A) Structures and biological activity of 44 pyrazolopyrimidine, CZ29 pyrrolopyrimidine, and 3 quinoline Amide TgCDPK1 inhibitors; B) Compounds 44, CZ29 (analog), and 3 bound to TgCDPK1.

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii and poses grave health concern for immunocompromised patients. T. gondii has a family of calcium dependent protein kinases (CDPKs) that control a variety of critical processes. Among these, TgCDPK1 is required for parasite motility, cell invasion, and egress and hence is essential both for in vitro growth of T. gondii and to cause infections in animals. Using existing X-ray cocrystal structures of pyrazolopyrimidine (PP) inhibitors bound to TgCDPK1, six new chemical series of inhibitors are rationally designed. The synthesis of analogs based on the most promising novel series is pursued, which resulted in potent TgCDPK1 inhibitors that effectively block parasite growth in cells. The resulting lead compounds 44 and 45 belonging to the imidazopyrazine chemical series demonstrate the promising potential of this new class of inhibitors for the treatment and possible cure of the Toxoplasmosis.