Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

The optimization
of compounds with multiple targets is a difficult
multidimensional problem in the drug discovery cycle. Here, we present
a systematic, multidisciplinary approach to the development of selective
antiparasitic compounds. Computational fragment-based design of novel
pteridine derivatives along with iterations of crystallographic structure
determination allowed for the derivation of a structure–activity
relationship for multitarget inhibition. The approach yielded compounds
showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L.
major PTR1, and selective submicromolar inhibition of parasite
dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining
design for polypharmacology with a property-based on-parasite optimization,
we found three compounds that exhibited micromolar EC50 values against T. brucei brucei while retaining
their target inhibition. Our results provide a basis for the further
development of pteridine-based compounds, and we expect our multitarget
approach to be generally applicable to the design and optimization
of anti-infective agents.