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  3. Improved Bicyclic Pyrrolidine Analogues Inhibit Toxoplasma gondii Growth In Vitro and Cure Infection In Vivo

Improved Bicyclic Pyrrolidine Analogues Inhibit Toxoplasma gondii Growth In Vitro and Cure Infection In Vivo

  • J Med Chem. 2025 Aug 28;68(16):17350-17363. doi: 10.1021/acs.jmedchem.5c00865.
Taher Uddin 1,  Han Xie 2,  Payal Mittal 3 4 5,  Chloe C Ence 2,  Shrushti Patil 1,  Amit Sharma 4,  Bruno Melillo 6 7,  Arnab K Chatterjee 2,  L David Sibley 1
Affiliations

Affiliations

  • 1 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63130, United States.
  • 2 Calibr-Skaggs at Scripps Research, La Jolla, California 92037, United States.
  • 3 ICMR-National Institute of Malaria Research (NIMR), NIMR, Sector-8, Dwarka, New Delhi 110077, India.
  • 4 Molecular Medicine-Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India.
  • 5 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • 6 Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142, United States.
  • 7 Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
PMID: 40778727 DOI: 10.1021/acs.jmedchem.5c00865
Abstract

Inhibition of phenylalanine tRNA synthetase (PheRS) by bicyclic pyrrolidines provides a potent and specific inhibition of Parasite growth. Herein, we describe novel bicyclic pyrrolidines designed to explore structure-activity relationships with Toxoplasma gondii vs human PheRS. Modification of the biaryl alkyne extension, which fits into the phenylalanine-binding site, showed a strong preference for ortho hydroxyl addition over meta and para. Further addition of N to both the proximal and distal phenyl rings of the biaryl alkyne and to the methoxyphenyl urea moiety, which fits into a unique auxiliary site present in the Parasite enzyme, identified compounds with reduced plasma protein binding and lower hERG activity. Finally, we identified a potent lead with improved pharmacokinetics, extended plasma exposure, central nervous system penetration, and low-dose cure of acute Infection in mouse. Collectively, these findings advance new candidates for the treatment of toxoplasmosis based on selective and potent inhibitors of Parasite PheRS.

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