Syntheses and characterization of novel oxoisoaporphine derivatives as dual inhibitors for cholinesterases and amyloid beta aggregation

A series of 3-substituted (5c–5f, 6c–6f) and 4-substituted (10a–10g) oxoisoaporphine derivatives were synthesized. It was found that all these synthetic compounds had IC50 values at micro or nano molar range for cholinesterase inhibition, and most of them could inhibit amyloid β (Aβ) self-induced aggregation with inhibition ratio from 31.8% to 57.6%. The structure–activity relationship studies revealed that the derivatives with higher selectivity on AChE also showed better inhibition on Aβ self-induced aggregation. The results from cell toxicity study indicated that most quaternary methiodide salts had higher IC50 values than the corresponding non-quaternary compounds. This study provided potentially important information for further development of oxoisoaporphine derivatives as lead compounds for the treatment of Alzheimer’s disease.

3-substituted (5c–5f, 6c–6f) and 4-substituted (10a–10g) oxoisoaporphine derivatives were synthesized and it was found that the derivatives with higher selectivity on AChE also showed better inhibition on Aβ (1–42) self-induced aggregation.Figure optionsDownload as PowerPoint slideHighlights
► 3-Substituted and 4-substituted oxoisoaporphine derivatives were synthesized.
► All synthetic compounds had strong inhibition on cholinesterase and Aβ aggregation.
► The derivatives with higher selectivity on AChE also showed better inhibition on Aβ self-induced aggregation.