The intention of this Special Issue is to focus on new aspects of drug discovery, including the search for new molecular targets of various diseases, the creation of new modern methods for diagnosing ...diseases, the development of new test systems and kits for assessing the selectivity and effectiveness of new drugs, the study of the molecular mechanisms of biologically active compounds, the formulation of new drugs, pharmacokinetic and pharmacodynamic studies, and preclinical trials of important molecules.
Chronic dietary ingestion of suitable phytochemicals may assist with limiting or negating neurodegenerative decline. Current therapeutics used to treat Alzheimer disease elicit broad adverse drug ...reactions, and alternative sources of cholinesterase inhibitors (ChEIs) are required. Herein, we screened methanolic extracts from seven commonly cultivated plants for their nutraceutical potential; ability to inhibit acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE), and provision of antioxidant activity through their 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) free radical scavenging capabilities. Potential neurotoxicity of plant extracts was examined via application to SHSY-5Y neuroblastoma cells and quantitation of cell viability. Methanolic extracts of
(Lemon),
(Red silk-cotton),
(Henna),
(Eucalyptus),
(Basil),
(Mandarin orange), and
(Spearmint) all displayed concentration-dependent inhibition of AChE and BuChE. The majority of extracts inhibited AChE and BuChE to near equipotency, with Henna and Eucalyptus extracts the two most potent ChEIs. All plant extracts were able to scavenge free radicals in a concentration-dependent manner, with Eucalyptus the most potent antioxidant. Toxicity of plant extracts to neuronal cells was concentration dependent, with Eucalyptus also the most toxic extract. Fractionation of plant extracts and analysis by mass spectrometry identified a number of plant polyphenols that might have contributed to the cholinesterase inhibition: 3-caffeoylquinic acid, methyl 4-caffeoylquinate, kaempferol-acetyl-glycoside, quercetin 3-rutinoside, quercetin-acetyl-glycoside, kaempferol 3-
-glucoside, and quercetin 3-
-glucoside. In silico molecular modeling of these polyphenols demonstrated their improved AChE and BuChE binding affinities compared to the current FDA-approved dual ChEI, galantamine. Collectively, all the plant extracts contained nutraceutical agents as antioxidants and ChEIs and, therefore, their chronic consumption may prove beneficial to combat the pathological deficits that accrue in Alzheimer disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Alzheimers disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) which is the most common cause of dementia in the elderly. It is characterized by the deficits ...in the cholinergic system and presence of characteristic hallmarks: neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes it became a target for the design of antialzheimer drugs. Cholinesterase inhibitors enhance cholinergic transmission indirectly, by inhibiting the enzyme which hydrolyses acetylcholine. It has been also demonstrated that acetylcholinesterase (AChE) is involved in the developement of amyloid plaques. Therefore, substances which are AChE inhibitors (AChEI) are the only drugs approved for the symptomatic treatment of AD. This review presents the main classes of cholinesterase inhibitors developed recently for the treatment of AD. We have started with the analogues of the existing drugs: tacrine, donepezil, rivastigmine and galantamine which are still of interest for many research groups. Among them there is a very interesting group - dual binding site inhibitors characterized by increased inhibitory potency against AChE and amyloid plaques formation. There is also a group of compounds with additional properties such as: antioxidant activity, affinity to 5-HT3 receptors, inhibition of N-methyltransferase that metabolize histamine, which can be beneficial for the treatment of AD. Furthermore there are some interesting compounds which belong to different chemical groups also of natural origin. In this review we sum up current research concerned with development of AChEIs which can be more effective in the future treatment of AD.
Serotonin 5‐HT6 receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the ...disease and the same effect was demonstrated for 5‐HT
6 antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease‐modifying effect. Combining BuChE inhibition, 5‐HT
6 antagonism, and antioxidant properties may result in multitarget‐directed ligands providing cognition‐enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5‐HT
6 antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5‐HT
6 receptors, BuChE inhibitory activity and antioxidant properties. Compound
12 with
K
i and
K
b values against 5‐HT
6 receptors of 41.8 and 74 nM, respectively, an IC
50 value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti‐Alzheimer's agents.
New indole‐based multitarget‐directed ligands merging inhibitory activity against BuChE, antagonistic activity at 5‐HT6 receptors and antioxidant properties were designed, synthesized, and evaluated in vitro. Due to its multidirectional in vitro activity, compound
12 (2‐(3‐(4‐(1‐(3‐chlorobenzyl)‐1
H‐indol‐4‐yl)piperazin‐1‐yl)propyl)isoindoline‐1,3‐dione) appears as a good starting point for further development of anti‐Alzheimer's agents.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The present study describes the synthesis, assessment of the anticholinesterase activity and the inhibition type of novel cis- and trans-3-arylaminocyclohexyl N,N-dimethylcarbamates. In vitro ...inhibition assay by Ellman's method with human blood samples showed that carbamates were selective for butyrylcholinesterase (BuChE) with compound concentration that inhibits 50% of enzyme activity (IC50) between 0.11 and 0.18 mmol L-1. cis- and trans-3-(4-Methoxyphenylamino)cyclohexyl N,N-dimethylcarbamate hydrochloride were the most active for BuChE, showing that the presence of methoxyl group enhanced the anticholinesterase activity. The enzyme kinetics studies indicate a noncompetitive inhibition against acetylcholinesterase (AChE) and mixed type inhibition for BuChE. Molecular modeling studies confirm the ability of carbamates to bind both the active and peripheral sites of the BuChE.
A novel series of cinnamic acid–tryptamine hybrids was designed, synthesized, and evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of the synthesized compounds ...displayed a clearly selective inhibition of butyrylcholinesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase (AChE) was detected. Among these cinnamic acid–tryptamine hybrids, compound 7d was found to be the most potent inhibitor of BChE with an IC50 value of 0.55 ± 0.04 μM. This compound showed a 14‐fold higher inhibitory potency than the standard drug donepezil (IC50 = 7.79 ± 0.81 μM) and inhibited BChE through a mixed‐type inhibition mode. Moreover, a docking study revealed that compound 7d binds to both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE. Also, compound 7d was evaluated against β‐secretase, which exhibited low activity (inhibition percentage: 38%).
Novel cinnamic acid–tryptamine hybrids were designed, synthesized, and evaluated as cholinesterase inhibitors. All of the synthesized compounds displayed selective inhibition of butyrylcholinesterase (BChE) but only a moderate inhibitory effect toward acetylcholinesterase was detected. Compound 7d was found to be the most potent inhibitor of BChE with an IC50 value of 0.55 ± 0.04 µM and a 14‐fold higher inhibitory potency than the standard drug donepezil.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
On the pattern of the potent and selective butyrylcholinesterase (BChE) inhibitors ethopropazine and Astra1397, sets of quinolizidinyl derivatives of bi- and tricyclic (hetero)aromatic systems were ...studied as dual, or BChE-selective inhibitors. All compounds exhibited activity against both cholinesterases, but inhibition of BChE was generally stronger, with submicromolar IC50 values for most of them (e.g. 15: IC50versus BChE = 0.15 μM; SI = 47). However, in a subset of quinolizidinyl derivatives of 6-hydroxycoumarin an inverted selectivity for acetylcholinesterase (AChE) was observed (e.g. 46: IC50versus AChE = 0.35 μM; SI = 0.06). Docking studies furnished a sound interpretation of the observed different enzyme activity. Several of the studied compounds have shown, in the past, additional pharmacological properties (as antagonism on presynaptic muscarinic autoreceptor; inhibition of enkephaline aminopeptidase and antipsychotic activity) of some relevance in Alzheimer’s disease, and may, therefore, represent hits for the development of interesting single-entity multi-target drugs.
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► Quinolizidinyl derivatives of bi- and tricyclic systems potently inhibit AChE and/or BChE. ► The thioxanthene derivative 15 inhibits preferentially BChE (IC50 = 0.15 μM, SI = 47). ► The acridine derivative 43 is a balanced AChE/BChE inhibitor (IC50 = 0.22 and 0.69 μM respectively). ► The 6-hydroxy coumarine derivative 46 inhibits preferentially AChE (IC50 = 0.35 μM, SI = 15). ► Remarkably periciazine 3 potently inhibits BChE (IC50 = 0.23 μM), many fold more than the common anti-psychotics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high ...acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765–3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids (
5a–
j, 4-carboxylic amide-7-oxo-7
H-dibenzo
de,
gquinoline, Ar-CONH(CH
2)
nNR) and their quaternary methiodide salts (
6a–
h, Ar-CONH(CH
2)
nN
+(CH
3)RI
−) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2–3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives
7 series and oxoaporphine derivatives
6 series with AChE from
Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Tacrine was the first drug to display beneficial effects on cognitive impairment of Alzheimer Disease (AD) patients. Unfortunately, many treated patients displayed related hepatotoxicity, and hence ...this drug was withdrawn. Notwithstanding, recent efforts have been directed to design small tacrine analogues targeting the underlying pathogenic mechanisms of AD. In this context, we have developed a number of pyranotacrines by changing the benzene fused ring in tacrine by a 4Hpyran. Based on this strategy, in this account we will show the tacrine analogues that we have designed, synthesized and evaluated as potential multipotent agents for AD in the last years. We have demonstrated that this approach is possible, and that a number of readily available tacrine analogues show cholinesterase inhibition power, as well as other pharmacological properties, such as calcium channel blockade, antioxidant properties, neuroprotection, Aβ-amyloid inhibition aggregation capacity, etc., making them suitable multipotent molecules for further development for the potential treatment of AD.
This collection of 10 papers includes original as well as review articles focused on the cholinesterase structural aspects, drug design and development of novel cholinesterase ligands, but also ...contains papers focused on the natural compounds and their effect on the cholinergic system and unexplored effects of donepezil.
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