Optimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic Toxoplasmosis.

ABSTRACT: 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 1H-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 tha

SUBMITTER: Janetka JW 

PROVIDER: S-EPMC7325724 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature