Synthesis and biological evaluation of 8-hydroxy-2,7-naphthyridin-2-ium salts as novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)

M Schiedel; A Fallarero; C Luise; W Sippl; P Vuorela; M Jung

doi:10.1039/c6md00647g

Synthesis and biological evaluation of 8-hydroxy-2,7-naphthyridin-2-ium salts as novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)

Medchemcomm. 2017 Jan 13;8(2):465-470. doi: 10.1039/c6md00647g. eCollection 2017 Feb 1.

Authors

M Schiedel¹, A Fallarero², C Luise³, W Sippl³, P Vuorela², M Jung¹

Affiliations

¹ Institute of Pharmaceutical Sciences , University of Freiburg , Albertstraße 25 , 79104 Freiburg im Breisgau , Germany . Email: [email protected] ; Tel: +49 761 203 6335.
² Pharmaceutical Design and Discovery Research Group , Division of Pharmaceutical Biosciences , Faculty of Pharmacy , University of Helsinki (UHEL) , Helsinki , Finland.
³ Institute of Pharmacy , Martin-Luther-University Halle-Wittenberg , Wolfgang-Langenbeck-Straße 4 , 06120 Halle (Saale) , Germany.

Abstract

By analogy with the natural product chelerythrine, which has been identified as an inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), we prepared a small series of 8-hydroxy-2,7-naphthyridin-2-ium salts. Spectroscopic analyses allowed us to elucidate the zwitterionic nature of 2,7-naphthyridin-1(7H)-ones, the neutral state of 8-hydroxy-2,7-naphthyridin-2-ium salts. Among the tested compounds, we identified dual inhibitors of AChE and BChE as well as an inhibitor showing a preferential inhibition of AChE over BChE. By in vitro characterization in combination with docking studies, we were able to identify structural features that influence the biological activity of 8-hydroxy-2,7-naphthyridin-2-ium salts.