The structure-based design and synthesis of selective inhibitors of Trypanosoma cruzi dihydrofolate reductase.
This paper describes the design and synthesis of potential inhibitors of Trypanosoma cruzi dihydrofolate reductase using a structure-based approach. A model of the structure of the T. cruzi enzyme was compared with the structure of the human enzyme. The differences were used to design modifications of methotrexate to produce compounds which should be selective for the parasite enzyme. The derivatives of methotrexate were synthesised and tested against the enzyme and intact parasites.
Zuccotto
F
F
Welsh School of Pharmacy, Cardiff University, UK.
Brun
R
R
Gonzalez Pacanowska
D
D
Ruiz Perez
L M
LM
Gilbert
I H
IH
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000201:enzymology*
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011994:Recombinant Proteins; D013762:Tetrahydrofolate Dehydrogenase