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  1. IPB Halle
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    • Trenner 0
    • Molecular Signal Processing
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        • Nutrient Sensing
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    • Bioorganic Chemistry
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        • Biofunctional Synthesis
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      • Secretariat & All Staff
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Wiemann, J.; Karasch, J.; Loesche, A.; Heller, L.; Brandt, W.; Csuk, R.; Piperlongumine B and analogs are promising and selective inhibitors for acetylcholinesterase Eur. J. Med. Chem. 139 222-231 (2017) DOI: 10.1016/j.ejmech.2017.07.081
  • Abstract
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  • RIS

Piperlongumine B (19), an alkaloid previously isolated from long pepper (Piper longum) has been synthesized for the first time in a short sequence and in good yield together with 19 analogs. Screening of these compounds in Ellman's assays showed several of them to be good inhibitors of acetylcholinesterase while being less active for butyrylcholinesterase. Activity of the compounds increased with the ring size of the heterocycle, and a maximum of activity was observed for an analog holding 12 methylene groups in the aliphatic side chain. These compounds may be regarded as promising candidates for the development of efficient inhibitors of acetylcholinesterase being useful for the treatment of Alzheimer's disease.

Publications

Heller, L.; Kahnt, M.; Loesche, A.; Grabandt, P.; Schwarz, S.; Brandt, W.; Csuk, R.; Amino derivatives of platanic acid act as selective and potent inhibitors of butyrylcholinesterase Eur. J. Med. Chem. 126 652-668 (2017) DOI: 10.1016/j.ejmech.2016.11.056
  • Abstract
  • BibText
  • RIS

A set of thirtyfive 30-norlupan derivatives (2–36) was prepared from the natural triterpenoid platanic acid (PA), and the hydroxyl group at C-3, the carboxyl group at C-17 and the carbonyl group at C-20 were modified. These derivatives were tested for their inhibitory activity for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) using Ellman's assay. Extra enzyme kinetic studies were performed. The most active compound was (3β, 20R)-3-acetyloxy-20-amino-30-norlupan-28-oate (32) showing a Ki value of 0.01 ± 0.003 μM for BChE. This compound proved to be a selective (FB = 851), mixed-type inhibitor for BChE.

Publications

Loesche, A.; Wiese, J.; Sommerwerk, S.; Simon, V.; Brandt, W.; Csuk, R.; Repurposing N,N'-bis-(arylamidino)-1,4-piperazinedicarboxamidines: An unexpected class of potent inhibitors of cholinesterases Eur. J. Med. Chem. 125 430-434 (2017) DOI: 10.1016/j.ejmech.2016.09.051
  • Abstract
  • BibText
  • RIS

Drug repurposing (=drug repositioning) is an effective way to cut costs for the development of new therapeutics and to reduce the time-to-market time-span. Following this concept a small library of compounds was screened for their ability to act as inhibitors of acetyl- and butyrylcholinesterase. Picloxydine, an established antiseptic, was shown to be an inhibitor for both enzymes. Systematic variation of the aryl substituents led to analogs possessing almost the same good properties as gold standard galantamine hydrobromide.

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