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In this study, the pyrazolopyridine scaffold was used to design three different series of integrated MTDLs that could inhibit the main causes of AD. They possess common structure features essential for such a goal. The planar pyrazolopyridine core allows binding with the catalytically active site of cholinesterase enzymes and intercalating between the residues of A\u03b2 and tau protein. In addition, the planar ring is attached to different linkers and hydrophobic side chains to prop interaction with the peripheral anionic site of AChE, preventing A\u03b2<jats:sub>1\u201042<\/jats:sub> aggregation. They also provide tools for binding with <jats:italic>h<\/jats:italic>GSK3\u03b2 hydrophobic tails responsible for tau hyperphosphorylation and NFTs formation. Moreover, basic nitrogen atoms are also present, which chelate biometals, hindering their oxidative damage to the brain. Compounds <jats:bold>15<\/jats:bold> and <jats:bold>23<\/jats:bold> fulfilled all the mentioned anticipated activities. Furthermore, compound <jats:bold>31<\/jats:bold>, which is the possible metabolite of the ethyl ester <jats:bold>23<\/jats:bold>, appeared as MTDL, proving that compound <jats:bold>23<\/jats:bold> would have a long duration of action. Finally, compounds <jats:bold>15<\/jats:bold> and <jats:bold>23<\/jats:bold> exhibited a wide safety range upon WI\u201038 cell line, obeyed Lipinski's rule of five, and could virtually penetrate the blood\u2013brain barrier.<\/jats:p>","DOI":"10.1002\/ardp.70025","type":"journal-article","created":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T18:30:26Z","timestamp":1750617026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pyrazolopyridine\u2010Containing Compounds as Multitargeted Anti\u2010Alzheimer Agents: Synthesis, Biological Evaluation, and In Silico Studies"],"prefix":"10.1002","volume":"358","author":[{"given":"Omnia M.","family":"Waly","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura University Mansoura Egypt"},{"name":"Pharmacy Center of Scientific Excellence, Faculty of Pharmacy Mansoura University Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3962-6409","authenticated-orcid":false,"given":"Selwan M.","family":"El\u2010Sayed","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura University Mansoura Egypt"},{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura National University Gamasa Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam A.","family":"Ghaly","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura University Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hussein I.","family":"El\u2010Subbagh","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy Mansoura University Mansoura Egypt"},{"name":"Pharmacy Center of Scientific Excellence, Faculty of Pharmacy Mansoura University Mansoura Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.02.001"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.10.019"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0b013e3283207d21"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80115-4"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr300009x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4CS00005F"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.04.038"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.05245.x"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986708785909111"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.6026\/97320630091023"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1619574114"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-019-0541-9"},{"key":"e_1_2_7_14_1","first-page":"1080","article-title":"Bioinorganic Chemistry of Copper and Zinc Ions Coordinated to Amyloid\u2010\u03b2 Peptide","volume":"7","author":"Faller P.","year":"2019","journal-title":"Dalton Transactions"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986711797535245"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201600161"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21434"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja312471h"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114152"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(03)00646-2"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115880"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00052a003"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20130013"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm500239b"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2022.2086867"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1139\/v88-074"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10593-009-0222-x"},{"key":"e_1_2_7_28_1","first-page":"148","article-title":"Synthesis, Antitumor and Anti\u2010HIV\u20101 Testing of Certain Thieno[2,3\u2010d]pyrimidine, Thieno[2,3\u2010d]imidazo[1,2\u2010c]pyrimidine and Thieno[2,3\u2010b][1,3]thiazine Derivatives","volume":"6","author":"Shehata I. 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