Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase

This paper concerns the design, synthesis, and evaluation of inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Initially study was m ade of the structures of the leishmanial and human enzyme active sites to s ee if there were significant differences which could be exploited for selec tive drug design. Then a series of compounds were synthesized based on 5-be nzyl-2,4-diaminopyrimidines. These compounds were assayed against the proto zoan and human enzymes and showed selectivity for the protozoan enzymes. Th e structural data was then used to rationalize the enzyme assay data. Compo unds were also tested against the clinically relevant forms of the intact p arasite. Activity was seen against the trypanosomes for a number of compoun ds. The compounds were in general less active against Leishmania. This latt er result may be due to uptake problems. Two of the compounds also showed s ome in vivo activity in a model of African trypanosomiasis.