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

Abstract

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.