Novel Morpholine-Bearing Quinoline Derivatives as Potential Cholinesterase Inhibitors: The Influence of Amine, Carbon Linkers and Phenylamino Groups

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC(50) values of 1.94 ± 0.13 μM and 28.37 ± 1.85 μM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC(50) values of 9.07 ± 1.34 μM and 6.05 ± 1.17 μM, respectively, which were superior to the control, Trolox (IC(50) = 11.03 ± 0.76 μM). It is worth noting that 3-aminoquinoline derivatives 12a–12d exhibited better drug-like properties.