• 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, 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

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

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

• 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

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

• 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

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 propionatepropionyl p-chlorophenyl acetonitrile

3-methyl butanol

Hemiketal

Cl

NC C

C2H5

CH-CH2-CH2-O

NH2C=NH

NH2

Cl

NC C

C2H5

NH2C=NH

NH

Dehydration

Rearrangement

Pyrimethamine

β-ethyl, β-isoamyl oxy p-chlorophenyl acetonitrile

Cl

NC C

C2H5

CH-CH2-CH2-O

NH2C=NH

NH2

Cl

NC C

C2H5

NH2C=NH

NH

Dehydration

Rearrangement

Pyrimethamine

β-ethyl, β-isoamyl oxy p-chlorophenyl acetonitrile