purine heterocyclic chemistry

1. ORGANIC CHEMISTRY
HRTEROCYCLIC CHEMISTRY
PURINE
unit-4
M.PHARM
Pharmaceutical chemistry
(1ST SEM)

2. PURINE
Purines are anticancer, antiviral in action. They are used in rheumatoid arthritis,
ulcerative colitis etc. some purines are shown below.

3. PURINE
ACYCLOVIR
NAME OF THE DRUG( TRADE NAME): Zovirax-400mg oral tablet (GSK)
ACTIVE CONSTITUENT: Acyclovir(guanine analogue)
COMMON NAME: Acyclo-G
IUPAC NAME: 2-amino-9-(2-hydroxyethoxymethyl)-1H-purin-6-one
CHEMICAL FORMULA: C8H11N5O3
MOL. WT.: 225.2g/mol
ENANTIOMERIC/RACEMIC: No chiral carbon is present
(achiral)
OPTICALACTIVITY: unspecified
DOSE: 400mg / 12 hr (For genital herpes),800mg/4hr(For HSV)
MELTING POINT: 256.50 C
PURITY: 100%(95-105% as per IP)
ASSAY: U.V (I.P. 2007,Vol.2, pg 70)
MOA: Acyclovir convert to acyclovir triphosphate by the action of thymidine kinase.
Acyclovir triphosphate can be incorporated into viral DNA and viral growth is inhibited
N
N
1
2
3
4
5
6
7
8
HN
N
O
H2N
O
OH
9

4. PURINE
SAR:
 Removal of –OH by L-valyl ester can
increase 10 times bioavailability
(Valacyclovir)
 Addition of –CH2 in side chain increases
safety profile(Gancyclovir)
 Removal of carbonyl group by –NH2 at
6th position can increase water solubility
but decreases metabolism and absorption
(Desciclovir)
 Addition of 3,5-dichlorobenzyl to –NH2
group at 2, will increase activity against
HSV(Herpes Simplex Virus).
USES:
Used for treatment of HSV(Herpes Simplex
Virus) and chickenpox.
ACYCLOVIR
Gancyclovir
HN
N
N
N
O
H2N
O
O
O
NH2
HCL
1
2
3
4
5
6 7
8
9
Valacyclovir
Acyclovir

5. PURINE
ACYCLOVIR
Hexamethyldisilazane is used to protect the amino and keto group of guanine
SYNTHESIS

6. PURINE
6-MERCAPTOPURINE
NAME OF THE DRUG( TRADE NAME): 6-Mercaptopurine(Zydus cadila
healthcare limited(biogen)
ACTIVE CONSTITUENT: 6-mercaptopurine (6-MP) ,Purine analogue
COMMON NAME: 6-MP
IUPAC NAME: 3,7-dihydropurine-6-thione
CHEMICAL FORMULA: C5H4N4S,H2O
MOL. WT.: 170.2 g/mol
ENANTIOMERIC/RACEMIC: No chiral carbon is present (achiral)
OPTICALACTIVITY: Unspecified
DOSE: 1.5mg/kg daily(50mg tablets) for leukemia
MELTING POINT: 3130C
PURITY: 100%(90-100% I.P.)
ASSAY: U.V.(specific absorbance 1165 at 325nm) (I.P. 2007,Vol.2, pg 737)

7. PURINE
MOA: The hypoxanthine-guanine phosphoribosyl transferase enzyme (HPRT) processes 6-MP to
thio-IMP (Thio-iminophosphate), which is then converted to thio-XMP(Thio xanthine
monophosphate) and thio-GMP. Subsequent metabolism of thio-GMP by kinases and reductases
yields thio-dGTP (thio-deoxy Guanosine triphosphate) which is incorporated into replicating
DNA strands and triggers the DNA mismatch-repair machinery, leading to cell cycle arrest and
apoptosis.
N
H
N
H
N
N
S
1
2
3
4
5 6
7
8
9
SAR:
• Substitution at 6th position with hydrophobic group will lead
to increased activity.
• Substitution at 6th position with carbon chain upto 15-16 will
increase activity but after that it decreases activity.
• Thione group is essential for activity.
USES:
Used for treatment of acute lymphatic leukemia, Ulcerative
colitis and Crohn’s disease.
6-MERCAPTOPURINE

8. PURINE
6-MERCAPTOPURINE
SYNTHESIS

9. PURINE
TENOFOVIR DISOPROXIL FUMARATE
NAME OF THE DRUG( TRADE NAME): Tenvir 300mg tablets (cipla)
ACTIVE CONSTITUENT: Prodrug , Converts to tenofovir
COMMON NAME: Tenofovir Disoproxil Fumarate
IUPAC NAME: [[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-
yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;but-2-enedioic acid
CHEMICAL FORMULA: C23H34N5O14P
MOL. WT.: 635.5g/mol
ENANTIOMERIC/RACEMIC: R(absolute
stereochemistry)
OPTICALACTIVITY: Unspecified
DOSE: 300mg/day( for HIV)
MELTING POINT: 113-1150C
PURITY: 100%(90-100%)
ASSAY: Liquid chromatography( I.P. 2007, Vol. 3,pg.1158)
MOA: Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with
the natural substrate deoxyadenosine 5'- triphosphate and, after incorporation into DNA, by DNA chain
termination.Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and
mitochondrial DNA polymerase γ
N
N N
N
NH2
O P
O
O
O
O O CH3
O O CH3
CH3
O
O CH3
H
H
O
HO
O
OH
1
2
3
4
5
6
7
8
9
Tenofovir disoproxil fumarate
CH3

10. PURINE
SAR: Removal of –CH3 will form adefovir disoproxil which is less potent
USES: Anti-HIV, anti-hepetitis -B
TENOFOVIR DISOPROXIL FUMARATE
N
N N
N
NH2
O P
O
O
O
O O CH3
O O CH3
CH3
O
O CH3
1
2
3
4
5
6
7
8
9
CH3
Adefovir disoproxil

11. PURINE
TINOFOVIR DISOPROXIL FUMARATE
SYNTHESIS
Adenine or 6-
amino purine
9-(2-Hydroxypropyl) adenine Diethyl P-toluene
Sulfonyloxy Methyl
Phosphonate (DESMP)
Tinofovir Disoproxil Fumarate
Tenofovir
CMIC- Chloromethyl Isopropyl Carbonate
Cl O O CH3
CH3
O

12. PURINE
VALACYCLOVIR
NAME OF THE DRUG( TRADE NAME): Valcivir(1000 and
500 mg) cipla
ACTIVE CONSTITUENT: Prodrug , converts to acyclovir
COMMON NAME: Valacyclovir
IUPAC NAME: 2-[(2-amino-6-oxo-1H-purin-9-
yl)methoxy]ethyl (2S)-2-amino-3-methylbutanoate;hydrochloride
CHEMICAL FORMULA: C13H21ClN6O4
MOL. WT.: 360.8g/mol
ENANTIOMERIC/RACEMIC: S(absolute stereochemistry)
OPTICALACTIVITY: unspecified
DOSE: For cold sores-2000 milligrams (mg) every 12 hours for
one day. For genital herpes 1st outbreak: Adults—1000
milligrams (mg) two times a day for ten days
MELTING POINT: 170-1720C
PURITY: 100%(90-110%) as per USP
ASSAY: Liquid chromatogtaphy( USP Revision Bulletin Official
May 1, 2012)

13. PURINE
VALACYCLOVIR
MOA: Valacyclovir is converted to acyclovir, which is converted to its triphosphate form,
acyclovir triphosphate (ACV-TP). ACV-TP competitively inhibits viral DNA polymerase,
incorporates into and terminates the growing viral DNA chain, and inactivates of the viral
DNA polymerase
USES: For herpes simplex, varicella zoster, cytomegalovirus infections

14. PURINE
VALACYCLOVIR
SYNTHESIS
Acyclovir
N-benzyloxy carbonyl-L-valine
DCC (N,N′-
Dicyclohexylcarbodiimide), DMAP
(N,N-Dimethylpyridin-4-amine), and
DMF( Dimethyl formamide)
Benzyloxy
carbonyl
valacyclovir
Valacyclovir hydrochloride

15. PURINE
AZATHIOPRINE
NAME OF THE DRUG( TRADE NAME): Imuran
25mg/50mg/75 mg(GSK)
ACTIVE CONSTITUENT: thiopurine
COMMON NAME: AZA
IUPAC NAME: 6-(3-methyl-5-nitroimidazol-4-
yl)sulfanyl-7H-purine
CHEMICAL FORMULA: C9H7N7O2S
MOL. WT.: 277.263 g/mol
ENANTIOMERIC/RACEMIC: Achiral
OPTICAL ACTIVITY: Unspecified
DOSE: Initial dose: 3 to 5 mg/kg orally once a day,
beginning at the time of transplant
Maintenance dose: 1 to 3 mg/kg orally once a day
MELTING POINT: 243.5 °C
PURITY: 100%(93-107%)
ASSAY: Liquid chromatography(USP 28- NF24, Pg-226)
1
2
3
4
5

16. PURINE
AZATHIOPRINE
MOA: i. Azathioprine inhibits the synthesis of purine in the
cell.
ii. This will further leads to the inhibition of synthesis of DNA
and RNA.
iii. Azathioprine also interacts with cellular metabolism and
results in the inhibition of mitosis
SAR: Substitution at 6th position with hydrophobic group will
lead to increased activity.
• Substitution at 6th position with carbon chain upto 15-16 will
increase activity but after that it decreases activity.
• Thione group is essential for activity.
USES: Immunosuppressive medication. It is used in rheumatoid
arthritis, granulomatosis with polyangiitis, Crohn's disease,
ulcerative colitis, systemic lupus erythematosus, and in kidney
transplants to prevent rejection.
N
N N
H
N
S
N
N
H3C
N
O
O
1
2
3
4
5
6
7
8
9
Azathioprine

17. PURINE
AZATHIOPRINE
SYNTHESIS

18. THANK YOU