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The novel derivatives are prepared thorough a divergent, chemo\u2010selective approach starting from N,S\u2010acetal intermediates. Compounds <jats:bold>13\u201317<\/jats:bold> are tested for their antimalarial and antileishmanial activity and their cytotoxicity is evaluated against human fibroblast. Pyrazoles <jats:bold>14\u2009d,e<\/jats:bold> and pyrimidine <jats:bold>17e<\/jats:bold> are identified as novel and effective antiplasmodial agents being able to inhibit, at micromolar concentrations, chloroquine(CQ)\u2010sensitive and CQ\u2010resistant <jats:italic>Plasmodium falciparum<\/jats:italic> strains, as well as <jats:italic>Leishmania infatum<\/jats:italic> and <jats:italic>Leishmania tropica<\/jats:italic> protozoa. Additionally, favorable pharmacokinetics and toxicity profiles are predicted for the compounds.<\/jats:p>","DOI":"10.1002\/cmdc.202500154","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T09:39:49Z","timestamp":1749721189000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antiprotozoal Activity of Highly Substituted Pyrazole and Pyrimidine Derivatives"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7003-7891","authenticated-orcid":false,"given":"Matteo","family":"Lusardi","sequence":"first","affiliation":[{"name":"Department of Pharmacy Universit\u00e0 degli Studi di Genova  viale Benedetto XV, 3 16132 Genova Italy"},{"name":"Molecular Modeling and Drug Discovery Laboratory Istituto Italiano di Tecnologia  Via Morego, 30 16163 Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9030-1066","authenticated-orcid":false,"given":"Nicoletta","family":"Basilico","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche Chirurgiche e Odontoiatriche Universit\u00e0 degli Studi di Milano  Via della Commenda, 10 20133 Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7531-3373","authenticated-orcid":false,"given":"Erika","family":"Iervasi","sequence":"additional","affiliation":[{"name":"Proteomics and Mass Spectrometry Unit IRCCS Ospedale Policlinico San Martino  L.go R. 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