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Approximately one in four deaths globally is associated with thrombotic events. Direct Factor Xa (fXa) inhibitors are widely used to prevent and treat this condition. Factor Xa is a well\u2010established pharmacological target for the design of oral anticoagulants due to its amplifying role in the coagulation process. In this study, a series of novel aryl\u2010lactam compounds based on 3,5\u2010disubstituted isoxazoles was synthesized and evaluated for their fXa inhibitory activity. Among them, compounds\n                    <jats:bold>10j<\/jats:bold>\n                    ,\n                    <jats:bold>10m<\/jats:bold>\n                    ,\n                    <jats:bold>10p<\/jats:bold>\n                    ,\n                    <jats:bold>10q<\/jats:bold>\n                    , and\n                    <jats:bold>10r<\/jats:bold>\n                    were identified as the most active, exhibiting IC\n                    <jats:sub>50<\/jats:sub>\n                    values between 83.7 and 160.5\u2009\u00b5M, consistent with moderate inhibitory activity. Moreover, these compounds prolonged PT and aPTT at concentrations of 200\u2013400\u2009\u03bcM, while not significantly affecting thrombin\u2010induced clot retraction. Also, by slowing the coagulation process and fXa generation through dilution of PT and aPTT reagents, these compounds prolonged clotting times at 100\u2009\u03bcM. Additionally, their in silico ADMET profiles were predicted, showing a balanced pharmacokinetic profile. In vitro cytotoxicity assays of these compounds in HEK\u2010294, EA.hy926, HaCat, and HCT\u2010116 cell lines revealed negligible to low cytotoxic effects. Finally, molecular docking and molecular dynamics simulations were conducted to rationalize the observed activity and to identify structural aspects that may support future optimization.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70281","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T12:00:36Z","timestamp":1783080036000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Convergent Strategy for Factor Xa Inhibition: Synthesis, Bioinformatics, and Biological Analysis of 3,5\u2010Disubstituted Isoxazoles"],"prefix":"10.1002","volume":"359","author":[{"given":"Sebasti\u00e1n","family":"Morales\u2010Guerrero","sequence":"first","affiliation":[{"name":"Escuela de Qu\u00edmica, Facultad de Qu\u00edmica y de Farmacia Pontificia Universidad Cat\u00f3lica de Chile  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Dur\u00e1n\u2010Osorio","sequence":"additional","affiliation":[{"name":"Escuela de Qu\u00edmica, Facultad de Qu\u00edmica y de Farmacia Pontificia Universidad Cat\u00f3lica de Chile  Santiago Chile"},{"name":"Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences Pontificia Universidad Cat\u00f3lica de Chile  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Burgos\u2010Ravanal","sequence":"additional","affiliation":[{"name":"Escuela de Qu\u00edmica y Farmacia, Facultad de Qu\u00edmica y de Farmacia Pontificia Universidad Cat\u00f3lica de Chile  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8664-0468","authenticated-orcid":false,"given":"Yanina","family":"Moglie","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica del Sur (CONICET\u2010UNS), Departamento de Qu\u00edmica Universidad Nacional del Sur  Bah\u00eda Blanca Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"M\u00e9ndez","sequence":"additional","affiliation":[{"name":"Thrombosis and Healthy Aging Research Center, VITALIS Longevity Center, Medical Technology School, Faculty of Health Sciences, Interuniversity Center for Healthy Aging Universidad de Talca  Talca Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mat\u00edas","family":"Orellana\u2010Saez","sequence":"additional","affiliation":[{"name":"Biosystems Engineering Laboratory, Department of Chemical and Bioprocess Engineering Universidad de Santiago de Chile (USACH)  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Fuentes","sequence":"additional","affiliation":[{"name":"Thrombosis and Healthy Aging Research Center, VITALIS Longevity Center, Medical Technology School, Faculty of Health Sciences, Interuniversity Center for Healthy Aging Universidad de Talca  Talca Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Poblete\u2010Castro","sequence":"additional","affiliation":[{"name":"Biosystems Engineering Laboratory, Department of Chemical and Bioprocess Engineering Universidad de Santiago de Chile (USACH)  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Vicente","family":"Gonz\u00e1lez\u2010Aramundiz","sequence":"additional","affiliation":[{"name":"Escuela de Qu\u00edmica y Farmacia, Facultad de Qu\u00edmica y de Farmacia Pontificia Universidad Cat\u00f3lica de Chile  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7507-1159","authenticated-orcid":false,"given":"Kamal","family":"Dua","sequence":"additional","affiliation":[{"name":"NICM Health Research Institute &amp; 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