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

• DOI: 10.26434/chemrxiv-2021-9fpln-v3
• Publication Date: 2022-02-01T13:42:02Z
• Authors: Ina Poehner; Antonio Quotadamo; Joanna Panecka-Ho...; Rosaria Luciani; Matteo Santucci; Pasquale Linciano; Giacomo Landi; Flavio Di Pisa; Lucia Dello Iacono; Cecilia Pozzi; Stefano Mangani; Sheraz Gul; Gesa Witt; Bernhard Ellinger; Maria Kuzikov; Nuno Santarem; Anabela Cordeiro-...; Maria Paola Costi; Alberto Venturelli; Rebecca Wade

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 anti-parasitic 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 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, whilst 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.