{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:51:38Z","timestamp":1774435898343,"version":"3.50.1"},"reference-count":61,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"CQE","doi-asserted-by":"publisher","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"IMS","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}]},{"name":"IMS","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}]},{"name":"IMS","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}]},{"name":"IMS","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}]},{"name":"IMS","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}]},{"name":"IMS","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"IMS","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"IMS","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"IMS","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}]},{"name":"IMS","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"IMS","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}]},{"name":"IMS","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}]},{"name":"IMS","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}]},{"name":"IMS","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}]},{"name":"IMS","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}]},{"name":"iMed.ULisboa","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}]},{"name":"iMed.ULisboa","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}]},{"name":"iMed.ULisboa","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}]},{"name":"iMed.ULisboa","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}]},{"name":"iMed.ULisboa","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}]},{"name":"iMed.ULisboa","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"iMed.ULisboa","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"iMed.ULisboa","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"iMed.ULisboa","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}]},{"name":"iMed.ULisboa","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"iMed.ULisboa","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}]},{"name":"iMed.ULisboa","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}]},{"name":"iMed.ULisboa","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}]},{"name":"iMed.ULisboa","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}]},{"name":"iMed.ULisboa","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}]},{"name":"BioISI","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}]},{"name":"BioISI","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}]},{"name":"BioISI","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}]},{"name":"BioISI","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}]},{"name":"BioISI","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}]},{"name":"BioISI","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"BioISI","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"BioISI","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"BioISI","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}]},{"name":"BioISI","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"BioISI","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}]},{"name":"BioISI","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}]},{"name":"BioISI","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}]},{"name":"BioISI","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}]},{"name":"BioISI","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}]},{"name":"MARE\u2014Marine and Environmental Sciences Centre","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}]},{"name":"Associated Laboratory ARNET","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}]},{"name":"Associated Laboratory ARNET","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}]},{"name":"Associated Laboratory ARNET","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}]},{"name":"Associated Laboratory ARNET","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}]},{"name":"Associated Laboratory ARNET","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}]},{"name":"Associated Laboratory ARNET","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"Associated Laboratory ARNET","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"Associated Laboratory ARNET","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"Associated Laboratory ARNET","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}]},{"name":"Associated Laboratory ARNET","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"Associated Laboratory ARNET","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}]},{"name":"Associated Laboratory ARNET","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}]},{"name":"Associated Laboratory ARNET","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}]},{"name":"Associated Laboratory ARNET","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}]},{"name":"Associated Laboratory ARNET","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}]},{"name":"the project BEAP MAR","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}]},{"name":"the project BEAP MAR","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}]},{"name":"the project BEAP MAR","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}]},{"name":"the project BEAP MAR","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}]},{"name":"the project BEAP MAR","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}]},{"name":"the project BEAP MAR","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"the project BEAP MAR","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"the project BEAP MAR","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"the project BEAP MAR","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}]},{"name":"the project BEAP MAR","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"the project BEAP MAR","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}]},{"name":"the project BEAP MAR","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}]},{"name":"the project BEAP MAR","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}]},{"name":"the project BEAP MAR","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}]},{"name":"the project BEAP MAR","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}]},{"name":"Interreg Atlantic Area","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}]},{"name":"Interreg Atlantic Area","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}]},{"name":"Interreg Atlantic Area","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}]},{"name":"Interreg Atlantic Area","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}]},{"name":"Interreg Atlantic Area","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}]},{"name":"Interreg Atlantic Area","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"Interreg Atlantic Area","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"Interreg Atlantic Area","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"Interreg Atlantic Area","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}]},{"name":"Interreg Atlantic Area","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"Interreg Atlantic Area","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}]},{"name":"Interreg Atlantic Area","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}]},{"name":"Interreg Atlantic Area","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}]},{"name":"Interreg Atlantic Area","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}]},{"name":"Interreg Atlantic Area","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}]},{"name":"European Union","award":["CEECIND\/03881\/2018\/CP1553\/CT0007"],"award-info":[{"award-number":["CEECIND\/03881\/2018\/CP1553\/CT0007"]}]},{"name":"European Union","award":["CEECINST\/00060\/2021\/CP2902\/CT0004"],"award-info":[{"award-number":["CEECINST\/00060\/2021\/CP2902\/CT0004"]}]},{"name":"European Union","award":["2023.06590.CEECIND"],"award-info":[{"award-number":["2023.06590.CEECIND"]}]},{"name":"European Union","award":["EXPL\/MED-QUI\/1017\/2021"],"award-info":[{"award-number":["EXPL\/MED-QUI\/1017\/2021"]}]},{"name":"European Union","award":["FCT NEURONS4"],"award-info":[{"award-number":["FCT NEURONS4"]}]},{"name":"European Union","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"European Union","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]},{"name":"European Union","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"European Union","award":["UID\/DTP\/04138\/2020"],"award-info":[{"award-number":["UID\/DTP\/04138\/2020"]}]},{"name":"European Union","award":["UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDP\/04138\/2020"]}]},{"name":"European Union","award":["UID\/04046\/2025"],"award-info":[{"award-number":["UID\/04046\/2025"]}]},{"name":"European Union","award":["UIDB\/04292\/2020"],"award-info":[{"award-number":["UIDB\/04292\/2020"]}]},{"name":"European Union","award":["UIDP\/04292\/2020"],"award-info":[{"award-number":["UIDP\/04292\/2020"]}]},{"name":"European Union","award":["LA\/P\/0069\/2020"],"award-info":[{"award-number":["LA\/P\/0069\/2020"]}]},{"name":"European Union","award":["EAPA_0032\/2022"],"award-info":[{"award-number":["EAPA_0032\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: While various nucleoside and nucleotide analogs have been approved as anticancer and antiviral drugs, their limitations, including low bioavailability and chemotherapeutic resistance, encourage the development of novel structures. In this context, and motivated by our previous findings on bioactive 3\u2032-O-substituted xylofuranosyl nucleosides and 5-guanidine xylofuranose derivatives, we present herein the synthesis and biological evaluation of 5\u2032-guanidino furanosyl nucleosides comprising 6-chloropurine and uracil moieties and a 3-O-benzyl xylofuranosyl unit. Methods: The synthetic methodology was based on the N-glycosylation of a 5-azido 3-O-benzyl xylofuranosyl acetate donor with the silylated nucleobase and a subsequent one-pot sequential two-step protocol involving Staudinger reduction of the thus-obtained 5-azido uracil and N7\/N9-linked purine nucleosides followed by guanidinylation with N,N\u2032-bis(tert-butoxycarbonyl)-N\u2032\u2032-triflylguanidine. The molecules were evaluated for their anticancer and anti-neurodegenerative diseases potential. Results: 5\u2032-Guanidino 6-chloropurine nucleosides revealed dual anticancer and butyrylcholinesterase (BChE)-inhibitory effects. Both N9\/N7-linked nucleosides exhibited mixed-type and selective submicromolar\/micromolar BChE inhibiton. The N9 regioisomer was the best inhibitor (Ki\/Ki\u2032 = 0.89 \u03bcM\/2.96 \u03bcM), while showing low cytotoxicity to FL83B hepatocytes and no cytotoxicity to human neuroblastoma cells (SH-SY5Y). Moreover, the N9-linked nucleoside exhibited selective cytotoxicity to prostate cancer cells (DU-145; IC50 = 27.63 \u03bcM), while its N7 regioisomer was active against all cancer cells tested [DU-145, IC50 = 24.48 \u03bcM; colorectal adenocarcinoma (HCT-15, IC50 = 64.07 \u03bcM); and breast adenocarcinoma (MCF-7, IC50 = 43.67 \u03bcM)]. In turn, the 5\u2032-guanidino uracil nucleoside displayed selective cytotoxicity to HCT-15 cells (IC50 = 76.02 \u03bcM) and also showed neuroprotective potential in a Parkinson\u2019s disease SH-SY5Y cells\u2019 damage model. The active molecules exhibited IC50 values close to or lower than those of standard drugs, and comparable, or not significant, neuro- and hepatotoxicity. Conclusions: These findings demonstrate the interest of combining guanidine moieties with nucleoside frameworks towards the search for new therapeutic agents.<\/jats:p>","DOI":"10.3390\/ph18050734","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T08:32:29Z","timestamp":1747384349000},"page":"734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["5\u2032-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5\u2032-Functionalized Nucleosides with Biological Potential"],"prefix":"10.3390","volume":"18","author":[{"given":"Jennifer","family":"Szilagyi","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed. C8, 5\u00b0 Piso, Campo Grande, 1749-016 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T\u00e2nia","family":"Moreira","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed. C8, 5\u00b0 Piso, Campo Grande, 1749-016 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9014-0570","authenticated-orcid":false,"given":"Rafael Santana","family":"Nunes","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed. C8, 5\u00b0 Piso, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"BioISI\u2014Instituto de Biosistemas e Ci\u00eancias Integrativas, Faculdade de Ci\u00eancias, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-1699","authenticated-orcid":false,"given":"Joana","family":"Silva","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre & ARNET\u2014Aquatic Research Network Associated Laboratory, ESTM, Polytechnic University of Leiria, Av. Porto de Pesca, Edif\u00edcio Cetemares, 1749-016 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1581-2127","authenticated-orcid":false,"given":"Celso","family":"Alves","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre & ARNET\u2014Aquatic Research Network Associated Laboratory, ESTM, Polytechnic University of Leiria, Av. Porto de Pesca, Edif\u00edcio Cetemares, 1749-016 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Martins","sequence":"additional","affiliation":[{"name":"MARE\u2014Marine and Environmental Sciences Centre & ARNET\u2014Aquatic Research Network Associated Laboratory, ESTM, Polytechnic University of Leiria, Av. Porto de Pesca, Edif\u00edcio Cetemares, 1749-016 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8796-1389","authenticated-orcid":false,"given":"Rebeca","family":"Alvari\u00f1o","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Facultade de Veterinaria, IDIS, Universidade de Santiago de Compostela, 27002 Lugo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6540-6357","authenticated-orcid":false,"given":"Niels V.","family":"Heise","sequence":"additional","affiliation":[{"name":"Bereich Organische Chemie, Martin-Luther-Universit\u00e4t Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7911-290X","authenticated-orcid":false,"given":"Ren\u00e9","family":"Csuk","sequence":"additional","affiliation":[{"name":"Bereich Organische Chemie, Martin-Luther-Universit\u00e4t Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8739-8768","authenticated-orcid":false,"given":"Nuno M.","family":"Xavier","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed. C8, 5\u00b0 Piso, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nrd4010","article-title":"Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases","volume":"12","author":"Jordheim","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14379","DOI":"10.1021\/acs.chemrev.6b00209","article-title":"Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogs","volume":"116","author":"Shelton","year":"2016","journal-title":"Chem. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hruba, L., Das, V., Hajduch, M., and Dzubak, P. (2023). Nucleoside-based anticancer drugs: Mechanism of action and drug resistance. Biochem. Pharmacol., 215.","DOI":"10.1016\/j.bcp.2023.115741"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106346","DOI":"10.1016\/j.jddst.2024.106346","article-title":"Unlocking the potential of cytarabine: A comprehensive review from molecular insights to advanced nanoformulations and Co-delivery strategies for enhanced drug efficacy","volume":"102","author":"Shabestari","year":"2024","journal-title":"J. Drug. Deliv. Sci. Technol."},{"key":"ref_5","first-page":"187","article-title":"Fludarabine in the treatment of chronic lymphocytic leukemia: A review","volume":"5","author":"Ricci","year":"2009","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"447","DOI":"10.2165\/00003495-199754030-00009","article-title":"Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer","volume":"54","author":"Noble","year":"1997","journal-title":"Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20","DOI":"10.2174\/157488408783329913","article-title":"AZT: An old drug with new perspectives","volume":"3","author":"Brisdelli","year":"2008","journal-title":"Curr. Clin. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1007\/s40265-014-0247-z","article-title":"Sofosbuvir: A review of its use in patients with chronic hepatitis C","volume":"74","author":"Keating","year":"2014","journal-title":"Drugs."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40121-023-00900-3","article-title":"Remdesivir for the Treatment of COVID-19: A Narrative Review","volume":"13","author":"Godwin","year":"2024","journal-title":"Infect Dis. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"183","DOI":"10.2174\/1574885518666230124123054","article-title":"Safety Profile of Molnupiravir with Significant Effect on COVID-19: A Review","volume":"18","author":"Mukherjee","year":"2023","journal-title":"Curr. Drug Ther."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Thomson, J.M., and Lamont, I.L. (2019). Nucleoside Analogues as Antibacterial Agents. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.00952"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10343","DOI":"10.1021\/acs.jmedchem.6b00325","article-title":"Nucleoside Derived Antibiotics to Fight Microbial Drug Resistance: New Utilities for an Established Class of Drugs?","volume":"59","author":"Serpi","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_13","unstructured":"Fisher, J., Mobashery, S., and Miller, M. (2017). Nucleoside Natural Product Antibiotics Targeting Microbial Cell Wall Biosynthesis. Antibacterials, Topics in Medicinal Chemistry, Springer."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1039\/D3NP00051F","article-title":"Purine nucleoside antibiotics: Recent synthetic advances harnessing chemistry and biology","volume":"41","author":"Motter","year":"2024","journal-title":"Nat. Prod. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1039\/C4OB00142G","article-title":"Microwave-assisted synthesis of novel purine nucleosides as selective cholinesterase inhibitors","volume":"12","author":"Schwarz","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1515\/pac-2016-0102","article-title":"Synthesis of glucopyranos-6\u2032-yl purine and pyrimidine isonucleosides as potential cholinesterase inhibitors. Access to pyrimidine-linked pseudodisaccharides through Mitsunobu reaction","volume":"88","author":"Batista","year":"2016","journal-title":"Pure Appl. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1002\/ejoc.201800245","article-title":"Furanosyl nucleoside analogs embodying triazole or theobromine units as potential lead molecules for Alzheimer\u2019s disease","volume":"2018","author":"Pereira","year":"2018","journal-title":"Eur. J. Org. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Xavier, N.M., de Sousa, E.C., Pereira, M.P., Loesche, A., Serbian, I., Csuk, R., and Oliveira, M.C. (2019). Synthesis and biological evaluation of structurally varied 5\u2032-\/6\u2032-isonucleosides and theobromine-containing N-isonucleosidyl derivatives. Pharmaceuticals, 12.","DOI":"10.3390\/ph12030103"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"108889","DOI":"10.1016\/j.carres.2023.108889","article-title":"Nucleoside analogues: N-glycosylation methodologies, synthesis of antiviral and antitumor drugs and potential against drug-resistant bacteria and Alzheimer\u2019s disease","volume":"532","author":"Maria","year":"2023","journal-title":"Carbohydr. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3845","DOI":"10.1039\/D4OB01657B","article-title":"Purine nucleosides as selective inhibitors of butyrylcholinesterase\u2014A multidisciplinary study","volume":"23","author":"Cachatra","year":"2025","journal-title":"Org. Biomol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tsesmetzis, N., Paulin, C.B.J., Rudd, S.G., and Herold, N. (2018). Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism. Cancers, 10.","DOI":"10.3390\/cancers10070240"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1515\/pac-2016-1218","article-title":"Synthesis and antiproliferative evaluation of novel azido nucleosides and their phosphoramidate derivatives","volume":"89","author":"Xavier","year":"2017","journal-title":"Pure Appl. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1515\/pac-2019-0106","article-title":"Novel dodecyl-containing azido and glucuronamide-based nucleosides exhibiting anticancer potential","volume":"91","author":"Xavier","year":"2019","journal-title":"Pure Appl. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"108352","DOI":"10.1016\/j.neuropharm.2020.108352","article-title":"Efficacy of acetylcholinesterase inhibitors in Alzheimer\u2019s disease","volume":"190","author":"Marucci","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_25","unstructured":"Chakraborti, S., Das, S., and Kim, C.-H. (2025). The role of acetylcholinesterase in cancer development and possible therapeutic applications. Pathophysiological Aspects of Proteases in Cancer, Academic Press."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Aguilar, B., Marquardt, J.U., Mu\u00f1oz-Delgado, E., L\u00f3pez-Dur\u00e1n, R.M., Guti\u00e9rrez-Ruiz, M.C., Gomez-Quiroz, L.E., and G\u00f3mez-Olivares, J.L. (2023). Changes in the Acetylcholinesterase Enzymatic Activity in Tumor Development and Progression. Cancers, 15.","DOI":"10.3390\/cancers15184629"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.acr.2021.05.001","article-title":"Acetylcholinesterase and human cancers","volume":"Volume 152","author":"Tew","year":"2021","journal-title":"Advances in Cancer Research"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/1759-7714.12249","article-title":"Role of acetylcholinesterase in lung cancer","volume":"6","author":"Xi","year":"2015","journal-title":"Thorac. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e202200180","DOI":"10.1002\/cmdc.202200180","article-title":"Synthesis and exploitation of the biological profile of novel guanidino xylofuranose derivatives","volume":"17","author":"Fortuna","year":"2022","journal-title":"ChemMedChem"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1080\/15257770.2019.1668563","article-title":"Development of gapmer antisense oligonucleotide with deoxyribonucleic guanidine (DNG) modifications","volume":"39","author":"Kojima","year":"2020","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9302","DOI":"10.1021\/acs.jpcb.9b06130","article-title":"Role of Guanidinium-Carboxylate Ion Interaction in Enzyme Inhibition with Implications for Drug Design","volume":"123","author":"Muttathukattil","year":"2019","journal-title":"J. Phys. Chem. B"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"113293","DOI":"10.1016\/j.ejmech.2021.113293","article-title":"Antimicrobial drugs bearing guanidine moieties: A review","volume":"216","author":"Kim","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Gomes, A.R., Varela, C.L., Pires, A.S., Tavares-da-Silva, E.J., and Roleira, F.M.F. (2023). Synthetic and natural guanidine derivatives as antitumor and antimicrobial agents: A review. Bioorg. Chem., 138.","DOI":"10.1016\/j.bioorg.2023.106600"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9007","DOI":"10.1016\/j.tet.2007.05.079","article-title":"Intramolecular and Intermolecular Schmidt Reactions of Alkyl Azides with Aldehydes","volume":"63","author":"Lee","year":"2007","journal-title":"Tetrahedron"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7147","DOI":"10.1016\/j.tetlet.2012.10.098","article-title":"An efficient synthesis of \u03b4-glyconolactams by intramolecular Schmidt\u2013Boyer reaction under microwave radiation","volume":"53","author":"Chen","year":"2012","journal-title":"Tetrahedron Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17213","DOI":"10.1073\/pnas.0508575102","article-title":"Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent","volume":"102","author":"Greig","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.pharmthera.2018.10.002","article-title":"Acetylcholine signaling system in progression of lung cancers","volume":"194","author":"Friedman","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e160152","DOI":"10.1172\/JCI160152","article-title":"Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse","volume":"132","author":"Nie","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"619","DOI":"10.3897\/pharmacia.70.e109841","article-title":"Cytotoxic activity of Galantamine hydrobromide against HeLa cell line","volume":"70","author":"Obreshkova","year":"2023","journal-title":"Pharmacia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1248\/bpb.33.1054","article-title":"Donepezil, a Potent Acetylcholinesterase Inhibitor, Induces Caspase-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells","volume":"33","author":"Ki","year":"2010","journal-title":"Biol. Pharm. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Skrzypek, A., Karpi\u0144ska, M., Juszczak, M., Grabarska, A., Wietrzyk, J., Krajewska-Ku\u0142ak, E., Studzi\u0144ski, M., Paszko, T., and Matysiak, J. (2022). Cholinesterases Inhibition, Anticancer and Antioxidant Activity of Novel Benzoxazole and Naphthoxazole Analogs. Molecules, 27.","DOI":"10.3390\/molecules27238511"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3425","DOI":"10.1039\/D4OB00312H","article-title":"Coumarin\u2013azasugar\u2013benzyl conjugates as non-neurotoxic dual inhibitors of butyrylcholinesterase and cancer cell growth","volume":"22","author":"Holmgard","year":"2024","journal-title":"Org. Biomol. Chem."},{"key":"ref_43","first-page":"45","article-title":"Effect of doxorubicin and daunorubicin on the activity of acetylcholinesterase in acute lymphoblastic leukamia","volume":"23","author":"Niazi","year":"2011","journal-title":"J. Ayub. Med. Coll. Abbottabad"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.cbi.2005.10.033","article-title":"Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11","volume":"157","author":"Hyatt","year":"2005","journal-title":"Chem. Biol. Interact."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1021\/acschemneuro.5b00329","article-title":"Sunitinib, a Clinically Used Anticancer Drug, Is a Potent AChE Inhibitor and Attenuates Cognitive Impairments in Mice","volume":"7","author":"Huang","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"367","DOI":"10.4103\/0973-1482.165869","article-title":"Serum butyrylcholinesterase and zinc in breast cancer","volume":"13","author":"Kumar","year":"2017","journal-title":"J. Can. Res. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6051092","DOI":"10.1155\/2022\/6051092","article-title":"BCHE as a Prognostic Biomarker in Endometrial Cancer and Its Correlation with Immunity","volume":"2022","author":"Liu","year":"2022","journal-title":"J. Immunol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ahmed, G.Y., Osman, A.A., and Mukhtar, A. (2024). Acetylcholinesterase enzyme among cancer patients a potential diagnostic and prognostic indicator a multicenter case\u2013control study. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-55604-6"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.tranon.2018.06.003","article-title":"Biphasic alteration of butyrylcholinesterase (BChE) during prostate cancer development","volume":"11","author":"Gu","year":"2018","journal-title":"Transl. Oncol."},{"key":"ref_50","first-page":"1817","article-title":"Damage to dopaminergic neurons by oxidative stress in Parkinson\u2019s disease (Review)","volume":"41","author":"Guo","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_51","first-page":"533","article-title":"The 6-hydroxydopamine model and parkinsonian pathophysiology: Novel findings in an older model","volume":"32","year":"2017","journal-title":"Neurolog\u00eda"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.toxlet.2012.11.015","article-title":"Neurotoxicity of \u201cecstasy\u201d and its metabolites in human dopaminergic differentiated SH-SY5Y cells","volume":"216","author":"Ferreira","year":"2013","journal-title":"Toxicol. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.neuro.2022.07.008","article-title":"The SH-SY5Y human neuroblastoma cell line, a relevant in vitro cell model for investigating neurotoxicology in human: Focus on organic pollutants","volume":"92","author":"Awabdh","year":"2022","journal-title":"Neurotoxicology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1517\/17460441.2012.714363","article-title":"The influence of lipophilicity in drug discovery and design","volume":"7","author":"Arnott","year":"2012","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s10822-005-8694-y","article-title":"Virtual computational chemistry laboratory\u2014Design and description","volume":"19","author":"Tetko","year":"2005","journal-title":"J. Comput. Aid. Mol. Des."},{"key":"ref_56","unstructured":"VCCLAB (2025, March 10). Virtual Computational Chemistry Laboratory. Available online: https:\/\/vcclab.org."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.2147\/DDDT.S238148","article-title":"Pre-Clinical Pharmacokinetics, Tissue Distribution and Physicochemical Studies of CLBQ14, a Novel Methionine Aminopeptidase Inhibitor for the Treatment of Infectious Diseases","volume":"14","author":"Ekpenyong","year":"2020","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Niazi, S.K. (2006). Handbook of Preformulation: Chemical, Biological, and Botanical Drugs, CRC Press.","DOI":"10.1201\/9781420006629"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1602\/neurorx.2.4.541","article-title":"Medicinal chemical properties of successful central nervous system drugs","volume":"2","author":"Pajouhesh","year":"2005","journal-title":"NeuroRx"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/jps.2600760902","article-title":"Hydrophobicity and Central Nervous System Agents: On the Principle of Minimal Hydrophobicity in Drug Design","volume":"76","author":"Hansch","year":"1987","journal-title":"J. Pharm. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"105589","DOI":"10.1016\/j.phrs.2021.105589","article-title":"Disclosing the potential of eleganolone for Parkinson\u2019s disease therapeutics: Neuroprotective and anti-inflammatory activities","volume":"168","author":"Silva","year":"2021","journal-title":"Pharmacol. Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/5\/734\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:33:55Z","timestamp":1760031235000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/5\/734"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,16]]},"references-count":61,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ph18050734"],"URL":"https:\/\/doi.org\/10.3390\/ph18050734","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,16]]}}}