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dc.contributor.authorElumalai, Vijayaragavan
dc.contributor.authorTrobec, Tomaz
dc.contributor.authorGrundner, Maja
dc.contributor.authorLabriere, Christophe
dc.contributor.authorFrangez, Robert
dc.contributor.authorSepcic, Kristina
dc.contributor.authorHansen, Jørn H
dc.contributor.authorSvensson, Johan
dc.date.accessioned2023-01-17T13:52:09Z
dc.date.available2023-01-17T13:52:09Z
dc.date.issued2022-07-01
dc.description.abstractThe management of neurological disorders such as dementia associated with Alzheimer's or Parkinson's disease includes the use of cholinesterase inhibitors. These compounds can slow down the progression of these diseases and can also be used in the treatment of glaucoma and myasthenia gravis. The majority of the cholinesterase inhibitors used in the clinic are derived from natural products and our current paper describes the use of a small marine pharmacophore to develop potent and selective cholinesterase inhibitors. Fourteen small inhibitors were designed based on recent discoveries about the inhibitory potential of a range of related marine secondary metabolites. The compounds were evaluated, in kinetic enzymatic assays, for their ability to inhibit three different cholinesterase enzymes and it was shown that compounds with a high inhibitory activity towards electric eel and human recombinant acetylcholinesterase (IC50 between 20–70 μM) could be prepared. It was also shown that this compound class was particularly active against horse serum butyrylcholinesterase, with IC50 values between 0.8–16 μM, which is an order of magnitude more potent than the clinically used positive control neostigmine. The compounds were further tested for off-target toxicity against both human umbilical vein endothelial cells and bovine and human erythrocytes and were shown to display a low mammalian cellular toxicity. Overall, the study illustrates how the brominated dipeptide marine pharmacophore can be used as a versatile natural scaffold for the design of potent, and selective cholinesterase inhibitors.en_US
dc.identifier.citationElumalai, Trobec, Grundner, Labriere, Frangez, Sepcic, Hansen, Svensson. Development of potent cholinesterase inhibitors based on a marine pharmacophore. Organic and biomolecular chemistry. 2022;20(28):5589-5601en_US
dc.identifier.cristinIDFRIDAID 2041873
dc.identifier.doi10.1039/d2ob01064j
dc.identifier.issn1477-0520
dc.identifier.issn1477-0539
dc.identifier.urihttps://hdl.handle.net/10037/28284
dc.language.isoengen_US
dc.publisherRoyal Society of Chemistryen_US
dc.relation.journalOrganic and biomolecular chemistry
dc.relation.projectIDNorges forskningsråd: 275043en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2022 The Author(s)en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.rightsAttribution 4.0 International (CC BY 4.0)en_US
dc.titleDevelopment of potent cholinesterase inhibitors based on a marine pharmacophoreen_US
dc.type.versionacceptedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's license is described as Attribution 4.0 International (CC BY 4.0)