Alzheimer disease (AD) is a complex disease related to multiple pathogenic mechanisms. A strategy to develop effective drugs is based on the so-called multi-target directed ligands (MTDL) by using hybrid compounds. So, in the present study, we have designed and synthesized two hybrids, containing the indanone-piperidine moiety of donepezil, a drug approved for the treatment of AD, and the lipoic acid scaffold, an antioxidant compound endowed with neuroprotective effects. One hybrid was synthesized in four steps with 42% global yield, and the other hybrid in six steps with 19% global yield. The latter hybrid displayed moderate inhibitory activity against human acetylcholinesterase (hAChE) and greater activity against human butyrylcholinesterases (hBuChE). The selectivity for hBuChE was further rationalized by theoretical study. Importantly, the second hybrid showed a good antioxidant activity, exhibiting better ability in scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals than lipoic acid. Keywords: donepezil-lipoic acid hybrids, Alzheimer disease, multi-target directed ligands IntroductionAlzheimer disease (AD) is the most common cause of dementia in aging population. It was estimated that, in 2010, about 35.6 millions of people suffered from dementia worldwide, and it is expected that this number might triplicate in the next 40 years.1 Patients affected by AD experience progressive cognitive impairment, such as a decline in short-term memory, loss of speech, language and motor coordination. 2,3 AD is pathologically characterized by an extracellular deposition of β-amyloid (Aβ) peptide into senile plaques, intracellular formation of neurofibrillary tangles (NFTs) containing a hyperphosphorylated form of Tau protein, oxidative stress, mitochondrial abnormality, neuroinflammatory processes and neuronal loss, mainly affecting the frontal cortex and hippocampus. 4,5 AD is also characterized by a reduction of acetylcholine (ACh) levels, which is correlated with the cognitive symptoms. 6 The "cholinergic hypothesis", proposed in 1982 by Bartus et al.,7 postulated that the cognitive decline experienced by patients with AD resulted from a deficiency of acetylcholine or cholinergic neurotransmission. In humans, acetylcholine is degraded in the synaptic cleft by two main classes of cholinesterase enzymes: acetyl-(AChE) and butyryl- (BuChE) 8 cholinesterases. Near the amyloid plaques and neurofibrillary tangles, an extensive oxidative stress has been observed 9 which is a result of an altered balance of formation of reactive oxygen species (ROS) versus scavenging activity. 5,10 The production of ROS is also related to calcium homeostasis; the misbalance of calcium influx affects the mitochondrial Terra et al. 739 Vol. 29, No. 4, 2018 enzymes and ROS production is a normal part of the electron transport chain. However, excessive levels of these species damage proteins, lipids and nucleic acids. 9AD is a complex disease related to multiple pathogenic mechanisms involving different molecular targets. All the dru...