Structure Activity Relationship of Primaquine

Piscean 9:11 AM

Primaquine belongs to 8-Amino Quinoline derivative which is used to treat malaria


Indication of Primaquine:

Radical cure or prevention of relapse in vivax malaria; after termination of chloroquine phosphate suppressive therapy in areas where vivax malaria is endemic [1].
SAR OF PRIMAQUINE
·         Methoxy group at Position 6 is responsible for optimum activity but this group is not essential for antimalarial activity.
·         If we replace the methoxy group at position 6 by hydroxyl group.it will show comparable (same) activity. While when ethoxy group is attached it will show low or negligible activity
·         If we replace methoxy group by methyl group at position 6 the compound will become inactive
·         Additional substitution on the quinoline nucleus tends to decrease both activity and toxicity.
·         The reduction of quinoline nucleus ( hetro ring ) at position 1 into 1,2,3,4 tetra hydro derivative (i.e primaquine ) this will show same pharmacological effect but its potency and toxicity will be decreases means require high dose .
·         In amino acid side chain, there are two amino group, for optimum activity, the distance between the two nitrogens of amino acid side chain should be 3-6 or 4-6 carbons means if less than 3 carbons, the activity will be decreases or if more than 6 carbons than also decreases.
·         The optimal activity is obtained when the alkyl chain contains 4 to 6 carbon atoms. The greatest activity appears to be achieved in alkyl groups containing 5 carbon atoms.
·         Any substitution on the quinoline ring will lead to decrease its antimalarial activity.


References
1. Tatro DS, Borgsdorf LR. A to Z drug facts. Facts & Comparisons; 2003.


Structure Activity Relationship of CHLOROQUINE

Piscean 12:10 PM


Chloroquine Inhibits parasite growth used for Prophylaxis and treatment of acute attacks of malaria caused by
·         Plasmodium vivax,
·         P malariae,
·         P ovale and
·         susceptible strains of P falciparum; extraintestinal amebiasis [1]
SAR OF CHLOROQUINE
·         Addition of –CH3 group at position #2 will reduce the activity as in santoquine
·         Addition of –CH3 group at position #8 will reduce the activity / totally loss the activity
·         Introduction of any other groups into the quinoline nucleus will reduce the activity
·         Halogens “chlorine “at position #1 produce maximum activity
·         The presences of diethyl diamino pentane as a side chain is optimum for activity as in chloroquine
·         OH group addition in side chain at ethyl group the Hydroxy chloroquine, which is less toxic and produce the high blood levels but slightly lowers the activity
·         Addition of alpha diethylaminocresol in place of diethyl –diamino pentane results in production of amodiaquine, which is less toxics and also less effective as compared to chloroquine.
·         Any substitution at position 1,2,5,6 will lead to decrease the pharmacological activity.

References
1. Tatro DS, Borgsdorf LR. A to Z drug facts. Facts & Comparisons; 2003.




Synthesis of hydrochlorthiazide

Piscean 10:58 AM

Hydrochlorthiazide is diuretic belongs to thiazide diuretics class which reduces the reabsorbtion of electrolytes in the renal tubule, this causes increased excretion of water and electrolytes, including

  • sodium, 
  • potassium, 
  • chloride, and
  • magnesium

Synthesis of Hydrochlorthiaizide




Reaction Summary

3-chloroaniline is reacted with chlorosulfonic acid to yield 4-amino-6-chlorobenzene-1,3-disulfonyldichlordie molecule which on subsequent amination yields 4-amino-6-chlorobenzene-1,3-disulfonamide, upon further treatment with formaldehyde it yields HydroChlorothiazide. 

Brief Pharmacology

Hydrochlorothiazide inhibits water reabsorption in the nephron (distal convoluted tubule) by inhibiting the sodium-chloride symporter

Used in treating high blood pressure and
management of edema.

Synthesis of Chlorothiazide

Piscean 11:39 AM

Chlorothiazide classifiedd as an antihypertensive drug that belongs to the class thiazide diuretic. Formerly known as benzothiadiazide. It belongs to NaCl co-transport inhibitor on the basis of mechanism of action and also classified in Diuretic Thiazide.


Synthesis




Reaction Summary

3-chloroaniline is reacted with chlorosulfonic acid to yield 4-amino-6-chlorobenzene-1,3-disulfonyldichlordie molecule which on subsequent amination yields 4-amino-6-chlorobenzene-1,3-disulfonamide, upon further treatment with formic acid it yields Chlorothiazide.



Brief Pharmacology

Chlorothiazide acts on Distal Convulated tubules, where they interefer with reabsorbtion of Sodium therby inhibiting Chloride rebasorbtion as well.

It is indicated as adjunctive therapy in

  • edema associated with congestive heart failure, 
  • hepatic cirrhosis, and 
  • corticosteroid and estrogen therapy. 
  • It is also indicated in the management of hypertension 


Synthesis of Dichlorphenamide (Diclofenamide)

Piscean 11:58 AM



Reaction Summary
The starting reaction takes place between 2-chlophenol and chlorosulphonic acid that yields 5-chloro-4-hydroxybenzene-1,3-disulfonyl dichloride, upon Aminolysis of last product will yield 4,5-dichlorobenzene-1,3-disulfonamide or Dichlorphenamide (Diclofenamide)

Brief Pharmacology

  • Dichlorphenamide is a sulfonamide and a carbonic anhydrase inhibitor.
  • Dichlorphenamide is used to treat glaucoma. By inhibiting the actions of carbonic anhydrase


Synthesis of Methazolamide

Piscean 6:21 AM


Synthesis of Methazolamide
Click to enlarge

Reaction Summary

Starting reaction occurs in-between hydrazine hydrate and ammonium thiocyanate that produces 1, 2-bis (thiocarbamoyl) hydrazine which on further treatment with phosgene undergoes rearrangements, particularly  molecular rearrangement through loss of ammonia to form 5-amino-2-mercapto-1, 3, 4-thiadiazole. Upon acylation of 5-amino-2-mercapto-1, 3, 4-thiadiazole gives a corresponding amide which on oxidation with aqueous chlorine affords the 2-sulphonyl chloride. Followed by treatment with CH3OH and NaOCH3 yields 5-acetamido-4-methyl-4,5-dihydro-1,3,4-thiadiazol-2-yl sulfochloridite The final step essentially consists of amidation by treatment with ammonia and resulting in the formation of Methazolamide.

Brief Pharmacology

  • Methazolamide is a carbonic anhydrase inhibitor.
  • Methazolamide Uses: Methazolamide is used in combination with other drugs to treat high pressure inside the eye due to glaucoma.
  • Methazolamide Uses: reduces fluid pressure in the eyeball by decreasing fluid formation in the eyeball.
  • Methazolamide Contraindications: allergic, or adrenal gland problems, low blood levels of potassium or sodium, kidney problems, liver problems



Synthesis of Acetazolamide

Piscean 11:01 AM



Reaction Summary
Starting reaction occurs in-between hydrazine hydrate and ammonium thiocyanate that produces 1, 2-bis (thiocarbamoyl) hydrazine which on further treatment with phosgene undergoes rearrangements, particularly  molecular rearrangement through loss of ammonia to form 5-amino-2-mercapto-1, 3, 4-thiadiazole. Upon acylation of 5-amino-2-mercapto-1, 3, 4-thiadiazole gives a corresponding amide which on oxidation with aqueous chlorine affords the 2-sulphonyl chloride. The final step essentially consists of amidation by treatment with ammonia.


Brief Pharmacology


  • Acetazolamide is prtotype in carbonic anhydrase inhibitors, 
  • Acetzolamide act at the proximal tubule, where carbonic anhydrase is membrane-bound and normally catalyses H2CO3-> H2O + CO2 in the lumen and the reverse reaction in the cytoplasm. By blocking CA, acetazolamide inhibit NaHCO3 reabsorption in the proximal tubule.
  • Used to treat 
  1. glaucoma, 
  2. drug-induced edema, 
  3. heart failure-induced edema, 
  4. centrencephalic epilepsy 
  5. and in reducing intraocular pressure after surgery.




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