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To assess their potential therapeutic efficacy, the entire library of synthesized compounds was screened for its inhibitory profiles against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), where most derivatives exhibited moderate to potent cholinesterase inhibitory activity. Notably, derivatives\n                    <jats:bold>4b<\/jats:bold>\n                    ,\n                    <jats:bold>4f<\/jats:bold>\n                    , and\n                    <jats:bold>4o<\/jats:bold>\n                    emerged as the most effective dual inhibitors, displaying strong potent activity against AChE (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.91\u2009\u00b1\u20090.02, 0.89\u2009\u00b1\u20090.01, and 0.74\u2009\u00b1\u20090.01\u2009\u00b5M, respectively; donepezil IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.68\u2009\u00b1\u20090.005\u2009\u00b5M) alongside significant BChE inhibition (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200910.19\u2009\u00b1\u20090.16, 9.59\u2009\u00b1\u20090.08, and 9.11\u2009\u00b1\u20090.01\u2009\u00b5M, respectively; donepezil IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20092.97\u2009\u00b1\u20090.01\u2009\u00b5M). The structure of the most active derivatives (\n                    <jats:bold>4b<\/jats:bold>\n                    ,\n                    <jats:bold>4f<\/jats:bold>\n                    , and\n                    <jats:bold>4o<\/jats:bold>\n                    ) was further confirmed by X\u2010ray crystallographic analysis. In addition, antioxidant evaluation of compounds\n                    <jats:bold>4b<\/jats:bold>\n                    ,\n                    <jats:bold>4f<\/jats:bold>\n                    , and\n                    <jats:bold>4o<\/jats:bold>\n                    demonstrated that derivative\n                    <jats:bold>4f<\/jats:bold>\n                    possessed the most superior radical scavenging profile (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200923.18\u2009\u00b1\u20090.33\u2009\u00b5M), representing approximately a 5.5\u2010fold enhancement in potency relative to ascorbic acid (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u2009128.20\u2009\u00b1\u20090.82\u2009\u00b5M). Molecular docking studies revealed favorable binding interactions of the lead derivatives within the catalytic binding pockets of both AChE and BChE, with docking scores comparable to those of the standard inhibitor. Furthermore, in silico ADME profiling demonstrated promising pharmacokinetic behavior, characterized by robust gastrointestinal absorption and excellent predicted blood\u2013brain barrier penetration, supporting the potential of these derivatives as promising multifunctional candidates for the development of anti\u2010Alzheimer agents.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70361","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:34:32Z","timestamp":1790775272000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, X\u2010Ray Crystallographic Characterization, Anticholinesterase and Antioxidant Evaluation, and Molecular Modeling of Novel Dispiroindene\u2010Pyrrolidine Derivatives as Multifunctional Anti\u2010Alzheimer Agents"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4497-5013","authenticated-orcid":false,"given":"Aisha A.","family":"Alsfouk","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy Princess Nourah Bint Abdulrahman University Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3179-3352","authenticated-orcid":false,"given":"Riham A.","family":"El\u2010Shiekh","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy Cairo University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8658-3897","authenticated-orcid":false,"given":"Benson M.","family":"Kariuki","sequence":"additional","affiliation":[{"name":"School of Chemistry Cardiff University Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8927-6032","authenticated-orcid":false,"given":"Eman","family":"Sabry","sequence":"additional","affiliation":[{"name":"National Research Centre Chemical Industries Research Institute Giza Dokki Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9584-2697","authenticated-orcid":false,"given":"Mohamed G.","family":"Abouelenein","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science Menoufia University Shebin El\u2010Koom Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-319X","authenticated-orcid":false,"given":"Asmaa","family":"Saleh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy Princess Nourah Bint Abdulrahman University Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9617-4985","authenticated-orcid":false,"given":"Mahmoud G. 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