Lecture-2015

1. • It is a class of antimalarial drugs containing 6-
membered heterocyclic ring containing 2
nitrogen atoms at a distance of 1 carbon atom
• Member of this class: pyrimethamine

2. 2, 4 diaminopyrimidine
• It is an antifolate
• This compound has been studied extensively and
maximum activity was noticed when a chlorophenyl
group was attached at position 5 and an electron
donating group (C2H5) at position 6
• Cl group should be at para position
• By such modifications-pyrimethamine-has maximum
activity

3. Pyrimethamine mechanism
• Interferes with utilization of folic acid inside
plasmodium by inhibiting dihydrofolate
reductase of the parasite
• Hence, there is no synthesis of folic acid,
which in needed for the synthesis of purine
and pyrimidine that are required for nucleic
acid. As a result, replication of plasmodium is
inhibited

4. Structure Activity Relationship
• 2 primary amino groups at position 2 and 4
when converted to 2o
or 3o
activity is reduced
• An aromatic ring is directly attached with
pyrimidine ring for maximum activity, if carbon
or N is inserted between them activity is
decreased
C
N

5. • If aromatic ring is replaced by hetrocyclic
compound activity is decreased
• Aromatic ring must contain an electron
withdrawing group at p-position
• Presence of e donating group at position 6 is
also necessary for activity

6. • When 2 rings are separated by a methylene,
antiplasmodial activity is decreased but
antibacterial activity is increased-
trimethoprim

7. • pyrimethamine is used in combination with
sulfadoxine (500mg) and the name is Fansidar, which is
used in treatment and prophylaxis of malaria. It
radically cures P. falciparum but clinically cures other
species
• Sulfonamide competes with PABA for synthesis of
dihydrofolate while pyrimethamine inhibits
dihydrofolate reductase –hence sequential inhibition
of purine and pyrimidine

8. Synthesis of pyrimethamine
Cl
CH2 CN
CH3-CH2-CO-OC2H5
C2H5ONa
Cl
NC HC
CO
C2H5
Cl
NC HC
COH
C2H5
CH-CH2-CH2-OH
CH-CH2-CH2-O
Para chlorophenyl acetonitrile
Ethyl propionate
propionyl p-chlorophenyl
acetonitrile
3-methyl butanol
Hemiketal

9. Cl
NC C
C2H5
CH-CH2-CH2-O
NH2C=NH
NH2
Cl
NC C
C2H5
NH
2C=NH
NH
Dehydration
Rearrangement
Pyrimethamine
β-ethyl, β-isoamyl oxy p-chlorophenyl
acetonitrile

10. Cl
NC C
C2H5
CH-CH2-CH2-O
NH2C=NH
NH2
Cl
NC C
C2H5
NH
2C=NH
NH
Dehydration
Rearrangement
Pyrimethamine
β-ethyl, β-isoamyl oxy p-chlorophenyl
acetonitrile