2,4-Diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase.
This paper describes the synthesis of 4'-substituted and 3',4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity.
Pez
Didier
D
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, CF10 3XF Cardiff, UK.
Leal
Isabel
I
Zuccotto
Fabio
F
Boussard
Cyrille
C
Brun
Reto
R
Croft
Simon L
SL
Yardley
Vanessa
V
Ruiz Perez
Luis M
LM
Gonzalez Pacanowska
Dolores
D
Gilbert
Ian H
IH
D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects; D018320:Leishmania major / Q000201:enzymology*; D017737:Macrophages, Peritoneal / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000166:cytology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D013762:Tetrahydrofolate Dehydrogenase