
• Osmotic diuretics are the agents that mobilise
fluids by increasing the osmotic pressure in
tubules.
• Examples; Mannitol, urea, glycerol, and
isosorbide
• Acts on the loop of Henle and the proximal
tubule
OH
O
H
OH N
H2 NH2
O
Glycerin Urea

16. ❖ MOA
➢When administered (often in a large dosage),
✓they significantly increase the osmolarity of plasma
and tubular fluid.
✓The osmotic force thus generated prevents water
reabsorption,
✓and also extracts water from the intracellular
compartment, expands extracellular fluid volume
and increases renal blood flow resulting in reduced
medulla tonicity.

17. Potassium-Sparing Diuretics
❖ Na+ Channel Inhibitors
• Examples; Triamterene(most active) and amiloride
➢ MOA
➢ These drugs act on Na+ channel in the luminal
membrane of collecting tubule and collecting duct.
➢ Inhibition of the sodium channel thus not only inhibits Na+ reabsorption but also
inhibits secretion of K+ and H+, resulting in conservation of K+ and H+.
❖ Aldosterone antagonists
➢ Spironolactone is the only available aldosterone (antidiuretic hormone, ADH)
antagonist
➢ Canrenone is the major active metabolite of spironolactone,
➢ Eplerenone, a newer aldosterone receptor antagonist with better ADH receptor
selectivity than spironolactone
N
N
N
N
N
H2
NH2
N
H2
Triamterene

18. ❖ MOA
• Spironolactone competitively inhibits binding of aldosterone to
its receptor and abolishes its biological effects
• Aldosterone, by binding to its receptor in the cytoplasm of
epithelial cells in collecting tubule and duct, increases
expression and function of Na+ channel and sodium pump, and
thus enhances sodium reabsorption..
O
O SCOCH3
O
CH3
CH3
Spironolactone