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 Tr ypanosoma cruzi dihydrofolate reductase using a structure-based approach. A model of the structure of the T cruzi enzyme was compared with the structu re of the human enzyme. The differences were used to design modifications o f methotrexate to produce compounds which should be selective for the paras ite enzyme. The derivatives of methotrexate were synthesised and tested aga inst the enzyme and intact parasites. (C) 1999 Elsevier Science Ltd. All ri ghts reserved.