Potent and Selective Inhibitors of CDPK1 from <i>T. gondii</i> and <i>C. parvum</i> Based on a 5‑Aminopyrazole-4-carboxamide Scaffold

5-Aminopyrazole-4-carboxamide was used as an alternative scaffold to substitute for the pyrazolopyrimidine of a known “bumped kinase inhibitor” to create selective inhibitors of calcium-dependent protein kinase-1 from both <i>Toxoplasma gondii</i> and <i>Cryptosporidium parvum</i>. Compounds with low nanomolar inhibitory potencies against the target enzymes were obtained. The most selective inhibitors also exhibited submicromolar activities in <i>T. gondii</i> cell proliferation assays and were shown to be nontoxic to mammalian cells

SAR Studies of 5‑Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of <i>Toxoplasma gondii</i> CDPK1

We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from <i>T. gondii</i>. The current work, through structure–activity relationship studies, led to the discovery of compounds (<b>34</b> and <b>35</b>) with improved characteristics over the starting inhibitor <b>1</b> in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds <b>34</b> and <b>35</b> were further demonstrated to be more effective than <b>1</b> in a mouse infection model and markedly reduced the amount of <i>T. gondii</i> in the brain, spleen, and peritoneal fluid, and <b>35</b> given at 20 mg/kg eliminated <i>T. gondii</i> from the peritoneal fluid