{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:56:25Z","timestamp":1792806985792,"version":"4.5.0"},"reference-count":67,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Multi\u2010target directed ligands (MTDLs) advocate for a novel therapeutic framework for Alzheimer's disease (AD) owing to its complicated multifactorial nature. Therefore, the present study focuses on designing and synthesizing pyrazolo[3,4\n                    <jats:italic>\u2010d<\/jats:italic>\n                    ]pyrimidine derivatives, followed by biological evaluation as MTDLs for AD. Most of the obtained derivatives showed potent AChE inhibitory efficacy, significant suppression of A\u03b2, and pronounced antioxidant activity in vitro. Compound\n                    <jats:bold>8b<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.346\u2009\u03bcM) and\n                    <jats:bold>9a<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.168\u2009\u03bcM) are the most potent inhibitors of AChE relative to donepezil (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.213\u2009\u03bcM). Furthermore, both\n                    <jats:bold>8b<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20091.475\u2009\u03bcM) and\n                    <jats:bold>9a<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20091.060\u2009\u03bcM) exhibited remarkable A\u03b2 inhibitory activity, surpassing that of donepezil (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20097.944\u2009\u03bcM). Also, they demonstrated remarkable antioxidant capacity, with an ORAC index of 1.66 and 0.90 Trolox equivalents. The in vivo investigation of the most potent compounds (\n                    <jats:bold>8b<\/jats:bold>\n                    and\n                    <jats:bold>9a<\/jats:bold>\n                    ) revealed a significant improvement in scopolamine\u2010induced cognitive deficits in animals. The molecular docking of compounds\n                    <jats:bold>8b<\/jats:bold>\n                    and\n                    <jats:bold>9a<\/jats:bold>\n                    within the human acetylcholinesterase (\n                    <jats:italic>h<\/jats:italic>\n                    AChE) active site showed auspicious binding with both catalytic active site (CAS) and peripheral anionic site (PAS). In addition, molecular dynamics (MD) simulations were employed to investigate the stability of compounds\n                    <jats:bold>8b<\/jats:bold>\n                    and\n                    <jats:bold>9a<\/jats:bold>\n                    within the\n                    <jats:italic>h<\/jats:italic>\n                    AChE active site and to support the reliability of the docking analysis. Finally, In silico physicochemical and pharmacokinetics prediction analyses were performed, and the findings were well aligned with their corresponding in vitro results. Overall, the results highlight\n                    <jats:bold>8b<\/jats:bold>\n                    and\n                    <jats:bold>9a<\/jats:bold>\n                    as potential multifunctional candidates for AD.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70259","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:08:25Z","timestamp":1773011305000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Design, Synthesis, In Vitro and In Vivo Biological Evaluation of Novel Pyrazolo[3,4\u2010\n                    <i>d<\/i>\n                    ]Pyrimidine\u2010Based Derivatives as Promising Multitarget Candidates for Alzheimer's Disease"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6650-6587","authenticated-orcid":false,"given":"Mohamed T. M.","family":"Nemr","sequence":"first","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamia W.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadeer S.","family":"Sayed","sequence":"additional","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demiana S.","family":"Mikhail","sequence":"additional","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101619"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-019-0362-7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.8b00517"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctim.2019.102294"},{"key":"e_1_2_8_6_1","first-page":"2","article-title":"Donepezil: An Important Prototype to the Design of New Drug Candidates for Alzheimer's Disease","volume":"14","author":"Cec\u00edlia Rodrigues Sim\u00f5es M.","year":"2014","journal-title":"Reviews in Medicinal Chemistry"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.02.021"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm300871x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X11311030006"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep42717"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2016.12.041"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-023-09021-z"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00203"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm000292e"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.21968"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(61)90145-9"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10593-015-1640-6"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103312"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.22082"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12039-019-1646-1"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-019-00429-x"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2019.05.026"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3md00041a"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm5008648"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.8b00376"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.13772"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2016.11.971"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules17067217"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.21123\/bsj.2019.16.4(Suppl.).1003"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.04.064"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.04.064"},{"key":"e_1_2_8_33_1","first-page":"327","article-title":"One\u2010Pot Synthesis of New Pyrazolo [3, 4, \u2010d] Pyrimidinederivatives and Study of Their Antioxidant and anticancer Activities","volume":"20","author":"Kadhim Z. Y.","year":"2020","journal-title":"Medico\u2010Legal Update"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560020312"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.09.031"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-019-00803-7"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2012.09.019"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00044-022-02941-8"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103387"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113224"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.2174\/1573406418666220827155615"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph17050655"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2014.01.010"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105754"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2015.08.042"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2008.12.015"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00104"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23116085"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.07.053"},{"key":"e_1_2_8_51_1","first-page":"1467","article-title":"Biological Activities of Synthetic Pyrimidine Derivatives","volume":"5","author":"Sathisha K. R.","year":"2016","journal-title":"World Journal Pharmaceutical of Research"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2007.12.009"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32205-4"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.2174\/157340808786733631"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep21826"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568015013358536"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21334"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20291"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21367"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm020017n"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.02.053"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsos.160696"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.13149"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2021.104895"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.7b00268"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2024.1453489"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00017"}],"container-title":["Drug Development Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70259","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ddr.70259","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70259","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T17:43:39Z","timestamp":1786038219000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/ddr.70259"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,3]]},"references-count":67,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/ddr.70259"],"URL":"https:\/\/doi.org\/10.1002\/ddr.70259","archive":["Portico"],"relation":{},"ISSN":["0272-4391","1098-2299"],"issn-type":[{"value":"0272-4391","type":"print"},{"value":"1098-2299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,3]]},"assertion":[{"value":"2026-01-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70259"}}