Development of potent cholinesterase inhibitors based on a marine pharmacophore

Elumalai, Vijayaragavan (author), Trobec, Tomaž (author), Grundner, Maja (author), Labriere, Christophe (author), Frangež, Robert (author), Sepčić, Kristina (author), Hansen, Jørn H. (author), Svenson, Johan (author)

The 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 inhibi- tors. 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 illus- trates how the brominated dipeptide marine pharmacophore can be used as a versatile natural scaffold for the design of potent, and selective cholinesterase inhibitors.

• Language: English
• Keywords: Nervous System Diseases, Cholinesterase Inhibitors
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: VF - Veterinary Faculty; BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Publication date: 01.01.2022
• Year: 2022
• Number of pages: Str. 5589-5601
• Numbering: Vol. 20, no. 28
• PID: 20.500.12556/RUL-140920
• UDC: 616:577
• ISSN on article: 1477-0539
• DOI: 10.1039/d2ob01064j
• COBISS.SI-ID: 114793219
• Publication date in RUL: 21.09.2022

Record is a part of a journal

• Title: Organic & biomolecular chemistry
• Shortened title: Org. biomol. chem.
• Publisher: Royal Society of Chemistry
• ISSN: 1477-0539
• COBISS.SI-ID: 19836967

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• Link: https://creativecommons.org/licenses/by/3.0/deed.en
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• Licensing start date: 21.09.2022