TY - JOUR
T1 - Bicyclic Pyrrolidine Inhibitors of Toxoplasma gondii Phenylalanine t-RNA Synthetase with Antiparasitic Potency In Vitro and Brain Exposure
AU - Ence, Chloe C.
AU - Uddin, Taher
AU - Borrel, Julien
AU - Mittal, Payal
AU - Xie, Han
AU - Zoller, Jochen
AU - Sharma, Amit
AU - Comer, Eamon
AU - Schreiber, Stuart L.
AU - Melillo, Bruno
AU - Sibley, L. David
AU - Chatterjee, Arnab K.
N1 - Publisher Copyright:
© 2024 American Chemical Society
PY - 2024/6/14
Y1 - 2024/6/14
N2 - 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 optimal 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 and ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analogue series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.
AB - 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 optimal 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 and ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analogue series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.
KW - anti-infective
KW - central nervous system infection
KW - small molecule inhibitor
KW - toxoplasmosis
UR - http://www.scopus.com/inward/record.url?scp=85193597734&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.4c00170
DO - 10.1021/acsinfecdis.4c00170
M3 - Article
C2 - 38743643
AN - SCOPUS:85193597734
SN - 2373-8227
VL - 10
SP - 2212
EP - 2221
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 6
ER -