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It is a pathologically complicated, multifactorial disease characterized by \u03b2\u2010amyloid precipitation, \u03b2\u2010amyloid oligomer production, decrease in cholinergic function, and dysregulation of other neurotransmitter systems. Due to the pathogenic complexity of AD, multitarget drugs that can simultaneously alternate multiple biological targets may enhance the therapeutic efficacy. Donepezil (DNP) is the most potent approved drug for the treatment of AD. It has a remarkable effect on a number of AD\u2010related processes, including cholinesterase activity, anti\u2010A\u03b2 aggregation, oxidative stress, and more. DNP resembles an excellent scaffold to be hybridized with other pharmacophoric moieties having biological activity against AD pathological factors. There have been significant attempts made to modify the structure of DNP to create new bioactive chemical entities with novel structural patterns. In this review, we highlight recent advances in the development of multiple\u2010target DNP\u2010hybridized models for the treatment of AD that can be used in the future in the rational design of new potential AD therapeutics. The design and development of new drug candidates for the treatment of AD using DNP as a molecular scaffold have also been reviewed and summarized.<\/jats:p>","DOI":"10.1002\/ardp.202200398","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T12:30:52Z","timestamp":1663936252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Development of new Alzheimer's disease drug candidates using donepezil as a key model"],"prefix":"10.1002","volume":"356","author":[{"given":"Kholoud I.","family":"Eissa","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy Cairo University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona M.","family":"Kamel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy Cairo University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamia W.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy Cairo University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6091-829X","authenticated-orcid":false,"given":"Asmaa E.","family":"Kassab","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy Cairo University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,9,23]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2019.04.015"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/1177390118757462"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12155"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2019.126927"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.09.031"},{"key":"e_1_2_8_7_1","volume-title":"Enzyme Inhibitors Involved in the Treatment of Alzheimer's Disease","author":"Revadigar V.","year":"2014"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25245789"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2009.218"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13670-018-0234-4"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1433"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00446"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10010040"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/11795735211029113"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2020.128793"},{"key":"e_1_2_8_16_1","first-page":"1","author":"Adeowo F. 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