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Among these, <jats:italic>Tg<\/jats:italic>CDPK1 is required for parasite motility, cell invasion, and egress and hence is essential both for in\u2009vitro growth of <jats:italic>T. gondii<\/jats:italic> and to cause infections in animals. Using existing X\u2010ray cocrystal structures of pyrazolopyrimidine (PP) inhibitors bound to <jats:italic>Tg<\/jats:italic>CDPK1, 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 <jats:italic>Tg<\/jats:italic>CDPK1 inhibitors that effectively block parasite growth in cells. The resulting lead compounds <jats:bold>44<\/jats:bold> and <jats:bold>45<\/jats:bold> 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.<\/jats:p>","DOI":"10.1002\/cmdc.202500440","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T07:03:53Z","timestamp":1754636633000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structure\u2010Based Drug Design of Novel Heterocyclic Scaffolds as TgCDPK1 Inhibitors"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1747-5689","authenticated-orcid":false,"given":"Anoopjit Singh","family":"Kooner","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics Washington University School of Medicine  St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariah","family":"Norman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics Washington University School of Medicine  St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9939-625X","authenticated-orcid":false,"given":"Igi","family":"Vilza","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology Washington University School of Medicine  St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8135-1675","authenticated-orcid":false,"given":"Michael P.","family":"Mannino","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics Washington University School of Medicine  St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Savari","family":"Dhason","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology Washington University School of Medicine  St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Helander","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics Washington University School of Medicine  St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1527-0705","authenticated-orcid":false,"given":"Shrushti","family":"Patil","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology Washington University School of Medicine  St. Louis MO 63110 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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