Open AccessOptimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic Toxoplasmosis
Author(s) -
James W. Janetka,
Allen T. Hopper,
Ziping Yang,
Jennifer Barks,
Mary Savari Dhason,
Qiuling Wang,
L. David Sibley
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00419
Subject(s) - chemistry , toxoplasma gondii , in vitro , kinase , in vivo , biochemistry , enzyme , ribose , toxoplasmosis , potency , stereochemistry , biology , virology , immunology , antibody , genetics
Calcium dependent protein kinase 1 (CDPK1) is an essential Ser/Thr kinase that controls invasion and egress by the protozoan parasite Toxoplasma gondii . The Gly gatekeeper of CDPK1 makes it exquisitely sensitive to inhibition by small molecule 1 H -pyrazolo[3,4- d ]pyrimidine-4-amine (PP) compounds that are bulky ATP mimetics. Here we rationally designed, synthesized, and tested a series of novel PP analogs that were evaluated for inhibition of CDPK1 enzyme activity in vitro and parasite growth in cell culture. Optimal substitution on the PP scaffold included 2-pyridyl ethers directed into the hydrophobic pocket and small carbocyclic rings accessing the ribose-binding pocket. Further optimization of the series led to identification of the lead compound 3a that displayed excellent potency, selectivity, safety profile, and efficacy in vivo . The results of these studies provide a foundation for further work to optimize CDPK1 inhibitors for the treatment of acute and chronic toxoplasmosis.