{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T09:06:04Z","timestamp":1784106364917,"version":"3.55.0"},"reference-count":82,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,7,14]]},"abstract":"<jats:p>\n                    Alzheimer's disease (AD) is recognized by the World Health Organization as a global public health priority. There is an urgent need to develop disease\u2010modifying therapies or treatments (DMT's) to prevent, delay, or slow the progression and target the primary AD pathophysiology mechanisms. Following previous works on the activity of tricyclic compounds in neuroprotection, this work focuses on the synthesis of novel xanthene derivatives. Eighteen compounds were obtained and assessed regarding their cytotoxicity, central nervous system (CNS) penetration, P\u2010glycoprotein (P\u2010gp) modulation, and neuroprotective effects against iron\u2010 and amyloid\u2010beta (A\u03b2)\u2010induced cytotoxicity. Generally, the derivatives were well tolerated by differentiated human neuroblastoma SH\u2010SY5Y cells at concentrations up to 25 \u03bcM. Regarding their ability to activate P\u2010gp, compounds\n                    <jats:bold>5<\/jats:bold>\n                    ,\n                    <jats:bold>7<\/jats:bold>\n                    ,\n                    <jats:bold>9<\/jats:bold>\n                    ,\n                    <jats:bold>11<\/jats:bold>\n                    ,\n                    <jats:bold>12,<\/jats:bold>\n                    and\n                    <jats:bold>16<\/jats:bold>\n                    showed the most significant increases in P\u2010gp activity. Neuroprotection assays demonstrated the ability of several xanthene derivatives to counteract iron (III)\u2010 and A\u03b2\u2010induced cytotoxicity. It was clearly demonstrated the P\u2010gp involvement in compound\u2010mediated ability to reverse the cytotoxicity induced by the A\u03b2\n                    <jats:sub>25\u201335<\/jats:sub>\n                    peptide. Additionally, parallel artificial membrane permeability assay (PAMPA) studies showed their potential to penetrate the blood\u2010brain barrier (BBB) and reach the CNS, which is a crucial requirement for their potential biological activity in AD.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70352","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:07:13Z","timestamp":1782875233000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Xanthene Derivatives for Neuroprotection in Alzheimer's Disease\u2014Synthesis and Biological Assessment"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6395-1469","authenticated-orcid":false,"given":"Miguel","family":"Maia","sequence":"first","affiliation":[{"name":"Marine Natural Products and Medicinal Chemistry Group CIIMAR\u2010 Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental  Matosinhos Portugal"},{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica Departamento de Ci\u00eancias Qu\u00edmicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Rita","family":"Monteiro","sequence":"additional","affiliation":[{"name":"UCIBIO \u2010 Laborat\u00f3rio de Toxicologia Departamento de Ci\u00eancias Biol\u00f3gicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"},{"name":"Associate Laboratory i4HB \u2013 Institute for Health and Bioeconomy Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rcia S.","family":"Martins","sequence":"additional","affiliation":[{"name":"Marine Natural Products and Medicinal Chemistry Group CIIMAR\u2010 Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental  Matosinhos Portugal"},{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica Departamento de Ci\u00eancias Qu\u00edmicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loreto","family":"Martinez\u2010Gonzalez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED) Instituto de Salud Carlos III  Madrid Spain"},{"name":"Centro de Investigaciones Biologicas \u201cMargarita Salas\u201d (CIB\u2010CSIC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Neurodegenerativas (CIBERNED) Instituto de Salud Carlos III  Madrid Spain"},{"name":"Centro de Investigaciones Biologicas \u201cMargarita Salas\u201d (CIB\u2010CSIC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO \u2010 Laborat\u00f3rio de Toxicologia Departamento de Ci\u00eancias Biol\u00f3gicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"},{"name":"Associate Laboratory i4HB \u2013 Institute for Health and Bioeconomy Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-7548","authenticated-orcid":false,"given":"Renata","family":"Silva","sequence":"additional","affiliation":[{"name":"UCIBIO \u2010 Laborat\u00f3rio de Toxicologia Departamento de Ci\u00eancias Biol\u00f3gicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"},{"name":"Associate Laboratory i4HB \u2013 Institute for Health and Bioeconomy Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4672","authenticated-orcid":false,"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[{"name":"Marine Natural Products and Medicinal Chemistry Group CIIMAR\u2010 Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental  Matosinhos Portugal"},{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica Departamento de Ci\u00eancias Qu\u00edmicas Faculdade de Farm\u00e1cia Universidade do Porto  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"1","article-title":"Background paper 6.11: Alzheimer Disease and Other Dementias","volume":"6","author":"Duthey B.","year":"2013","journal-title":"A Public Health Approach to Innovation"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ca.980080612"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.13439"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph12010041"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD005593"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa013128"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00472"},{"key":"e_1_2_10_9_1","unstructured":"LiverTox: Clinical and Research Information on Drug\u2010Induced Liver Injury [Internet] \u201cTacrine \u201d accessed 2012 https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK547868\/."},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1994.03510370044030"},{"key":"e_1_2_10_11_1","unstructured":"Withdrawn | Non\u2010malignant Hematological Neurological and Other Disorder Indications Accelerated Approvals \u201d accessed May 7 2026 https:\/\/www.fda.gov\/drugs\/accelerated\u2010approval\u2010program\/withdrawn\u2010non\u2010malignant\u2010hematological\u2010neurological\u2010and\u2010other\u2010disorder\u2010indications\u2010accelerated 2026."},{"key":"e_1_2_10_12_1","unstructured":"\u201cBiogen to Realign Resources for Alzheimer's Disease Franchise accessed May 7 2026 https:\/\/investors.biogen.com\/news\u2010releases\/news\u2010release\u2010details\/biogen\u2010realign\u2010resources\u2010alzheimers\u2010disease\u2010franchise 2024."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.30"},{"key":"e_1_2_10_14_1","unstructured":"\u201cFDA Converts Novel Alzheimer's Disease Treatment to Traditional Approval \u201d accessed May 7 2026 https:\/\/www.fda.gov\/news\u2010events\/press\u2010announcements\/fda\u2010converts\u2010novel\u2010alzheimers\u2010disease\u2010treatment\u2010traditional\u2010approval 2023."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_10_16_1","unstructured":"\u201cFDA approves treatment for adults with Alzheimer's disease \u201d accessed May 7 2026 https:\/\/www.fda.gov\/drugs\/news\u2010events\u2010human\u2010drugs\/fda\u2010approves\u2010treatment\u2010adults\u2010alzheimers\u2010disease 2024."},{"key":"e_1_2_10_17_1","unstructured":"\u201cDonanemab in early symptomatic Alzheimer Disease: The TRAILBLAZER\u2010ALZ2 Randomised Clinical Trial \u201d accessed May 7 2026 https:\/\/www.ean.org\/research\/resources\/neurology\u2010updates\/detail\/donanemab\u2010in\u2010early\u2010symptomatic\u2010alzheimer\u2010disease\u2010the\u2010trailblazer\u2010alz2\u2010randomised\u2010clinical\u2010trial 2023."},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.2174\/187152709787601867"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24270"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci10498"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/cn300077c"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471\u20104159.2001.00113.x"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2014.04.001"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2012.00054"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15148"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1438"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2008.02.002"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M201750200"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2020.107554"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571\u2010200210000\u201000005"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.113085"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010014\u20101333\u20104"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044\u2010020\u201002544\u20101"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24040707"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010014\u20101193\u2010y"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ddc1010004"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408440802004049"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161212802430530"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2014.11.013"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2006.08.008"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14071456"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2017.10.014"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2016.12.002"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/720658"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25122782"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arabjc.2017.01.006"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10534\u2010005\u20102997\u20102"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1039\/C2DT12159J"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108398"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2010.05.003"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/js9701364"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0223\u20105234(03)00012\u20106"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm990968"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.2.4.541"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201600182"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci700257y"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci990307l"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.42.976"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.40.127"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci500467k"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm000942e"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.2174\/138955708786786453"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-803961-8.50011-7"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2005.05.135"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm501266w"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2009.01.108"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582\u2010021\u201000545\u20101"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1139\/v67\u2010233"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo951613a"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201900763"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6RA17546E"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010019\u20101605\u20103"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033\u2010020\u201005925\u20102"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.0c00614"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2023.108373"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2023.115522"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471\u20104159.2008.05332.x"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.3233\/jad\u2010170354"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2024.117841"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1021\/cn3000982"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.3390\/md15030083"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plefa.2017.07.003"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70352","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.70352","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70352","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T08:34:16Z","timestamp":1784104456000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.70352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":82,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2026,7,14]]}},"alternative-id":["10.1002\/cmdc.70352"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.70352","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]},"assertion":[{"value":"2026-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70352"}}