7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment

Korábečný, Jan; Andrš, Martin; Nepovimová, Eugenie; Doležal, Rafael; Babkova, Katerina; Horova, Anna; Maliňák, Dávid; Mezeiová, Eva; Górecki, Lukáš; Šepsová, Vendula; Hrabinová, Martina; Soukup, Ondřej; Jun, Daniel; Kuča, Kamil

doi:10.3390/molecules201219836

Cited by 38 publications

(26 citation statements)

References 47 publications

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“…Since tacrine has demonstrated very mild improvements in the cognitive functions of AD patients, medicinal chemists were prompted to undertake the design and testing of hybrid molecules containing tacrine and an antioxidant moiety. Such a multipotent approach toward targeting the oxidative stress component in AD included the introduction of novel tacrine-melatonin (Spuch et al 2010), tacrine-coumarin (Hamulakova et al 2014), tacrine-gallamine (Elsinghorst et al 2007), tacrine-resveratrol (Jerabek et al 2017), tacrine-scutellarin (Spilovska et al 2017), tacrine-anisidine (Korabecny et al 2015), tacrine-trolox (Nepovimova et al 2015) and related hybrid molecules (Fig. 2).…”

Section: Multifunctional Drugs Containing Metal-chelating and Oxidatimentioning

confidence: 99%

Management of oxidative stress and other pathologies in Alzheimer’s disease

et al. 2019

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Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, characterized by the formation, aggregation and accumulation of amyloid beta, perturbed metal (copper, iron and zinc) homeostasis, metal-induced oxidative stress, neuroinflammation, aberrant activity of acetylcholinesterase (AChE) and other pathologies. The aim of this review is to discuss the current therapies based on the "combination-drugs-multitargets" strategy to target multiple pathologies to block the progression of pathogenesis of AD. In addition to cholinergic and amyloid targets, a significant effort is focused on targeting the metal-induced oxidative stress component of the disease. The main focus of research is based on modifications of existing drugs with specific biological activity. Tacrine was the first AChE inhibitor to be introduced into clinical practice and has been frequently used for the design of multitarget-directed ligands. A number of hybrid compounds containing tacrine and structural moieties derived from natural sources such as flavonoids [quercetin, rutin, coumarin, gallamine, resveratrol, scutellarin, anisidine, hesperetin, (−)-epicatechin] and other molecules (melatonin, trolox) have also been applied to function as multitarget-directed ligands. Most of these hybrids are potent inhibitors of AChE and butyrylcholinesterase and also of amyloid-beta aggregation. In addition, the antioxidant functionality, represented by coumarins, melatonin and other antioxidant molecules reduces the level of oxidative stress via ROS-scavenging mechanisms, as well as via chelation of redox-active Cu and Fe, thus suppressing the formation of ROS via the Fenton reaction. Various medicinal plants are under investigation for their ability to ameliorate symptoms of AD. The therapeutic potency of huperzine A and B, ginseng, curcumin and other compounds is manifested predominantly by the inhibitory action toward AChE, antioxidant or radical-scavenging and redox metal-chelating activity, inhibition of amyloid-beta aggregation and tau-protein hyperphosphorylation and antiinflammatory activity. Flavonoids not only function as antioxidants and metal-chelating agents, but also interact with protein kinase and lipid kinase signaling pathways, and others involving mitogen-activated protein kinase, NF-kappaB and tyrosine kinase. Among the most promising group of substances with potential activity against AD are the flavonoids, including myricetin, morin, rutin, quercetin, fisetin, kaempferol, apigenin and glycitein, which have been shown, in vitro, to possess antiamyloidogenic and fibril-destabilization activity, as well as being able to act as metal chelators and to suppressing oxidative stress. In terms of the clinical use of multifunctional hybrids, herbal drugs or flavonoids against AD, some remaining challenges are to establish the ideal dose to develop effective formulations to preserve bioavailability and to determine the stage when they should be administered. If the onset of the disease could be delayed by a decade, the number of AD vic...

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Section: Multifunctional Drugs Containing Metal-chelating and Oxidatimentioning

confidence: 99%

Management of oxidative stress and other pathologies in Alzheimer’s disease

et al. 2019

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“…The CAS comprises the catalytic triad His447, Glu334 and Ser203, and Trp86. Good h AChE inhibitors are able to bind both sites .…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease

Fernandes

Cunha

Sakata

et al. 2017

Archiv der Pharmazie

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Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC values of 0.64-51.09 μM. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC (0.64 μM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD.

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“…The heterodimer of 7-MEO-TA and NMDA antagonist 1-adamantylamin (24 of Figure 7, Table 1) connected through a thiourea linker, inhibited AChE (IC 50 = 470 nM) and BChE (IC 50 = 110 nM) moderately with poor selectivity [59]. The other analog of the series 7-MEOTA-p-anisidine hybrid (25 of Figure 7) showed weaker AChE inhibition (IC 50 = 1350 nM) than tacrine (IC 50 = 320 nM) but stronger than 7-MEOTA (IC 50 = 10,000 nM) [60]. Among the reported tacrine-selegiline heterodimers [61], the analog 26 ( Figure 7) showed significant AChE (IC 50 = 22.6 nM), BChE (IC 50 = 9.39 nM) and MAO-A/B (0.37, 0.18 µM) inhibition [62].…”

Section: Tacrine Analogsmentioning

confidence: 99%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

AND

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Alzheimer's Disease (AD) is characterized by the loss of memory and learning ability in elderly patients affecting large population worldwide. The enzyme Acetylcholinesterase (AChE), (E.C.3.1.1.7) plays a major role in the hydrolysis of the released neurotransmitter acetylcholine. Most of the clinically used drugs to treat AD are Acetylcholinesterase Inhibitors (AChEIs). These drugs can provide symptomatic benefits only and suffer with loss of therapeutic potential with time. Therefore, there is an urgent need of novel cholinesterase inhibitors with wider therapeutic window for the treatment of AD. The strategies targeting the AChE enzyme along with other target(s) like Butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals (Cu 2+ , Zn 2+ , or Fe 2+), antioxidant properties and free radical scavenging capacity have been mainly focused in the last five years. A number of hybrid molecules incorporating sub-structures with the desired well-established pharmacological profile into a single scaffold have been investigated. The main sub structures used in developing these molecules are derived from diverse chemical classes such as acridine, quinoline, carbamates, huperzine and other heterocyclic analogs. It has been followed by optimization of activity through structural modifications of the prototype molecules for developing the Structure Activity Relationship (SAR). This has led to the development of novel molecules with desired AChE inhibitory activity along with other desirable pharmacological properties. This review summarizes the current therapeutic strategies for the development of these AChEI in the last seven years.

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7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment

Cited by 38 publications

References 47 publications

Management of oxidative stress and other pathologies in Alzheimer’s disease

Management of oxidative stress and other pathologies in Alzheimer’s disease

Synthesis, Molecular Modeling, and Evaluation of Novel Sulfonylhydrazones as Acetylcholinesterase Inhibitors for Alzheimer's Disease

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

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