Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer’s disease

Rosini, Michela; Simoni, Elena; Bartolini, Manuela; Tarozzi, Andrea; Matera, Riccardo; Milelli, Andrea; Hrelia, Patrizia; Andrisano, Vincenza; Bolognesi, María Laura; Melchiorre, Carlo

doi:10.1016/j.ejmech.2011.09.001

Cited by 81 publications

(43 citation statements)

References 38 publications

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“…We have been most intrigued with therapeutic avenues that focus on mitochondrial involvement in the etiology of the disease [Tillement et al, 2011;Breuer et al, 2012;Chung et al, 2012;Manji et al, 2012;Milone, 2012;Schapira, 2012;Swerdlow, 2012;Breuer et al, 2013;Selfridge et al, 2013;Pagano et al, 2014;Swerdlow et al, 2014;Gody n et al, 2016], and a number of mitochondria-targeted small molecules, such as dimebon [Moreira et al, 2010], MitoQ [Su et al, 2010;Carvalho et al, 2012;Reddy et al, 2012], and lipoic acid derivatives [Bolaños et al, 2009;Rosini et al, 2011;Mecocci and Polidori, 2012;Anand et al, 2014], have reached various stages of clinical trials. However, the results to date with these first-generation synthetic compounds have not been encouraging [Miller, 2010;Galasko et al, 2012;Danta and Piplani, 2014] and their mechanisms of action, target access engagement, and other pharmaceutical properties have not always been clear.…”

Section: Mitochondria and Alzheimer Diseasementioning

confidence: 99%

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Irwin

Moos

Faller

et al. 2016

Drug Development Research

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Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Mitochondria and Alzheimer Diseasementioning

confidence: 99%

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Irwin

Moos

Faller

et al. 2016

Drug Development Research

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“…Although ALA and DHLA garner much attention as bioprotective agents against a host of diseases susceptible to reactive oxygen species (ROS) [Liu et al, 2002a[Liu et al, , 2002bBilska and Włodek, 2005;Rosini et al, 2011], including radiation exposure scenarios [Ramachandran and Nair, 2011] and heavy metal toxicity [Gomes and Negrato, 2014;Nicolson et al, 2014], ALA is not a "drug-friendly" molecule. It has poor pharmacokinetic properties [Biewenga et al, 1997;Gora˛ca et al, 2011;Keith et al, 2012] that are not compatible with a lasting therapeutic effect in vivo [Hermann et al, 1996;Teichert and Preiss, 2002;Nicolson et al, 2014].…”

Section: Lipoic Acid and Butyric Acid: Bioprotection Against Reactivementioning

confidence: 99%

Bioprotective Carnitinoids: Lipoic Acid, Butyrate, and Mitochondria‐Targeting to Treat Radiation Injury: Mitochondrial Drugs Come of Age

Steliou

Faller

Pinkert

et al. 2015

Drug Development Research

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Preclinical Research Given nuclear-power-plant incidents such as the 2011 Japanese Fukushima-Daiichi disaster, an urgent need for effective medicines to protect against and treat the harmful biological effects of radiation is evident. To address such a challenge, we describe potential strategies herein including mitochondrial and epigenetic-driven methods using lipoic and butyric acid ester conjugates of carnitine. The antioxidant and other therapeutically beneficial properties of this class of agents may protect against ionizing radiation and resultant mitochondrial dysfunction. Recent studies of the compounds described herein reveal the potential-although further research and development is required to prove the effectiveness of this approach-to provide field-ready radiation-protective drugs.

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“…27,28 In 2005, Rosini et al 29 reported the synthesis of lipocrine, an LA-tacrine hybrid, which further inspired the development of other hybrids featuring an LA fragment connected with N 1 -ethyl-N 1 -(2-methoxy-benzyl)-hexane-1,6-diamine moiety or with rivastigmine. 26 Although there are works involving the hybridization of the benzyl-piperidine moiety of donepezil with LA, to our knowledge, there is no report on the hybridization of the indanone-piperidine moiety with LA. Therefore, in the present study, following a simple synthetic route, we have designed and synthesized two hybrids containing the indanone-piperidine moiety of donepezil and the LA scaffold with the aim of achieving new MTDLs for the treatment of AD.…”

Section: Introductionmentioning

confidence: 99%

“…25 On the basis of such activities, LA can exert beneficial effects in AD, possibly stabilizing cognitive functions. 26 Thus, LA is a good prototype to design new hybrids to combat AD, and previously developed LA hybrids maintained the antioxidant activity and showed other beneficial activities such as inhibition of AChE and BuChE as well as neuroprotective and anti-inflammatory activity. 27,28 In 2005, Rosini et al 29 reported the synthesis of lipocrine, an LA-tacrine hybrid, which further inspired the development of other hybrids featuring an LA fragment connected with N 1 -ethyl-N 1 -(2-methoxy-benzyl)-hexane-1,6-diamine moiety or with rivastigmine.…”

Section: Introductionmentioning

confidence: 99%

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

Terra¹,

Silva²,

Tramarin³

et al. 2017

J. Braz. Chem. Soc.

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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...

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Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer’s disease

Cited by 81 publications

References 38 publications

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Bioprotective Carnitinoids: Lipoic Acid, Butyrate, and Mitochondria‐Targeting to Treat Radiation Injury: Mitochondrial Drugs Come of Age

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

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