Parlar_2022_Arch.Pharm.(Weinheim)__e2200519

A series of piperidine-3-carbohydrazide-hydrazones bearing phenylethyl, phenylpropyl, and phenylbutyl substituents on piperidine nitrogen were designed and synthesized as cholinesterase (ChE) inhibitors. The title compounds were screened for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory activitiessand antioxidant capacities, and the active ones for Abeta(42) self-aggregation inhibition, in vitro. The chemiluminescence method was used to determine the effect of the selected compounds on the reactive oxygen species (ROS) levels in brain tissue. Physicochemical properties were calculated by thesMOE program. Kinetic analysis and molecular modeling studies were also carried out for the most active compounds. Generally, the final compounds exhibited moderate to good AChE or BuChE inhibitory activity. Among them, 3g and 3j showed the most potent activity against AChE (IC(50) = 4.32 microM) and BuChE (IC(50) = 1.27 microM), respectively. The kinetic results showed that both compounds exhibited mixed-type inhibition. Among the selected compounds, nitro derivatives (3g, 4g, ands5g) provided better Abeta(42) inhibition. According to the chemiluminescence assay, 4i exhibited the most active superoxide free-radical scavenger activity and 3g, 3j, and 4i showed similar scavenger activity on other ROS. All results suggested that 3g, 3j, and 4i have good AChE/BuChE, Abeta(42) inhibitory potentials and antioxidant capacities and can therefore be suggested as promising multifunctional agents to combat Alzheimer's disease.