Inhibition of calcium dependent protein kinase 1 (CDPK1) by pyrazolopyrimidine analogs decreases establishment and reoccurrence of central nervous system disease by Toxoplasma gondii

J Med Chem. 2017 Sep 21. doi: 10.1021/acs.jmedchem.7b01192. [Epub ahead of print]

Rutaganira FU, Barks J, Dhason MS, Wang Q, Lopez MS, Long S, Radke JB, Jones NG, Maddirala AR, Janetka JW, El Bakkouri M, Hui R, Shokat KM, Sibley LD.

Abstract

Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are essential to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goals of increasing selectivity over host enzymes, improving anti-parasite potency, and improving metabolic stability. The resulting lead compound 24 exhibits excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.

PMID:

28933846

DOI:

10.1021/acs.jmedchem.7b01192