Synthesis and Testing of 5-Benzyl-2,4-diaminopyrimidines as Potential Inhibitors of Leishmanial and Trypanosomal Dihydrofolate Reductase

Abstract

Dihydrofolate reductase is a drug target that has not been thoroughly investigated in leishmania and trypanosomes. Work has previously shown that 5-benzyl-2,4-diaminopyrimidines are selective inhibitors of the leishmanial and trypanosome enzymes. Modelling predicted that alkyl/aryl substitution on the 6-position of the pyrimidine ring should increase enzyme activity of 5-benzyl-2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Various compounds were prepared and evaluated against both the recombinant enzymes and the intact organisms. The presence of a substituent had a small or negative effect on activity against the enzyme or intact parasites compared to unsubstituted compounds.

Keywords::

• Dihydrofolate Reductase
• Trypanosoma Brucei
• Trypanosoma Cruzi
• Leishmania