3D-QSAR studies of azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives as anti-AChE and anti-AD agents by the CoMFA method

[Display omitted] ► This paper analyzed a new series of azaoxoisoaporphine derivatives. ► The derivatives showed high inhibition on Aβ aggregation but no ChE inhibition. ► A statistically significant and physically meaningful 3D-QSAR model was derived. ► The molecular shape, size, and charge were crucial for AChE inhibition. In the present study, a series of novel azaoxoisoaporphine derivatives were reported and their inhibitory activities toward acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Aβ aggregation were evaluated. The new compounds remained high inhibitory potency on Aβ aggregation, with inhibitory activity from 29.42% to 89.63% at a concentration of 10μM, but had no action on AChE or BuChE, which was very different from our previously reported oxoaporphine and oxoisoaporphine derivatives. By 3D-QSAR studies, we constructed a reliable CoMFA model (q2=0.856 and r2=0.986) based on the inhibitory activities toward AChE and discovered key information on structure and anti-AChE activities among the azaoxoisoaporphine, oxoaporphine, and oxoisoaporphine derivatives. The model was further confirmed by the test-set validation (q2=0.873, r2=0.937, and slope k=0.902) and Y-randomization examination. The statistically significant and physically meaningful 3D-QSAR/CoMFA model provided better insight into understanding the inhibitory behaviors of those chemicals, which may provide useful information for the rational molecular design of azaoxoisoaporphine derivatives anti-AChE and anti-AD agents.