Donepezil–tacrine hybrid related derivatives as new dual binding site inhibitors of AChE

Alonso, D. A.; Dorronsoro, Isabel; Rubio, Laura; Muñoz, P.; Garcı́a-Palomero, Esther; Monte, Maria del; Bidon‐Chanal, Axel; Orozco, Modesto; Luque, F. Javier; Castro, Ana; Medina, Miguel; Martı́nez, Ana

doi:10.1016/j.bmc.2005.09.029

Cited by 147 publications

(91 citation statements)

References 44 publications

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“…These tacrine heterodimers are usually obtained by connecting natural or synthetic compounds by a linker of suitable length. Examples of tacrine-based heterodimer families include the combination of tacrine with structural units such as tacrine-huperzine A [17e19], tacrine-donepezil [16,20,21], tacrine-indole [22], tacrinee 4-Oxo-4H-chromene [10] and tacrine-8-hydroxyquinoline [23].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

Costa

Lopes

Russowsky

et al. 2013

European Journal of Medicinal Chemistry

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a b s t r a c tA novel series of tacrine-lophine hybrids was synthesized and tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC 50 in the nanomolar concentration scale. The key step is the one-pot four component condensation reaction of 9-aminoalkylamino-1,2,3,4-tetrahydroacridines, benzil, different substituted aromatic aldehydes and NH 4 OAc, using InCl 3 as the best catalyst. Tacrine-lophine hybrids were found to be potent and selective inhibitors of cholinesterases. As an extension of the four component approach to tetrasubstituted imidazoles, a new series of bis-(2,4,5-triphenyl-1H-imidazoles) or bis(n)-lophines was tested against AChE and BuChE.

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Section: Introductionmentioning

confidence: 99%

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

Costa

Lopes

Russowsky

et al. 2013

European Journal of Medicinal Chemistry

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“…13,14 Many prototypes for new drugs based on the hybridization strategy have been developed starting from donepezil fragments, i.e., indanone-piperidine moiety or piperidine-benzyl fragment. 13 Furthermore, donepezil hybrids with tacrine, 15,16 diaminobenzyl group, 17 ferulic acid, 18 coumarin, 19 among others 13 have been prepared. Hybrids containing the piperidine-benzyl moiety of donepezil and lipoic acid (LA) ( Figure 2) were described by the groups of Kim et al, 20 Lee et al, 21 Prezzavento et al, 22 and Estrada et al 23 The hybrids showed activity against cholinesterase (ChE) enzymes, antagonism toward σ1 receptors, β-secretase inhibition and antioxidant activity.…”

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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“…1 exhibited an excellent AChE inhibitory activity. The phthalimide ring occupied a similar position at the peripheral site and remained stacked onto the aromatic ring of Trp279 [2]. Compound C (m = 3) displayed the remarkable rat cortex AChE inhibition (190-fold higher than physostigmine).…”

Section: Introductionmentioning

confidence: 99%

Novel acetylcholinesterase inhibitors: Synthesis and structure–activity relationships of phthalimide alkyloxyphenyl N,N-dimethylcarbamate derivatives

Zhao

Yang

Mei

et al. 2009

Pesticide Biochemistry and Physiology

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a b s t r a c tBased on the multiple binding sites of acetylcholinesterase (AChE), a series of AChE inhibitors: phthalimide alkyloxyphenyl N,N-dimethylcarbamate were designed and synthesized. AChE inhibitory activity and structure-activity relationship of the compounds were researched also. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different alkyloxy chain length and position between phthalimide and phenyl N,N-dimethylcarbamate (PDM). The biological properties of the series were investigated by considering the activity on isolated enzyme. Some of the newly synthesized derivatives, when tested on isolated AChE from head of housefly (Musca domestica), were more active than PDM. The compounds J1, J2 and K1-K8 demonstrated higher inhibitory activity (5-to 404-fold) for AChE than that of PDM. In particular, compound K1 displayed the best AChE inhibition (404-fold higher than PDM), which suggested that phthalimide group of K1 strongly bound at the residues lining the gorge while phenyl N,N-dimethylcarbamate bound at the catalytic site.

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Donepezil–tacrine hybrid related derivatives as new dual binding site inhibitors of AChE

Cited by 147 publications

References 44 publications

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

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

Novel acetylcholinesterase inhibitors: Synthesis and structure–activity relationships of phthalimide alkyloxyphenyl N,N-dimethylcarbamate derivatives

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