Synthesis of β-fluoropyrrolidines designed to reduce hERG affinity in a class of antiparasitic compounds.

Malaria is a parasitic disease caused by the parasite Plasmodium which results in hundreds of thousands of deaths per year. The need for new drugs for the treatment of this disease is imperative as new resistant strains of Plasmodium emerge. Previously, our group reported two related series of pyrrolidine-based antimalarial compounds. While both series were found to be orally efficacious in a mouse infection model, some analogs also showed modest affinities for the hERG ion channel. Herein, we describe the attempted synthesis of β-fluoro substituted pyrrolidine analogs of both chemotypes. In this work, we observed position-dependent chemical instability of fluorine on the pyrrolidine ring. β-Fluoro substituted pyrrolidine (±)-3 was tested in the P. falciparum 3D7 assay and showed a 40-fold loss of anti-Plasmodium potency with little change in weak hERG affinity at 10 μM. In an effort to expand the utility of this work, pyrrolidine (±)-1 and fluoropyrrolidine (±)-3 were also tested against the related apicomplexan parasite Cryptosporidium parvum which causes cryptosporidiosis. Both compounds showed modest potency (EC50 = 10 μM and 12 μM, respectively), implying this series could be further optimized for treatment for cryptosporidiosis.