Rational Approach To Discover Multipotent Anti-Alzheimer Drugs

Rosini, Michela; Andrisano, Vincenza; Bartolini, Manuela; Bolognesi, María Laura; Hrelia, Patrizia; Minarini, Anna; Tarozzi, and Andrea; Melchiorre, Carlo

doi:10.1021/jm049112h

Cited by 221 publications

(185 citation statements)

References 21 publications

Supporting

Mentioning

182

Contrasting

Order By: Relevance

“…[9][10][11] However, the complexity of combined therapy protocols leads to the recent search for alternative therapeutic strategies based on multifunctional compounds. [12][13][14][15][16] Thus, following the same strategy, we have decided to develop new bifunctional compounds as drug candidates for anti-AD therapy, by conjugating, in the same compound, molecular fragments for both neurorestorative and neuroprotective roles, such as the inhibition of acetylcholinesterase (AChE) and the antioxidation.…”

Section: Introductionmentioning

confidence: 99%

Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

Šebestı́k¹,

Marques²,

Falé

et al. 2010

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

Šebestı́k¹,

Marques²,

Falé

et al. 2010

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

“…Hence, it is possible that dual inhibitors of both AChE and BuChE would represent a novel therapeutic approach for use in mild, moderate and, particularly, severe dementia [29] . Notably, rational approaches to generate multifunctional cholinesterase inhibitors have been reported by many research groups [30][31][32][33][34] . Moreover, a number of researchers have indicated that AD is related to changes in oxidative metabolism [35,36] .…”

Section: Discussionmentioning

confidence: 99%

Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors

et al. 2009

View full text Add to dashboard Cite

Aim: To design novel bifunctional derivatives of huperzine B (HupB) based on the concept of dual binding site of acetylcholinesterase (AChE) and evaluate their pharmacological activities for seeking new drug candidates against Alzheimer's disease (AD). Methods: Novel 16-substituted bifunctional derivatives of HupB were synthesized through chemical reactions. The inhibitory activities of the derivatives toward AChE and butyrylcholinesterase (BuChE) were determined in vitro by modified Ellman's method. Cell viability was quantified by the reduction of MTT. Results: A new preparative method was developed for the generation of 16-substituted derivatives of HupB, and pharmacological trials indicated that the derivatives were multifunctional cholinesterase inhibitors targeting both AChE and BuChE. Among the derivatives tested, 9c, 9e, 9f, and 9i were 480 to 1360 times more potent as AChE inhibitors and 370 to 1560 times more potent as BuChE inhibitors than the parent HupB. Further preliminary pharmacological trials of derivatives 9c and 9i were performed, including examining the mechanism of AChE inhibition, the substrate kinetics of the enzyme inhibition, and protection against hydrogen peroxide (H 2 O 2 )-induced cytotoxicity in PC12 cells. Conclusion: Preliminary pharmacological evaluation indicated that 16-substituted derivatives of HupB, particularly 9c and 9i, would be potentially valuable new drug candidates for AD therapy, and further exploration is needed to evaluate their pharmacological and clinical efficacies.

show abstract

“…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. 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.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

mentioning

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.

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Rational Approach To Discover Multipotent Anti-Alzheimer Drugs

Cited by 221 publications

References 21 publications

Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

Bifunctional phenolic-choline conjugates as anti-oxidants and acetylcholinesterase inhibitors

Novel 16-substituted bifunctional derivatives of huperzine B: multifunctional cholinesterase inhibitors

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

Contact Info

Product

Resources

About