2. Academic Validation
  3. Bicyclic pyrrolidine inhibitors of Toxoplasma gondii phenylalanine t-RNA synthetase with antiparasitic potency in vitro and brain exposure

Bicyclic pyrrolidine inhibitors of Toxoplasma gondii phenylalanine t-RNA synthetase with antiparasitic potency in vitro and brain exposure

  • bioRxiv. 2024 Feb 28:2024.02.28.582607. doi: 10.1101/2024.02.28.582607.
Chloe C Ence 1,  Taher Uddin 2,  Julien Borrel 3,  Payal Mittal 4 5,  Han Xie 1,  Jochen Zoller 3,  Amit Sharma 4,  Eamon Comer 3,  Stuart L Schreiber 3 6,  Bruno Melillo 3 7,  L David Sibley 2,  Arnab K Chatterjee 1
Affiliations

Affiliations

  • 1 Calibr at Scripps Research, La Jolla, CA 92037, USA.
  • 2 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63130, USA.
  • 3 Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02142, USA.
  • 4 Molecular Medicine-Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India.
  • 5 ICMR-NIMR, Sector-8, Dwarka, New Delhi-110077, India, Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
  • 6 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • 7 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
PMID: 38464220 DOI: 10.1101/2024.02.28.582607
Abstract

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to Parasite growth inhibition in vitro and in vivo, including in models of Toxoplasma 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.

Keywords

anti-infective; central nervous system infection; small molecule inhibitor; toxoplasmosis.

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