{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:12:09Z","timestamp":1790856729584,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EUROPEAN UNION project entitled \u201cDiagnostic and Drug Discovery Initiative for Alzheimer\u2019s Disease\u201d (D3i4AD)","award":["FP7-PEOPLE-2013-IAPP"],"award-info":[{"award-number":["FP7-PEOPLE-2013-IAPP"]}]},{"name":"EUROPEAN UNION project entitled \u201cDiagnostic and Drug Discovery Initiative for Alzheimer\u2019s Disease\u201d (D3i4AD)","award":["612347"],"award-info":[{"award-number":["612347"]}]},{"name":"EUROPEAN UNION project entitled \u201cDiagnostic and Drug Discovery Initiative for Alzheimer\u2019s Disease\u201d (D3i4AD)","award":["PTDC\/QUI-QFI\/29527\/2017"],"award-info":[{"award-number":["PTDC\/QUI-QFI\/29527\/2017"]}]},{"name":"EUROPEAN UNION project entitled \u201cDiagnostic and Drug Discovery Initiative for Alzheimer\u2019s Disease\u201d (D3i4AD)","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"EUROPEAN UNION project entitled \u201cDiagnostic and Drug Discovery Initiative for Alzheimer\u2019s Disease\u201d (D3i4AD)","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"FUNDA\u00e7\u00e3O PARA A CI\u00eaNCIA E A TECNOLOGIA (FCT, PORTUGAL)","award":["FP7-PEOPLE-2013-IAPP"],"award-info":[{"award-number":["FP7-PEOPLE-2013-IAPP"]}]},{"name":"FUNDA\u00e7\u00e3O PARA A CI\u00eaNCIA E A TECNOLOGIA (FCT, PORTUGAL)","award":["612347"],"award-info":[{"award-number":["612347"]}]},{"name":"FUNDA\u00e7\u00e3O PARA A CI\u00eaNCIA E A TECNOLOGIA (FCT, PORTUGAL)","award":["PTDC\/QUI-QFI\/29527\/2017"],"award-info":[{"award-number":["PTDC\/QUI-QFI\/29527\/2017"]}]},{"name":"FUNDA\u00e7\u00e3O PARA A CI\u00eaNCIA E A TECNOLOGIA (FCT, PORTUGAL)","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"FUNDA\u00e7\u00e3O PARA A CI\u00eaNCIA E A TECNOLOGIA (FCT, PORTUGAL)","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"Centro de Qu\u00edmica Estrutural","award":["FP7-PEOPLE-2013-IAPP"],"award-info":[{"award-number":["FP7-PEOPLE-2013-IAPP"]}]},{"name":"Centro de Qu\u00edmica Estrutural","award":["612347"],"award-info":[{"award-number":["612347"]}]},{"name":"Centro de Qu\u00edmica Estrutural","award":["PTDC\/QUI-QFI\/29527\/2017"],"award-info":[{"award-number":["PTDC\/QUI-QFI\/29527\/2017"]}]},{"name":"Centro de Qu\u00edmica Estrutural","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"Centro de Qu\u00edmica Estrutural","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]},{"name":"Institute of Molecular Sciences","award":["FP7-PEOPLE-2013-IAPP"],"award-info":[{"award-number":["FP7-PEOPLE-2013-IAPP"]}]},{"name":"Institute of Molecular Sciences","award":["612347"],"award-info":[{"award-number":["612347"]}]},{"name":"Institute of Molecular Sciences","award":["PTDC\/QUI-QFI\/29527\/2017"],"award-info":[{"award-number":["PTDC\/QUI-QFI\/29527\/2017"]}]},{"name":"Institute of Molecular Sciences","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"Institute of Molecular Sciences","award":["LA\/P\/0056\/2020"],"award-info":[{"award-number":["LA\/P\/0056\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Alzheimer\u2019s Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of A\u03b2 plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N7\/N9 linkage to the purine. Their AChE\/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N9-linked 6-deoxy-\u03b1-d-mannosylpurine structure, while all three tested \u03b2-d-derivatives appeared as non-selective inhibitors. The N9-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-\u03b1-l-mannosyl N9-linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility.<\/jats:p>","DOI":"10.3390\/ph16010054","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T03:50:32Z","timestamp":1672631432000},"page":"54","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exploring Mannosylpurines as Copper Chelators and Cholinesterase Inhibitors with Potential for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"16","author":[{"given":"Ignazio","family":"Schino","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Biofordrug Srl, Via Dante 95, 70019 Triggiano, Italy"},{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Cantore","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Biofordrug Srl, Via Dante 95, 70019 Triggiano, Italy"},{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4570-1981","authenticated-orcid":false,"given":"Modesto","family":"de Candia","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5016-5805","authenticated-orcid":false,"given":"Cosimo D.","family":"Altomare","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5693-0229","authenticated-orcid":false,"given":"Catarina","family":"Maria","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal"},{"name":"Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, Largo da Torre, 2825-149 Caparica, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4741-115X","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Barros","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6428-2153","authenticated-orcid":false,"given":"Vasco","family":"Cachatra","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia","family":"Calado","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2454-1795","authenticated-orcid":false,"given":"Karina","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6119-9602","authenticated-orcid":false,"given":"Adilson A.","family":"Freitas","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7909-637X","authenticated-orcid":false,"given":"Maria J.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 N. C.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola A.","family":"Colabufo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3790-7952","authenticated-orcid":false,"given":"Am\u00e9lia P.","family":"Rauter","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, Campo Grande, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1007\/s10571-017-0555-4","article-title":"Effects of Acetylcholine on \u03b2-Amyloid-Induced cPLA2, Activation in the TB Neuroectodermal Cell Line: Implications for the Pathogenesis of Alzheimer\u2019s Disease","volume":"38","author":"Polverino","year":"2018","journal-title":"Cell Mol. 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