1. Pharmaceutical Chemistry II Lecture 2 & 3
Joseph O. Oweta | PHC 3201

2. Diurectics Are chemicals that increase the rate of urine formation.
Primarily act by direct inhibition of Na+ transport along the nephron.
2o / indirect actions may occur as a result of 1o diuretic actions.
Are X-teristic of each class and determined by locus of diuretic action and downstream nephron response
Both 1o and 2o X-tics determine the electrolyte secretion pattern
E.g. some combination of natriuretic, chloruretic, saluretic, kaliuretic, bicabonuretic or calciruretic properties

3. Therapeutic classes of diuretics

4. 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.

5. Mechanism of Action of CAI’s

6. Acetazolamide
N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide

7. Methazolamide
N-[(5-aminosulfamoyl)-3-methyl-1,3,4-thiadiazole-2-yl]Acetamide

8. 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.

9. Methazolamide

10. 4,5-Dichloro-1,3-benzenedisulfonamide
Dichlorphenamide
4,5-Dichloro-1,3-benzenedisulfonamide

11. Synthesis of acetazolamide

12. Synthesis of Acetazolamide
Synthesis of acetazolamide is based on the production of 2-amino-5mercapto-1,3,4-thiadiazole, which is synthesised from the reaction between ammonium thiocynate and hydrazine to form hydrazino-N,N’-bis-(thiourea).
2-amino-5mercapto-1,3,4-thiadiazole cycles into thiazole upon reacting with phosgene.
Acyclation with acetic anhydride gives 2-acetylamino-5-mercapto-1,3,4-thiadiazole -5-sulfonyl chloride which is reacted with ammonia to give acetazolamide

13. Thiazide and thiazide like diuretics
The compounds in this group are mostly analogues of 1,2,4-benzothiadiazine-1,1-dioxide.

14. Examples

15. 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.

16. Structures of thiazides

17. Synthesis of chlorothiazide

18. Hydrochlorothiazide

19. Hydroflumethiazide

20. Methyclothiazide

21. 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.

22. 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.

23. Loop Diuretics/ High Ceiling Diuretics
Loop diuretics 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.
Because of 6Cl- pumped inside

24. Loop Diuretics/ High Ceiling Diuretics
TAL responsible for 35% reabsorption of filtered sodium.
Therefore loop diuretics are highly efficacious or “High Ceiling Diuretics”
The Na+ —K+ —2Cl– symport and sodium pump together generate a positive lumen potential that drives the reabsorption of Ca++ and Mg++,
Therefore, Ca++ and Mg++ inhibited as well.

25. Chemistry There are two major chemical classes of loop diuretics:
Organomercuricals
5-Sulfamoyl-2-aminobenzoic acid derivatives and 5-sulfamoyl-3-aminobenzoic acid derivatives.
4-amino-3-pyridinesulfonoylureas
Phenoxyacetic Acids
Organomercuricals
Hepatotoxic and Cardiotoxic
Erratic activity
Lag time of activity

26. 5-Sulfamoyl-2-aminobenzoic acid derivatives Furosemide
4-Chloro-N-fufuryl-5-sulphamoylanthracillic acid

27. 5-sulfamoyl-3-aminobenzoic acid derivatives. Bumetanide
3-butylamino-4-phenoxy-5-sulphamoylbenzoic acid

28. SAR’s
The substituent at C1 must be acidic…the carboxyl group gives optimal activity.
A sulfamoyl group in the C5 is a pre-requisite for optimal high ceiling diuretic activity.
The activating group in the C4 position can be Cl- or CF3 as was with thiazide diuretics.
Phenoxy, alkoxy, anilino, benzyl or benzoyl groups substituted at 4th position decreases diuretic activity.
Furfuryl, benzyl and thienyl methyl group at 2-position increases the activity.

29. 4-amino-3-pyridinesulfonoylureas Torsemide
Assignment:
Draw the structure of Torsemide
Understand and Justify its chemical Class
Give the systematic Name of Torsemide

30. Phenoxyacetic acid derivatives Ethacrynic Acid
2,3-dichloro-4-(2-methylenebutyryl)phenoxyacetic acid

31. Mechanism of Action
Reacts with sulfhydryl containing nucleophiles to form sulphydryl conjugates of ethacrynic acid.

32. Structure Activity Relationship
Optimal activity is achieved in phenoxyacetic acid derivatives when….
An oxyacetic acid is placed at C1 position of benzene ring
A sulfhydryl –reactive acrylol moiety is located para to the oxyacetic acid group
Activating groups (i.e., Cl-) occuppy either C3 or C2 and C3
Alkyl substituents of two or four positions occupy the position α to carbonyl on the acryloyl moiety
Hydrogen atoms occupy the terminal position of the carbon-carbon double bond of the acryloyl moiety

33. Potassium sparing diuretics
Spironolactone
It inhibits the re-absorption of 2-3% of the filtered load sodium by competitively inhibiting the action of aldosterone.
So the passage of luminal fluid sodium in to and potassium, hydrogen ions out of the late distal convoluted tubule and the early collecting tubule cell is enhanced.
So they enhance the water, sodium and chloride excretion.

34. Triamterene & Amiloride
These drugs plug the sodium channels in the luminal membrane of the principal cell at site IV and there by inhibiting the electrogenic entry of 2-3% of the filtered load sodium in these cells.
They decrease the antiluminal membrane bound Na+/K+-ATPase activity, lead to decrease in cellular extrusion of sodium and in the cellular uptake of potassium at site-IV.

35. Aldosterone Antagonists

36. Sodium Channel Inhibitors

37. Triamterene cont’d

38. Structures (3)

39. Synthesis of amiloride

40. Other diuretics Mannitol Is D-mannitol, a hexahydric alcohol
Forms white, crystalline powder of free flowing granules
Freely soluble in water
Solutions sterilised by autoclaving

41. Urea It is the diamide of carbonic acid, H2NCONH2
It forms white, crystalline powder or transparent crystals
It is odourless or almost odourless, but may gradually develop a slight odour of ammonia upon long standing
It is slightly hygroscopic and is stored in well-closed containers
It is freely soluble in water
Sterilised by filtration