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A preclinically guided selection approach was conducted, combining optimized\u00a0in silico, in vitro\/ex vivo, and\u00a0in vivo  assays to guide pharmacokinetic-driven compound selection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Preliminary sorting was enabled by several in vitro\/ex vivo assays (intestinal permeability, plasma protein binding, blood-to-plasma ratio, and microsomal stability), adapted for high lipophilicity. To challenge this sorting, the most promising and the least promising 3-HPAs were selected for further in vivo studies in\n                      <jats:italic>Plasmodium berghei<\/jats:italic>\n                      -infected mice (concentration\u2013time profiles and racemate separation). Finally, a physiologically based pharmacokinetic model was built for the overall most promising 3-HPA to gain initial insights into its pharmacokinetic behavior in humans.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The most hydrophilic compounds, TKK130 (a low-extraction drug) and SAKK381 (a high-extraction drug), presented the most promising in vitro\/ex vivo pharmacokinetic profiles (i.e., the highest intestinal permeability and unbound plasma fraction). In particular, TKK130 was favorable because the blood-to-plasma ratio indicated a slight preference for distribution into red blood cells. One of the most lipophilic 3-HPAs, SAKK394 (a low-extraction drug), exhibited the poorest in vitro\/ex vivo profile. In vivo, TKK130 demonstrated a sustained pharmacokinetic profile with the highest dose-adjusted total exposure over time, the lowest enantioselective clearance, and a 100% cure rate without signs of toxicity. The physiologically based pharmacokinetic model for the most promising TKK130 demonstrated a good fit to the in vivo data. Extrapolation to humans enabled the first human pharmacokinetic prediction, which was compared to the profile of lumefantrine. Profiles in adults were characterized by high interindividual variability (e.g., total exposure of 814\u20133856\u00a0ng\/mL\u00a0h) and food effects (e.g., total exposure (fasted 1846\u00a0ng\/mL\u00a0h vs. fed 3407\u00a0ng\/mL\u00a0h)).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>TKK130 was identified as the most favorable compound of the novel antimalarial 3-hydroxypropanamidines because of its encouraging pharmacokinetic profile, combined with its excellent in vivo efficacy and lack of observed toxicity in mice. TKK130 is a promising candidate for further preclinical and clinical development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12936-026-05837-9","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T07:16:19Z","timestamp":1773126979000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative preclinical strategy for pharmacokinetic profiling and candidate selection of 3-hydroxypropanamidines: a promising antimalarial class"],"prefix":"10.1186","volume":"25","author":[{"given":"Alena","family":"Moritz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bastian","family":"Hirn-Derksen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia","family":"Klein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Held","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Wittlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Rottmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Kurz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bjoern B.","family":"Burckhardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"5837_CR1","unstructured":"World Health Organization. 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