{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:58:17Z","timestamp":1784030297204,"version":"3.55.0"},"reference-count":54,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T00:00:00Z","timestamp":1669939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001332","name":"CSIR","doi-asserted-by":"publisher","award":["P90807"],"award-info":[{"award-number":["P90807"]}],"id":[{"id":"10.13039\/501100001332","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Berberrubine is a naturally occurring isoquinoline alkaloid and a bioactive metabolite of berberine. Berberine exhibits a wide range of pharmacological activities, including cholinesterase inhibition. The cholinesterase inhibitors provide symptomatic treatment for Alzheimer's disease; however, multitarget\u2010directed ligands have the potential as disease\u2010modifying therapeutics. Herein, we prepared a series of C9\u2010substituted berberrubine derivatives intending to discover dual cholinesterase and beta\u2010site amyloid\u2010precursor protein cleaving enzyme 1 (BACE\u20101) inhibitors. Most synthesized derivatives possessed balanced dual inhibition (AChE and BChE) activity in the submicromolar range and a moderate inhibition against BACE\u20101. Two most active ester derivatives, <jats:bold>12a<\/jats:bold> and <jats:bold>11d<\/jats:bold>, display inhibition of AChE, BChE, and BACE\u20101. The 3\u2010methoxybenzoyl ester derivative, <jats:bold>12a<\/jats:bold>, inhibits electric eel acetylcholinesterase (EeAChE), equine serum butyrylcholinesterase (eqBChE), and human hBACE\u20101 with IC<jats:sub>50<\/jats:sub> values of 0.5, 4.3, and 11.9\u2009\u03bcM, respectively and excellent BBB permeability (<jats:italic>P<\/jats:italic><jats:sub>e<\/jats:sub>\u2009=\u20098\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>\u2009cm\/s). The ester derivative <jats:bold>12a<\/jats:bold> is metabolically unstable; however, its ether analog <jats:bold>13<\/jats:bold> is stable in HLM and exhibits inhibition of AChE, BChE, and BACE\u20101 with IC<jats:sub>50<\/jats:sub> values of 0.44, 3.8, and 17.9\u2009\u03bcM, respectively. The ether analog also inhibits self\u2010aggregation of A\u03b2 and crosses BBB (<jats:italic>P<\/jats:italic><jats:sub>e<\/jats:sub>\u2009=\u20097.3\u2009\u00d7\u200910<jats:sup>\u22126<\/jats:sup>\u2009cm\/s). Administration of <jats:bold>13<\/jats:bold> at 5\u2009mg\/kg (iv) in Wistar rats showed excellent plasma exposure with AUC<jats:sub>0\u2212\u221e<\/jats:sub> of 28,834\u2009ng\u2009min\/ml. In conclusion, the multitargeted berberrubine ether derivative <jats:bold>13<\/jats:bold> is CNS permeable and has good ADME properties.<\/jats:p>","DOI":"10.1002\/ddr.22017","type":"journal-article","created":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T00:58:51Z","timestamp":1670029131000},"page":"121-140","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Multitargeted C9\u2010substituted ester and ether derivatives of berberrubine for Alzheimer's disease: Design, synthesis, biological evaluation, metabolic stability, and pharmacokinetics"],"prefix":"10.1002","volume":"84","author":[{"given":"Rinky","family":"Raghuvanshi","sequence":"first","affiliation":[{"name":"Natural Products &amp; Medicinal Chemistry Division CSIR\u2010Indian Institute of Integrative Medicine  Jammu India"},{"name":"Academy of Scientific &amp; Innovative Research  Ghaziabad 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