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In this work, four alkyl esters of homarine were synthesized and screened by using <jats:italic>Electrophorus electricus<\/jats:italic> AChE and rat brain AChE\u2010rich fraction. Results showed that all homarine alkyl esters are able to inhibit AChE by a competitive inhibition mode. The effectiveness of AChE inhibition increases with the alkyl side chain length of the homarine esters, being HO\u2212C<jats:sub>16<\/jats:sub> (IC<jats:sub>50<\/jats:sub>=7.57\u00b13.32\u2005\u03bcM and K<jats:sub>i<\/jats:sub>=18.96\u00b12.28\u2005\u03bcM) the most potent inhibitor. The fluorescence quenching studies confirmed that HO\u2212C<jats:sub>16<\/jats:sub> is the compound with higher selectivity and affinity for the tryptophan residues in the catalytic active site of AChE. Preliminary cell viability studies showed that homarine esters display no toxicity for human neuronal SH\u2010SY5Y cells. Thus, the long\u2010chain homarine esters emerge as new anti\u2010cholinesterase agents, with potential to be considered for therapeutic applications development.<\/jats:p>","DOI":"10.1002\/cmdc.202100265","type":"journal-article","created":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T02:06:06Z","timestamp":1627956366000},"page":"3315-3325","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Homarine Alkyl Ester Derivatives as Promising Acetylcholinesterase Inhibitors"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0006-750X","authenticated-orcid":false,"given":"Karen G.","family":"Jo\u00e3o","sequence":"first","affiliation":[{"name":"REQUIMTE\/LAQV, Laborat\u00f3rio de Farmacognosia, Departamento de Qu\u00edmica, Faculdade de Farm\u00e1cia Universidade do Porto  Rua de Jorge Viterbo Ferreira, N\u00b0\u2005228 4050-313 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4170-0092","authenticated-orcid":false,"given":"Romeu A.","family":"Videira","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Laborat\u00f3rio de Farmacognosia, Departamento de Qu\u00edmica, Faculdade de Farm\u00e1cia Universidade do Porto  Rua de Jorge Viterbo Ferreira, N\u00b0\u2005228 4050-313 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1149-6876","authenticated-orcid":false,"given":"F\u00e1tima","family":"Paiva\u2010Martins","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias Universidade do Porto  Rua do Campo Alegre 1021\/1055 4169-007 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0740-4396","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Valent\u00e3o","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Laborat\u00f3rio de Farmacognosia, Departamento de Qu\u00edmica, Faculdade de Farm\u00e1cia Universidade do Porto  Rua de Jorge Viterbo Ferreira, N\u00b0\u2005228 4050-313 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0384-7592","authenticated-orcid":false,"given":"David M.","family":"Pereira","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Laborat\u00f3rio de Farmacognosia, Departamento de Qu\u00edmica, Faculdade de Farm\u00e1cia Universidade do Porto  Rua de Jorge Viterbo Ferreira, N\u00b0\u2005228 4050-313 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9764-3920","authenticated-orcid":false,"given":"Paula B.","family":"Andrade","sequence":"additional","affiliation":[{"name":"REQUIMTE\/LAQV, Laborat\u00f3rio de Farmacognosia, Departamento de Qu\u00edmica, Faculdade de Farm\u00e1cia Universidade do Porto  Rua de Jorge Viterbo Ferreira, N\u00b0\u2005228 4050-313 Porto Portugal"}]}],"member":"311","published-online":{"date-parts":[[2021,8,26]]},"reference":[{"key":"e_1_2_7_1_1","first-page":"1455","volume":"45","author":"Nazim M.","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03088-y"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X11311030006"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1678899"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nurt.2008.10.040"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2010.01.042"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01192"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/99.3.459"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(76)91936-X"},{"key":"e_1_2_7_10_1","first-page":"1","author":"Birks J. 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