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![Scheme 9. (A) Structure of amido-(36a-p), amino-(37 and 39a-e), and iminotacrines 38a,b [90,94]. (B) Synthesis of amidotacrines 36a-p. (C) Synthesis of amino-(37 and 39a-e) and iminotacrines 38a,b. Reagents and conditions: (i) BF 3 ·Et 2 O, toluene, ∆, 4 h, 84%; (ii) 1-methylpyrazole-4-boronic acid pinacol ester or 5-pyrimidineboronic acid pinacol ester, Na 2 CO 3 , Pd(PPh 3 ) 4 , 1,4-dioxane/H 2 O, ∆, 2 h, 52%; (iii) NH 4 OH or N 2 H 4 ·H 2 O, MeOH, 60 • C, 2-3 h, 73-85%; (iv) LiOH·H 2 O, THF/H 2 O/MeOH, rt, 3 h, 79-90%; (v) benzylamine or phenylethylamine or phenylpropylamine, T 3 P, TEA, DMF, 60 • C, 4 h, 59-67%; (vi) 5-amino-1-methyl-1H-pyrazole, HATU, DIPEA, DMF, rt, 12 h, 63-71%; (vii) 70% H 2 SO 4 , ∆, 5 h; (viii) R-C 6 H 4 -CHO, pyridine, ∆, 6 h, 87-90%; (ix) NH 2 NH-Bz, ∆, 1 h, 84%; (x) X-R (where X = Cl or Br), 1,4-dioxane, ∆, 5-10 h, 69-89%.](profile/Todd-Eckroat/publication/343745924/figure/fig4/AS:926263220916233@1597849769554/Scheme-9-A-Structure-of-amido-36a-p-amino-37-and-39a-e-and-iminotacrines-38a-b.png)
Scheme 9. (A) Structure of amido-(36a-p), amino-(37 and 39a-e), and iminotacrines 38a,b [90,94]. (B) Synthesis of amidotacrines 36a-p. (C) Synthesis of amino-(37 and 39a-e) and iminotacrines 38a,b. Reagents and conditions: (i) BF 3 ·Et 2 O, toluene, ∆, 4 h, 84%; (ii) 1-methylpyrazole-4-boronic acid pinacol ester or 5-pyrimidineboronic acid pinacol ester, Na 2 CO 3 , Pd(PPh 3 ) 4 , 1,4-dioxane/H 2 O, ∆, 2 h, 52%; (iii) NH 4 OH or N 2 H 4 ·H 2 O, MeOH, 60 • C, 2-3 h, 73-85%; (iv) LiOH·H 2 O, THF/H 2 O/MeOH, rt, 3 h, 79-90%; (v) benzylamine or phenylethylamine or phenylpropylamine, T 3 P, TEA, DMF, 60 • C, 4 h, 59-67%; (vi) 5-amino-1-methyl-1H-pyrazole, HATU, DIPEA, DMF, rt, 12 h, 63-71%; (vii) 70% H 2 SO 4 , ∆, 5 h; (viii) R-C 6 H 4 -CHO, pyridine, ∆, 6 h, 87-90%; (ix) NH 2 NH-Bz, ∆, 1 h, 84%; (x) X-R (where X = Cl or Br), 1,4-dioxane, ∆, 5-10 h, 69-89%.
Source publication
Acetylcholinesterase is an important biochemical enzyme in that it controls acetylcholine-mediated neuronal transmission in the central nervous system, contains a unique structure with two binding sites connected by a gorge region, and it has historically been the main pharmacological target for treatment of Alzheimer’s disease. Given the large pro...
Citations
... Tacrine was the first FDA-approved cholinesterase (ChE) inhibitor for treating Alzheimer's disease (AD) [46,47]. However, the lack of sufficient selectivity led to adverse effects, particularly hepatotoxicity [48]. Previous studies demonstrated the hepatoprotective properties of 4-phenyltetrahydroquinolines, which were designed based on the structure of tacrine [18,21,22]. ...
... Previous studies demonstrated the hepatoprotective properties of 4-phenyltetrahydroquinolines, which were designed based on the structure of tacrine [18,21,22]. The appeal of these compounds stems from their diverse structural and biological characteristics [48][49][50]. In this study, we investigated the toxicity profile and hepatoprotective effects of four novel 4-phenyltetrahydroquinoline derivatives and their potential mechanisms of action. ...
Background
The liver serves as a metabolic hub within the human body, playing a crucial role in various essential functions, such as detoxification, nutrient metabolism, and hormone regulation. Therefore, protecting the liver against endogenous and exogenous insults has become a primary focus in medical research. Consequently, the potential hepatoprotective properties of multiple 4-phenyltetrahydroquinolines inspired us to thoroughly study the influence of four specially designed and synthesized derivatives on carbon tetrachloride (CCl4)-induced liver injury in rats.
Methods and results
Seventy-seven Wistar albino male rats weighing 140 ± 18 g were divided into eleven groups to investigate both the toxicity profile and the hepatoprotective potential of 4-phenyltetrahydroquinolines. An in-vivo hepatotoxicity model was conducted using CCl4 (1 ml/kg body weight, a 1:1 v/v mixture with corn oil, i.p.) every 72 h for 14 days. The concurrent treatment of rats with our newly synthesized compounds (each at a dose of 25 mg/kg body weight, suspended in 0.5% CMC, p.o.) every 24 h effectively lowered transaminases, preserved liver tissue integrity, and mitigated oxidative stress and inflammation. Moreover, the histopathological examination of liver tissues revealed a significant reduction in liver fibrosis, which was further supported by the immunohistochemical analysis of α-SMA. Additionally, the expression of the apoptotic genes BAX and BCL2 was monitored using real-time PCR, which showed a significant decrease in liver apoptosis. Further investigations unveiled the ability of the compounds to significantly decrease the expression of autophagy-related proteins, Beclin-1 and LC3B, consequently inhibiting autophagy. Finally, our computer-assisted simulation dockingonfirmed the obtained experimental activities.
Conclusion
Our findings suggest that derivatives of 4-phenyltetrahydroquinoline demonstrate hepatoprotective properties in CCl4-induced liver damage and fibrosis in rats. The potential mechanism of action may be due to the inhibition of autophagy in liver cells.
... [13] Consequently, there is a high demand for new tacrine analogs with improved safety profiles and multitargeted properties, leading to the exploration of various synthetic strategies to obtain such compounds. [14] Many studies in the literature have reported that the use of tacrine derivatives as inhibitors of the AChE enzyme may also inhibit carbonic anhydrase enzymes, which play an effective role in the determination of many diseases (such as gastric and duodenal ulcers, glaucoma, mountain sickness, epilepsy, osteoporosis, and neurological disorders). In fact, our group's research on this subject has demonstrated the properties of tacrine derivatives as inhibitors of effective carbonic anhydrase enzymes. ...
In this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two‐step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a–e and 4a–e using a Suzuki–Miyaura cross‐coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5‐Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer‐specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7‐bis(4‐(methylthio)phenyl)tacrine ( 3d ), 5,7‐bis(4‐(trifluoromethoxy)phenyl)tacrine ( 3e ), 2,4‐bis(4‐(trifluoromethoxy)phenyl)‐7,8,9,10‐tetrahydro‐6H‐cyclohepta[b]quinolin‐11‐amine ( 4e ), and 6,8‐dibromotacrine ( 3 ), emerged as the most promising candidates for preclinical studies.
... AChE regulates neuronal signal transmission by controlling ChE in CNS (central nervous system). AChE protein comprises unique structure consisting of a gorge region linked catalytic active site (CAS) and a peripheral anionic site (PAS) (Eckroat et al., 2020). AChE enzyme catalyzes acetylcholine (ACh) to hydrolyze into acetate and choline, thereby stopping synaptic neuronal transmission (Moreira et al., 2022), while AChE inhibitors seize esterase activity and prevent disease progression (Fig. 1). ...
Alzheimer's disease (AD) leads to gradual memory loss including other compromised cognitive abilities. Acetylcholinesterase (AChE), an important biochemical enzyme from the cholinesterase (ChE) family, is recognized as primary pharmacological target for treating AD. Currently marketed drugs for AD treatment are primarily AChE inhibitors and coumarin derivatives comprising a wide variety of pharmacological activities have proved their efficacy towards AChE inhibition. Ensaculin (KA-672 HCl), a compound that belong to the coumarin family, is a clinical trial candidate for AD treatment. Therefore, a ligand library was prepared with 60 reported coumarin derivatives for field-based 3D-QSAR and pharmacophore modelling. The field-based 3D-QSAR model obtained at partial least square (PLS) factor 7, was the best validated model that predicted activity closer to original activity for each ligand introduced. The contour maps demonstrated spatial distribution of favourable and unfavorable steric, hydrophobic, electrostatic and H-bond donor and acceptor contours around coumarin nucleus. The best pharmacophore model, ADHRR_1 exhibited five essential pharmacophoric features of four different traits for optimum AChE inhibition. Virtual screening through ADHRR_1 accompanied with molecular docking and MM/GBSA identified 10 HITs from a 4,00,000 coumarin derivatives from PubChem database. HITs comprised docking scores ranging from −12.096 kcal/mol to −8.271 kcal/mol and compared with the reference drug Donepezil (-8.271 kcal/mol). ADME properties analysis led into detecting two leads (HIT 1 and HIT 2) among these 10 HITs. Molecular Dynamics Simulation indicated thermodynamic stability of the complex of lead compounds with AChE protein. Finally, thorough survey of the experimental results from 3D-QSAR modelling, pharmacophore modelling and molecular docking interactions led us to develop the lead formula I for future advancements in treating AD through AChE inhibitors.
... Inhibition of acetylcholinesterase is a dominant strategy for the management of AD symptoms. Cholinesterase inhibitors, i.e., tacrine, donepezil, galanthamine, metrifonate, and rivastigmine, are shown in Figure 1 [7][8][9][10]. ...
The study aimed to evaluate the potential of piperidine-based 2H chromen-2-one derivatives against targeted enzymes, i.e., cholinesterase’s and monoamine oxidase enzymes. The compounds were divided into three groups, i.e., 4a–m ((3,4-dimethyl-7-((1-methylpiperidin-4-yl)oxy)-2H-chromen-2-one derivatives), 5a–e (3,4-dimethyl-7-((1-methypipridin-3-yl)methoxy)-2H-chromen-2-one derivatives), and 7a–b (7-(3-(3,4-dihydroisoquinolin-2(1H)-yl)propoxy)-3,4-dimethyl-2H-chromen-2-one derivatives) with slight difference in the basic structure. The comprehensive computational investigations were conducted including density functional theories studies (DFTs), 2D-QSAR studies, molecular docking, and molecular dynamics simulations. The QSAR equation revealed that the activity of selected chromen-2-one-based piperidine derivatives is being affected by the six descriptors, i.e., Nitrogens Count, SdssCcount, SssOE-Index, T-2–2-7, ChiV6chain, and SssCH2E-Index. These descriptor values were further used for the preparation of chromen-2-one based piperidine derivatives. Based on this, 83 new derivatives were created from 7 selected parent compounds. The QSAR model predicted their IC50 values, with compound 4 k and 4kk as the most potent multi-targeted derivative. Molecular docking results exhibited these compounds as the best inhibitors; however, 4kk exhibited greater activity than the parent compounds. The results were further validated by molecular dynamic simulation studies along with the suitable physicochemical properties. These results prove to be an essential guide for the further design and development of new piperidine based chromen-2-one derivatives having better activity against neurodegenerative disorder.
... The CAS can be divided into regions, including the stearic site, which contains the catalytic triad (Ser203, His447, Glu334), the anionic site (Trp86, Tyr133, Tyr337, Phe338), the oxyanion hole (Gly121, Gly122, Ala204), and the acyl pocket (Phe295 and Phe297). The gorge region is 20 Å deep and 5 Å wide, connects the CAS to the PAS and its compound is primarily aromatic amino acids [6]. Some AChE reversible inhibitors interact at the CAS, such is the case of tacrine (Cognex ® ) which interacts with Trp86, and galantamine (Razadyn ® , Nivalin ® ) interacts with anionic subsite and with the aromatic gorge. ...
... Compound (1) exhibited the highest activity for both concentrations tested; this may be due to the benzylidene ring's presence in the oxazole group's side chain. Compound (7) closely resembles compounds (5) and (6), but the last two lack a -OH group in the benzylidene ring and are weak at 100 µM, whereas it showed moderate activity at 300 µM. Compound (3) is inactive at 100 µM, probably due to the chloro substituent in the benzylidene ring; however, at 300 µM, it shows moderate inhibitory activity. ...
... We conducted comprehensive enzyme kinetics experiments to determine the binding affinity, represented by the enzyme-inhibitor complex dissociation constant (K i ), of hAChE for compounds (1) to (7) (as shown in Table 1). The inhibition constants (K i ) for AChE ranged from 2 to 198 µM, with the inhibition potency increasing in the following order: (1) < (7) < (3) < (2) < (4) < (5) < (6). AChE demonstrated the highest affinity for compounds lacking substitutions on the benzylidene ring ((1)), highlighting the significance of a high lipophilic group for achieving potent inhibition (K i = 2.08 ± 0.36 µM). ...
We synthesized seven (Z)-benzylidene-2-(E)-styryloxazol-5(4H)-ones derivatives of cinnamic acid and evaluated the ability of these compounds to inhibit human acetylcholinesterase (hAChE). The most potent compound was evaluated for cognitive improvement in short-term memory. The seven compounds reversibly inhibited the hAChE between 51 and 75% at 300 μM, showed an affinity (Ki) from 2 to 198 μM, and an IC50 from 9 to 246 μM. Molecular docking studies revealed that all binding moieties are involved in the non-covalent interactions with hAChE for all compounds. In addition, in silico pharmacokinetic analysis was carried out to predict the compounds’ blood–brain barrier (BBB) permeability. The most potent inhibitor of hAChE significantly improved cognitive impairment in a modified Y-maze test (5 μmol/kg) and an Object Recognition Test (10 μmol/kg). Our results can help the rational design of hAChE inhibitors to work as potential candidates for treating cognitive disorders.
... lipase inhibitor), acarbose (α-glucosidase), and galantamine (AChE inhibitor), have already been used to treat some major diseases, such as type-2-diabetes mellitus (T2DM), Alzheimer's disease (AD), and obesity [3][4][5][6][7]. This is primarily driven by their considerable structural diversity and the general perception that they tend to be safer compared with chemically synthesized compounds. ...
This study assessed the halophyte species Limonium spathulatum (Desf.) as a possible source of natural ingredients with the capacity to inhibit enzymes related to relevant human health disorders and food browning. Extracts using food-grade solvents such as water and ethanol were prepared by maceration from dried L. spathulatum leaves. They were evaluated for in vitro inhibition activity of enzymes such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), α-glucosidase, tyrosinase and lipase, related to Alzheimer’s disease, type-2-diabetes mellitus, skin hyperpigmentation, and obesity, respectively. These extracts were also appraised for in vitro acute toxicity on tumoral and non-tumoral cell lines and their chemical composition by high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS/MS). The extracts were more effective towards BChE than AChE. The best results were obtained with the hydroethanolic and water extracts, with IC50 values of 0.03 mg/mL and 0.06 mg/mL, respectively. The hydroethanolic extract had the highest capacity to inhibit α-glucosidase (IC50: 0.04 mg/mL), higher than the positive control used (acarbose, IC50 = 3.14 mg/mL). The ethanol extract displayed the best inhibitory activity against tyrosinase (IC50 = 0.34 mg/mL). The tested samples did not inhibit lipase and exhibited low to moderate cytotoxic activity against the tested cell lines. The hydroethanolic extract had a higher diversity of compounds, followed by the ethanol and water samples. Similar molecules were identified in all the extracts and were mainly hydroxybenzoic acids, hydroxycinnamic acids, and flavonoids. Taken together, these results suggest that L. spathulatum should be further explored as a source of bioactive ingredients for the food, cosmetic, and pharmaceutical industries.
... However, the detailed and in-depth mechanism by which this compound inhibits AChE has not been reported in detail yet. The AchE enzyme has three regions for ligand binding: the peripheral aromatic site (PAS), catalytic active site (CAS), and gorge, with speci c residues involved (Eckroat et al. 2020 Con ict of interest: the authors declare that there is no con ict of interest. ...
Purpose : Neurodegenerative diseases, including Alzheimer disease, are associated with oxidative stress and disruption of cholinergic neurotransmission. Thus the search for molecules capable of modulating ROS production and acetylcholine function is crucial. The aim of this study was to evaluate the inhibitory potential of nine imidazole derivatives against AChE in vitro. In silico Molecular Docking and ADMET studies were conducted on the most potent compounds 3a, 3e, 3g, and 3h to predict their drug-likeness, pharmacokinetics, and toxicity properties. In Addition, we evaluated the potential protective effects of the compound 3a (2-metyl-3H-imidazo[2,1-c][1,2,4]triazol-3-yl)(4-phenyl)methanone), on murine oligodendrocytes (158N) cultured in the absence or presence of 7β-OHC (20 μg/mL, 24 h).
Methods: The cell viability was measured at 570 nm wavelength. We analyzed Catalase (CAT) and glutathione peroxidase (GPx) activity using photometric techniques.
Results: Among the tested compounds, compounds 3a, 3e, 3g, and 3h exhibited significant inhibition effects on acetylcholinesterase (AChE) in comparison to the positive control donopezil. Molecular docking studies indicated that the compound 3a, with a favorable affinity, occupied the active site of AChE. Furthermore, the results demonstrated that a concentration of 31,5μg/mL of compound 3a could attenuate the toxic effect induced by 7β-OHC on 158N cells, and GPx and CAT activities were restored to normal.
Conclusion : These data demonstrate the anticholinesterase and protective activities of (2-metyl-3H-imidazo[2,1-c][1,2,4]triazol-3-yl)(4-phenyl)methanone) against the toxicity induced by 7β-OHC in 158N cells.
... In fact, it is well known that the AChE active site is smaller than the BChE, which explains why the compound's largest ligands are better BChE inhibitors than AChE [55,56]. The tested molecules generally have IC 50 values in the same range (μM) as other previously published tacrine derivatives [57]. Additional human AChE and BChE inhibitory activity assay data for 5aa-5ib are provided in the Supplementary material. ...
... Our findings showed that 5bb was the best AChE inhibition among the other molecules tested, probably because its binding pose and interactions are similar to the tacrine (a classic AChE inhibitor) (Fig. 6), suggesting that the size of the molecule plays an essential role in AChE. Some researchers have reported similar data for tacrine derivatives [45,46,57]. Both molecules interact at the bottom of the AChE active site near the catalytic triad (Ser203, His447, and Glu334), making hydrophobic interactions with Trp86, Tyr124, and Tyr337. ...
An efficient [4 + 2] cyclization protocol to synthesize a series of twelve examples of 1,2,3-triazolo[4,5-b]aminoquinolines (5) as novel structurally modified tacrines was obtained by reacting readily accessible precursors (i.e., 3-alky(aryl)-5-amino-1,2,3-triazole-4-carbonitriles (3)) and selected cycloalkanones (4) of five-, six-, and seven-membered rings. We evaluated the AChE and BChE inhibitory activity of the novel modified tacrines 5, and the compound derivatives from cyclohexanone (4b) showed the best AChE and BChE inhibitory activities. Specifically, 1,2,3-triazolo[4,5-b]aminoquinolines 5bb obtained from 3-methyl-carbonitrile (3b) showed the highest AChE (IC50 = 12.01 μM), while 5ib from 3-sulfonamido-carbonitrile (3i) was the most significant inhibitor for BChE (IC50 = 1.78 μM). In general, the inhibitory potency of compound 5 was weaker than the pure tacrine reference, and our findings may help to design and develop novel anticholinesterase drugs based on modified tacrines.
... This hypothesis was further strengthened after it was shown that treatment with an acetylcholinesterase inhibitor, tetrahydroaminoacridine (THA, Tacrine), produced clinical improvements in AD patients [188]. Although tacrine was the first acetylcholinesterase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of AD and provided modest improvement in cognitive and memory symptoms in mild AD patients, it was withdrawn due to its severe hepatotoxicity [189,190]. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood–brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.
... In 2019, Girek et al. summarized phyto-THA hybrids [37]. In addition, in 2020, Eckroat et al. summarized structural analogues of THA developed in 2015-2020 [38]. ...
... In 2019, Girek et al. summarized phyto-THA hybr [37]. In addition, in 2020, Eckroat et al. summarized structural analogues of THA dev oped in 2015-2020 [38]. ...
Alzheimer’s disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the “one drug–multiple targets” strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.
