Synthesis and cholinesterase inhibitory activity study of Amaryllidaceae alkaloid analogues with N-methyl substitution

Polycyclic compounds with N-methyl substitution, structurally related to Amaryllidaceae alkaloids, have been synthesised, together with their analogues bearing a quaternary nitrogen atom. To prevent the lone electron pair of the nitrogen from interfering with the reaction sequence, two approaches to the synthesis were investigated: N-oxidation and Boc protection of the nitrogen. The second method was more successful due to the limited stability of N-oxides in the halocyclisation step. An asymmetric version of the synthesis was also developed for this type of compounds. The prepared products were tested in vitro for their cholinesterase inhibitory activity and the results were rationalised by molecular docking studies with human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). In general, our products were more active against BuChE than against AChE, and it was noted that larger ligands should be prepared for future studies, since in some cases acetylcholine can still fit into the active site along with the bound ligand.

Automated summary

In this study, polycyclic compounds with N-methyl substitution, structurally related to Amaryllidaceae alkaloids, were synthesised. Two approaches, N-oxidation and Boc protection of the nitrogen, were investigated to avoid interference of the nitrogen lone electron pair with the reaction sequence. The products prepared showed higher activity against BuChE than AChE, indicating a need for larger ligands in future studies.