Structural Insights into the Development of Cycloguanil Derivatives as Pteridine-Reductase-1 Inhibitors.

Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of PTR1 (PTR1). A small library of cycloguanil derivatives was developed, resulting in and having IC values of 692 and 186 nM, respectively, toward PTR1. Structural analysis revealed that the increased potency of and is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, cell-growth-inhibition tests indicated that is also effective on . The simultaneous inhibition of DHFR and PTR1 activity in is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.