Bicyclic pyrrolidine inhibitors of phenylalanine t-RNA synthetase with antiparasitic potency and brain exposure.

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition and , including in models of infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular to achieve sufficient exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs. host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency, ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analog series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.