Sf. Chowdhury et al., Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase, J MED CHEM, 42(21), 1999, pp. 4300-4312
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.