Two Novel Donepezil-Lipoic Acid Hybrids: Synthesis, Anticholinesterase and Antioxidant Activities and Theoretical Studies

Abstract

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...

Naturally Occurring Antioxidant Therapy in Alzheimer’s Disease

“…Similar mechanisms have also been reported for other antioxidant compounds that have shown promise in studies utilizing animal subjects to model the onset and course of progression of AD, and the impacts of novel drugs and/or compounds as therapeutic options. Antioxidants that have been explored in combination with other compounds in both cellular and animal models of AD including but not limited to ebselen and donepezil [ 409 ], lipoic acid and donepezil [ 410 ], ferulic acid and tacrine (the first AChE inhibitor approved for AD, but now discontinued) [ 411 ], and polyphenolic hybrids [ 412 , 413 ].…”

Pd-Catalyzed Direct Modification of an Anti-Alzheimer’s Disease Drug: Synthesis and Biological Evaluation of α-Aryl Donepezil Analogues

“…Several donepezil derivatives have been prepared to find better anti-AD compounds. Previous modifications of donepezil only focused on the N -benzylpiperidine group 8 − 11 or the terminal benzene ring. 12 Besides these, donepezil was also conjugated with different moieties like tacrine 13 and huperzine A.…”

“…Several donepezil derivatives have been prepared to find better anti-AD compounds. Previous modifications of donepezil only focused on the N -benzylpiperidine group − or the terminal benzene ring . Besides these, donepezil was also conjugated with different moieties like tacrine and huperzine A. , All the previous modifications used the de novo synthesis pathway, in which various fragments were introduced in the beginning, and so, more synthetic steps were necessary for the preparation of structural diverse donepezil derivatives.…”