Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 6, Issue 12, Pages 1184-1189Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.5b00319
Keywords
Toxoplasma gondii; calcium-dependent protein kinase-1; enzyme inhibitor; structure-activity relationship studies
Categories
Funding
- National Institute of Allergy and Infectious Diseases
- National Institute of Child Health and Human Development of the National Institutes of Health [R01AI089441, R01AI111341, R01HD080670]
- United States Department of Agriculture [2014-06183]
- United States Department of Veterans Affairs Biomedical Laboratory Research and Development [BX002440]
- U.S. Department of Energy Office of Basic Energy Sciences [DE-AC02-76SF00515]
- National Institutes of Health [P41GM103393]
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We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from T. gondii. The current work, through structure-activity relationship studies, led to the discovery of compounds (34 and 35) with improved characteristics over the starting inhibitor 1 in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds 34 and 35 were further demonstrated to be more effective than 1 in a mouse infection model and markedly reduced the amount of T. gondii in the brain, spleen, and peritoneal fluid, and 35 given at 20 mg/kg eliminated T. gondii from the peritoneal fluid.
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