- Research Article
- Open Access
Crystal structure, DFT calculations and evaluation of 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione as AChE inhibitor
© The Author(s) 2018
- Received: 14 May 2018
- Accepted: 19 June 2018
- Published: 25 June 2018
- AChE inhibitor
- Alzheimer’s disease
- Crystal structure
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Since the gradual damage to neurons leads to an irreversible deterioration of memory and learning, the afflicted person is eventually unable to carry out cognitive functions [1, 2]. AD is the most common form of dementia in the elderly population , accounting for 60–80% of all cases [4–6].
The pathogenesis of AD involves the accumulation of soluble amyloid-β peptide , the dysfunction of the cholinergic system, and the deposition of tau neurofibrillary tangles in the brain . These physiological changes lead to confusion, memory loss, impaired cognitive and emotional function, and finally dementia .
The main drug target is acetylcholinesterase (AChE) , which hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses and thus terminates nerve transmission. Since low levels of this signaling molecule are associated with the development of AD, high levels of the same are considered desirable in patients [10–13].
According to the cholinergic hypothesis, impairments in the cholinergic pathway play a pivotal role in the pathogenesis of AD . The main mechanism for enhancing the level of ACh is the inhibition of AChE, which is presently the most effective strategy for treating AD. Hence, the current treatments are cholinesterase inhibitors that target AChE and butyrylcholinesterase (BuChE), and antagonists of N-methyl-d-aspartate (NMDA) receptor [1, 2].
In addition to depleting Ach (low concentrations), human AChE accelerates the metabolic rate of formation of the amyloid-β peptide, which exacerbates the clinical progression of AD [15, 16]. Other proteins involved in the development of this disease are tau, α-synuclein and apoE4, and all of them are regulated by the activity of AChE . AChE inhibitors (AChEIs) are the only type of drug approved for the treatment of AD.
The phthalimide ring (isoindoline-1,3-dione) represents an important privileged substructure in diverse molecules exhibiting neuroprotective agents, antioxidant, antihypertensive activity, etc. [18–20]. Numerous reports have identified phthalimide derivatives as potent inhibitors of AChE [21–24] and BuChE [1, 25].
Paneck et al. synthesized and evaluated phthalimide saccharin derivatives, finding one of these to be a selective AChEI that significantly impeded the accumulation of amyloid-β . Simoni et al. developed other new compounds with an indole moiety in their structure that are able to simultaneously inhibit AChE and amyloid-β aggregation .
The pharmacophore isoindoline-1,3-dione is known to interact with great affinity at the peripheral anionic site (PAS) of human AChE. To optimize the interaction with the catalytic active site at the same time, the linker between the radical of the drug and the isoindoline-1,3-dione should include an oligomethylene .
Hebda et al. described how phthalimide groups interact with the PAS site of AChE. They found that the two carbonyl groups of phthalimide facilitate hydrogen bonding with AChE, and the replacement of phthalimide groups with a heteroaromatic moiety reduces potency . It has also been explained how an electron donating group as a methoxy substituent, particularly in the para position, confers higher potency to the drug. In the case of electron withdrawing groups, such as chlorine or fluorine moieties, the ortho position provides a greater inhibitory effect on AChE . Finally, it was reported how the ability of a ligand to bend (due to alkyl chains) improves its interaction with the anionic and acyl pocket of AChE. Hence, the presence of alkyl chains may be necessary for excellent potency in a competitive or non-competitive inhibitor .
Taking into account the above information the compound was design based on the literature, where is described that for good inhibitory effect on AChE the molecule must have an isoindoline group, the presence of 2 carbonyl groups and also the presence of electron donating groups as methoxy moiety, additionally the presences of methylenes are required for good potency. The aim of the current study was to synthesize and crystallize 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione, then compare its molecular X-ray structure with that of the same compound simulated for molecular modeling. Furthermore, its activity as an AChEI was determined in vitro and ED50 in vivo.
Comparison between modeled and crystal geometric structures of 1
− 2 760 740.50
E LUMO (kJ/mol)
E HOMO (kJ/mol)
Bond lengths (Å)
Bond angles (°)
Torsion angles (°)
Geometric parameters of the intermolecular interactions of compound 1
x, y − 1, z
x, y + 1, z − 1
The absence of strong hydrogen bonding donors results in the participation of only one imide carbonyl in hydrogen bonding. The selective activation of one imide carbonyl group of the N-phenethylimides by Brønsted acids, such as BBr3 , TfOH  or organometallics , leads to regioselective intramolecular cyclization to deliver tetrahydroisoquinoline derivatives [37, 38]. This selective regiochemical polarization could be involved in the mode of action of compound 1 as an AChEI, as previously proposed .
In vitro experiments to determine AChE inhibition
In summary, the crystal of 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione was obtained and analyzed by x-ray crystallography to determine its geometric structure, which was compared to the optimized structure predicted in the in silico experiment. No significant difference existed between these two structures (experimental and computational modeling) when comparing bond lengths or bond angles. Furthermore, an interesting crystalline network was formed by hydrogen bonding acceptors and soft-hydrogen bonding donors, as well as by dispersive π–π interactions. Finally, an evaluation was made of the inhibitory effect of 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione on AChE, finding a competitive inhibition with a Ki of 330–930 µM (95% confidence interval). The acute toxicity is far less (LD50 > 1600 mg/kg) than that of AChE inhibitors currently on the market almost 3000-fold less toxic than Neostigmine LD50 = 0.54 ± 0.03 mg/kg. Therefore, future studies are needed to explore the inhibitory activity of this and related isoindoline-1,3-dione derivatives.
All reagents and solvents were used as received from the commercial supplier (Sigma-Aldrich). All reactions were carried out in an oven-dried flask, agitating the mixtures with a stirring bar and concentrating them with a standard rotary evaporator. The melting point was measured in open-ended capillary tubes with a Stuart® SMP40 automatic melting point apparatus, and is uncorrected. Infrared (IR) spectra were obtained on a 100 FT-IR spectrometer (Perkin-Elmer) with a universal ATR accessory. Thin layer chromatography was performed on 0.25 mm thick silica gel 60 F254 plates (Merck, Darmstadt, Germany) and spots were detected under UV light. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Varian Mercury 300 spectrometer (1H, 300 MHz; 13C, 75 MHz) with tetramethylsilane (TMS) as internal reference. Chemical shifts (δ) are expressed in parts per million (ppm). Other parameters contemplated were the integration area, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constant (Hz). Electrospray ionization (ESI) high-resolution mass spectrometry was performed on a Bruker micrOTOf-Q-II instrument.
Chemical synthesis and crystallization
2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione was synthesized by employing a reported procedure with slight modifications . In brief, 491 mg (1.50 mmol) phthalic anhydride and 244 mg (1.00 mmol) 2-(3,4-dimethoxyphenyl)ethylamine were mixed and placed into a 50 mL round-bottom flask, then stirred and heated to gentle melting at 150–200 °C for 15–20 min until a dark-yellow color appeared. The reaction was cooled to room temperature and monitored by TLC (using ethyl acetate:hexane in an 8:2 proportion as eluent) before adding 40 mL ethyl acetate and sonicating the reaction to achieve complete dissolution. After the mixture was placed in a separation funnel, 50 mL of water (pH 13) were added (three times) to eliminate the excess of phthalic anhydride. The ethyl acetate was recovered and enough Na2SO4 and activated carbon were added to be able to filter the mixture. Finally, the solvent was evaporated under a vacuum and the product was recrystallized four times in CH2Cl2 solution to obtain 0.301 g of colorless block-like crystals (suitable for X-ray) in 90% yield, m.p. = 171–172 °C; IR (ATR, cm−1) ύ: 3063 (C–H, Aromatic), 2943 (C–H, Aliphatic), 2842 (O–CH3, Aliphatic), 1705 (C=O), 1600 (C=C), 1466 (CH2), 1427 (CH3), 1394 (C–N), 1228 (O–CH3). 1H NMR (CDCl3, 300 MHz) δ 2.93 (t, H-11), 3.90 (t, H-10), 3.80 (s, H-19), 3.83 (s, H-18), 6.78 (m, H-13,16,17), 7.70 (m, H-5,6), 7.82 (m, H-4,7); 13C NMR (CDCl3, 75 MHz) δ 168.2 (C-1,3), 123.19 (C-4,7), 132.0 (C-5,6), 130.4 (C-8,9), 39.3 (C-10), 34.0 (C-11), 133.9 (C-12), 111.1 (C-13), 148.7 (C-14), 147.6 (C-15), 111.8 (C-16), 120.8 (C-17), 55.7 (C-18,19). ESI (m/z): 334.0956 [M+Na] .
X-ray diffraction methods
Single-crystal X-ray diffraction data was recorded on a D8 Quest CMOS (Bruker, Karlsruhe, Germany) area detector diffractometer with Mo K α radiation, λ = 0.71073 Å. The structure was solved by using direct methods in the SHELXS97  program of the WinGX package . The final refinement was performed by the full-matrix least-squares method on F2 on the SHELXL97 program. H atoms on C were geometrically positioned and treated as riding atoms, with C–H = 0.93–0.98 Å, and Uiso(H) = 1.5 Ueq(C). The Mercury program was utilized for visualization, molecular graphics and analysis of crystal structures . Material was prepared for publication with PLATON software . The crystallographic data were deposited with the Cambridge Crystallographic Data Centre (CCDC) as supplementary publication CCDC number 1563664. Copies of the data can be obtained free of charge upon request from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (Fax: +44-01223-336033 or E-Mail: firstname.lastname@example.org).
Crystal data for C18H17NO4 (M = 311.3 g/mol): triclinic, space group P − 1 (No. 2), a = 7.4363(4) Å, b = 8.7363(4) Å, c = 12.1212(5) Å, α = 89.573(2), β = 80.073(2), γ = 74.650(2)°, V = 747.40(6) Å3, Z = 2, T = 163(2) K, Dcalc = 1.38 g/cm3, 16,483 reflections measured (2.4° ≤ 2Θ ≤ 25.5°), and 2750 unique (Rint = 0.088, Rsigma = 0.0561) were used in all calculations. The final value of R1 was 0.049 (I > 2σ(I)) and of wR2 0.135 (for all data), GooF = 1.058 and Abs. coefficient = 0.098, min/max (eÅ−3), and ΔF = 0.249/− 0.302.
The optimization and vibrational frequency calculations were performed on Gaussian 09 software  with the DFT: B3LYP/6-311G basis set.
In vitro experiments on AChE inhibition
AChE inhibition was evaluated for compound 1 and a known inhibitor, neostigmine, employing the colorimetric method reported by Bonting and Featherstone , with a few modifications. This method determines the remaining amount of ACh by measuring the formation of hydroxamic acid from the choline ester after incubation with the enzyme. The color produced by the reaction with acid ferric chloride is related to enzymatic activity, the value of which was established by fitting the data to a typical curve (Fig. 7).
Briefly, Electrophorus electricus was the source of AChE (Sigma Chemical Co. C1682) for the assay. A mixture was made with 0.1 M buffer (pH 8), 0.2 units of AChE, and increasing concentrations of ACh iodide (0.2, 0.8, 1.6, 3.2, 6.4, 9.6 and 12.8 mM) as the substrate for the enzymatic reaction, and 20 min later the alkaline hydroxylamine reagent was added. The test or reference compound was placed in the assay solution (at 0.2, 0.4 or 0.8 mM) and incubated with the enzyme for 20 min at 37 °C. Subsequently, addition was made of the alkaline hydroxylamine reagent and finally the FeCl3 reagent. The changes in absorbance at 540 nm were recorded following 10 min of incubation in a Benchmark BIO-RAD. To exclude interference due to the effects of the reference solution, the parameters were determined with the blank, which was the same volume of solution with the drugs, buffered reagents and the enzyme but without acetylthiocholine. The reaction rates were compared, and the inhibition in the presence of the test compounds was calculated. The Ki of each AChE-inhibitor was estimated by using a curve constructed with the steady-state enzyme inhibition constants.
In vivo experiment (Lethal doses 50) on mice
Briefly, three different groups of 3 (CD1 male mice 20–25 g) were formed, after that each group received one established concentration that was 10, 100 and 1000 mg/kg of our tested compound to determine a range of toxicity. They were observed by 24 h, without presenting toxicity. After that we formed 3 new groups that were used to opening more of the dose spectrum based on first results, this was to probe new doses 1200, 1400 and 1600 mg/kg [50, 51].
The chemical synthesis and spectroscopic analysis were carried out by EAJ and JBC; the NMR experiments and synthesis of the crystal structure were performed and analyzed by IIPM and FJMM; the interpretation of data was conducted by JGTF; in vitro experiments on AChE inhibition were carried out by MASU and EAJ. The paper was drafted by EAJ and IIPM. All authors participated in discussing the different versions of the manuscript. All authors read and approved the final manuscript.
We are grateful to the Instituto Politécnico Nacional and CONACYT-Mexico.
All the authors declare that there is no competing interests related to the design of the study, the collection and analyses of data, the writing of the manuscript, or the decision to publish the results.
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- Anand P, Singh B (2013) A review on cholinesterase inhibitors for Alzheimer’s disease. Arch Pharm Res 36:375–399. https://doi.org/10.1007/s12272-013-0036-3 View ArticlePubMedGoogle Scholar
- Bajda M, Więckowska A, Hebda M et al (2013) Structure-based search for new inhibitors of cholinesterases. Int J Mol Sci 14:5608–5632. https://doi.org/10.3390/ijms14035608 View ArticlePubMedPubMed CentralGoogle Scholar
- Zollo A, Allen Z, Rasmussen HF et al (2017) Sortilin-related receptor expression in human neural stem cells derived from Alzheimer’s disease patients carrying the APOE epsilon 4 allele. Neural Plast 2017:1892612. https://doi.org/10.1155/2017/1892612 View ArticlePubMedPubMed CentralGoogle Scholar
- Rojas-Gutierrez E, Muñoz-Arenas G, Treviño S et al (2017) Alzheimer’s disease and metabolic syndrome: a link from oxidative stress and inflammation to neurodegeneration. Synapse. https://doi.org/10.1002/syn.21990 View ArticlePubMedGoogle Scholar
- Cermakova P, Nelson M, Secnik J et al (2017) Living alone with Alzheimer’s disease: data from SveDem, the Swedish Dementia Registry. J Alzheimers Dis 58:1265–1272. https://doi.org/10.3233/JAD-170102 View ArticlePubMedPubMed CentralGoogle Scholar
- Czarnecka K, Szymański P, Girek M et al (2017) Tetrahydroacridine derivatives with fluorobenzoic acid moiety as multifunctional agents for Alzheimer’s disease treatment. Bioorg Chem 72:315–322. https://doi.org/10.1016/j.bioorg.2017.05.003 View ArticlePubMedGoogle Scholar
- Hamodat H, Cash MK, Fisk JD, Darvesh S (2017) Cholinesterases in normal and Alzheimer’s disease primary olfactory gyrus. Neuropathol Appl Neurobiol. https://doi.org/10.1111/nan.12423 View ArticlePubMedGoogle Scholar
- Cascella M, Bimonte S, Muzio MR et al (2017) The efficacy of epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: an overview of pre-clinical studies and translational perspectives in clinical practice. Infect Agent Cancer 12:1–7. https://doi.org/10.1186/s13027-017-0145-6 View ArticleGoogle Scholar
- Nwidu LL, Elmorsy E, Thornton J et al (2017) Anti-acetylcholinesterase activity and antioxidant properties of extracts and fractions of Carpolobia lutea. Pharm Biol 55:1875–1883. https://doi.org/10.1080/13880209.2017.1339283 View ArticlePubMedPubMed CentralGoogle Scholar
- Kocyigit UM, Taslimi P, Gezegen H et al (2017) Evaluation of acetylcholinesterase and carbonic anhydrase inhibition profiles of 1,2,3,4,6-pentasubstituted-4-hydroxy-cyclohexanes. J Biochem Mol Toxicol. https://doi.org/10.1002/jbt.21938 View ArticlePubMedGoogle Scholar
- Bhakta HK, Park CH, Yokozawa T et al (2017) Potential anti-cholinesterase and β-site amyloid precursor protein cleaving enzyme 1 inhibitory activities of cornuside and gallotannins from Cornus officinalis fruits. Arch Pharm Res 40:836–853. https://doi.org/10.1007/s12272-017-0924-z View ArticleGoogle Scholar
- Pisani L, Catto M, De Palma A et al (2017) Discovery of potent dual binding site acetylcholinesterase inhibitors via homo- and heterodimerization of coumarin-based moieties. ChemMedChem 12:1–11. https://doi.org/10.1002/cmdc.201700282 View ArticleGoogle Scholar
- Parruca Sakata R, Figueiro M, Fabio Kawano D, Pereira Almeida W (2017) Effect on acetylcholinesterase and anti-oxidant activity of synthetic chalcones having a good predicted pharmacokinetic profile. Med Chem (Los Angeles) 13:1–10. https://doi.org/10.2174/1573406413666170525125730 View ArticleGoogle Scholar
- Li F, Liu Y, Yuan Y et al (2017) Molecular interaction studies of acetylcholinesterase with potential acetylcholinesterase inhibitors from the root of Rhodiola crenulata using molecular docking and isothermal titration calorimetry methods. Int J Biol Macromol 104:527–532. https://doi.org/10.1016/j.ijbiomac.2017.06.066 View ArticlePubMedGoogle Scholar
- Carvajal FJ, Inestrosa NC (2011) Interactions of AChE with Aβ aggregates in Alzheimer’s brain: therapeutic relevance of IDN 5706. Front Mol Neurosci 4:19. https://doi.org/10.3389/fnmol.2011.00019 View ArticlePubMedPubMed CentralGoogle Scholar
- Dinamarca MC, Arrázola M, Toledo E et al (2008) Release of acetylcholinesterase (AChE) from β-amyloid plaques assemblies improves the spatial memory impairments in APP-transgenic mice. Chem Biol Interact 175:142–149. https://doi.org/10.1016/j.cbi.2008.05.026 View ArticlePubMedGoogle Scholar
- Ozadali-Sari K, Tüylü Küçükkılınç T, Ayazgok B et al (2017) Novel multi-targeted agents for Alzheimer’s disease: synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substitutedpiperazin-1-yl)phenyl]benzimidazoles. Bioorg Chem 72:208–214. https://doi.org/10.1016/j.bioorg.2017.04.018 View ArticlePubMedGoogle Scholar
- Ahmed HEA, Abdel-Salam HA, Shaker MA (2016) Synthesis, characterization, molecular modeling, and potential antimicrobial and anticancer activities of novel 2-aminoisoindoline-1,3-dione derivatives. Bioorg Chem 66:1–11. https://doi.org/10.1016/j.bioorg.2016.03.003 View ArticlePubMedGoogle Scholar
- Shakir R, Muhi-Eldeen ZA, Matalka KZ, Qinna NA (2012) Analgesic and toxicity studies of aminoacetylenic isoindoline-1,3-dione derivatives. ISRN Pharmacol 2012:1–7. https://doi.org/10.5402/2012/657472 View ArticleGoogle Scholar
- Kim HS, Kim Y, Doddareddy MR et al (2007) Design, synthesis, and biological evaluation of 1,3-dioxoisoindoline-5-carboxamide derivatives as T-type calcium channel blockers. Bioorg Med Chem Lett 17:476–481. https://doi.org/10.1016/j.bmcl.2006.10.042 View ArticlePubMedGoogle Scholar
- Mary A, Renko DZ, Guillou C, Thal C (1998) Potent acetylcholinesterase inhibitors: design, synthesis, and structure–Activity relationships of bis-interacting ligands in the galanthamine series. Bioorg Med Chem 6:1835–1850. https://doi.org/10.1016/S0968-0896(98)00133-3 View ArticlePubMedGoogle Scholar
- Zhao Q, Yang G, Mei X et al (2009) Novel acetylcholinesterase inhibitors: synthesis and structure-activity relationships of phthalimide alkyloxyphenyl N, N-dimethylcarbamate derivatives. Pestic Biochem Physiol 95:131–134. https://doi.org/10.1016/j.pestbp.2009.04.018 View ArticleGoogle Scholar
- Alipour M, Khoobi M, Foroumadi A et al (2012) Novel coumarin derivatives bearing N-benzyl pyridinium moiety: potent and dual binding site acetylcholinesterase inhibitors. Bioorg Med Chem 20:7214–7222. https://doi.org/10.1016/j.bmc.2012.08.052 View ArticlePubMedGoogle Scholar
- Si W, Zhang T, Zhang L et al (2016) Design, synthesis and bioactivity of novel phthalimide derivatives as acetylcholinesterase inhibitors. Bioorg Med Chem Lett 26:2380–2382. https://doi.org/10.1016/j.bmcl.2015.07.052 View ArticlePubMedGoogle Scholar
- Musiał A, Bajda M, Malawska B (2007) Recent developments in cholinesterases inhibitors for Alzheimer’s disease treatment. Curr Med Chem 14:2654–2679. https://doi.org/10.2174/092986707782023217 View ArticlePubMedGoogle Scholar
- Panek D, Więckowska A, Wichur T et al (2017) Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation. Eur J Med Chem 125:676–695. https://doi.org/10.1016/j.ejmech.2016.09.078 View ArticlePubMedGoogle Scholar
- Simoni E, Bartolini M, Abu IF et al (2017) Multitarget drug design strategy in Alzheimer’s disease: focus on cholinergic transmission and amyloid-β aggregation. Fut Med Chem 9:953–963. https://doi.org/10.4155/fmc-2017-0039 View ArticleGoogle Scholar
- Guzior N, Bajda M, Skrok M et al (2015) Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and β-amyloid aggregation inhibitors with neuroprotective properties. Eur J Med Chem 92:738–749. https://doi.org/10.1016/j.ejmech.2015.01.027 View ArticlePubMedGoogle Scholar
- Hebda M, Bajda M, Więckowska A et al (2016) Synthesis, molecular modelling and biological evaluation of novel heterodimeric, multiple ligands targeting cholinesterases and amyloid beta. Molecules 21:1–24. https://doi.org/10.3390/molecules21040410 View ArticleGoogle Scholar
- Kiametis AS, Silva MA, Romeiro LAS et al (2017) Potential acetylcholinesterase inhibitors: molecular docking, molecular dynamics, and in silico prediction. J Mol Model 23:67–72. https://doi.org/10.1007/s00894-017-3228-9 View ArticlePubMedGoogle Scholar
- Allen FH, Kennard O, Watson DG et al (1987) Tables of bond lengths determined by X-ray and neutron diffraction Part 1 Bond lengths in organic compounds. J Chem Soc Perkin Trans 2 213:S1. https://doi.org/10.1039/p298700000s1 View ArticleGoogle Scholar
- Bernstein J, Davis RE, Shimoni L, Chang N-L (1995) Patterns in hydrogen bonding: functionality and graph set analysis in crystals. Angew Chemie Int Ed English 34:1555–1573. https://doi.org/10.1002/anie.199515551 View ArticleGoogle Scholar
- García-Báez EV, Martínez-Martínez FJ, Höpfl H, Padilla-Martínez II (2003) π-Stacking interactions and C–H···X (X=O, aryl) hydrogen bonding as directing features of the supramolecular self-association in 3-carboxy and 3-amido coumarin derivatives. Cryst Growth Des 3:35–45. https://doi.org/10.1021/cg0255826 View ArticleGoogle Scholar
- Selvakumar J, Makriyannis A, Ramanathan CR (2010) An unusual reactivity of BBr(3): accessing tetrahydroisoquinoline units from N-phenethylimides. Org Biomol Chem 8:4056–4058. https://doi.org/10.1039/c0ob00269k View ArticlePubMedPubMed CentralGoogle Scholar
- Selvakumar J, Rao RS, Srinivasapriyan V et al (2015) Synthesis of condensed tetrahydroisoquinoline class of alkaloids by employing TfOH-mediated imide carbonyl activation. Eur J Org Chem 2015:2175–2188. https://doi.org/10.1002/ejoc.201403617 View ArticleGoogle Scholar
- Maity AK, Roy S (2014) Multimetallic iridium-tin (Ir-Sn 3) catalyst in N-acyliminium ion chemistry: synthesis of 3-substituted isoindolinones via intra- and intermolecular amidoalkylation reaction. Adv Synth Catal 356:2627–2642. https://doi.org/10.1002/adsc.201400234 View ArticleGoogle Scholar
- Aranzamendi E, Sotomayor N, Lete E (2017) Phenolic activation in Chiral Brønsted acid-catalyzed intramolecular α-amidoalkylation reactions for the synthesis of Fused isoquinolines. ACS Omega 2:2706–2718. https://doi.org/10.1021/acsomega.7b00170 View ArticleGoogle Scholar
- Pandey VK, Anbarasan P (2014) One-pot cascade trifluoromethylation/cyclization of imides: synthesis of α-trifluoromethylated amine derivatives. J Org Chem 79:4154–4160. https://doi.org/10.1021/jo5002998 View ArticlePubMedGoogle Scholar
- Bautista-Aguilera OM, Esteban G, Chioua M et al (2014) Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids. Drug Des Devel Ther 8:1893–1910. https://doi.org/10.2147/DDDT.S69258 View ArticlePubMedPubMed CentralGoogle Scholar
- Liu Z, Zhang A, Sun H et al (2017) Two decades of new drug discovery and development for Alzheimer’s disease. RSC Adv 7:6046–6058. https://doi.org/10.1039/C6RA26737H View ArticleGoogle Scholar
- Cayman Chemical (2015) Donepezil. In: Safety data sheets collection. vol 1, pp 1–5. https://www.caymanchem.com/msdss/13245m.pdf. Accessed 13 June 2018
- Cayman Chemical (2016) Physostigmine. In: Safety data sheets collection. vol 1, pp 1–6. https://www.caymanchem.com/msdss/13027m.pdf. Accessed 13 June 2018
- Andrade-Jorge E, Bahena-Herrera JR, Garcia-Gamez J et al (2017) Novel synthesis of isoindoline/isoindoline-1,3-dione derivatives under solventless conditions and evaluation with the human D2receptor. Med Chem Res 26:2420–2431. https://doi.org/10.1007/s00044-017-1942-6 View ArticleGoogle Scholar
- Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr Sect A Found Crystallogr 64:112–122. https://doi.org/10.1107/S0108767307043930 View ArticleGoogle Scholar
- Farrugia LJ (1999) WinGX suite for small-molecule single-crystal crystallography. J Appl Crystallogr 32:837–838. https://doi.org/10.1107/S0021889899006020 View ArticleGoogle Scholar
- Macrae CF, Edgington PR, McCabe P et al (2006) Mercury: visualization and analysis of crystal structures. J Appl Crystallogr 39:453–457. https://doi.org/10.1107/S002188980600731X View ArticleGoogle Scholar
- Spek AL (2009) Structure validation in chemical crystallography. Acta Crystallogr Sect D Biol Crystallogr 65:148–155. https://doi.org/10.1107/S090744490804362X View ArticleGoogle Scholar
- Frisch MJ, Trucks GW, Schlegel HB et al (2009) Gaussian 09, Revision E. 01. Gaussian, WallingfordGoogle Scholar
- Bonting SL, Featherstone RM (1956) Ultramicro assay of the cholinesterases. Arch Biochem Biophys 61:89–98. https://doi.org/10.1016/0003-9861(56)90319-8 View ArticlePubMedGoogle Scholar
- Chinedu E, Arome D, Ameh F (2013) A new method for determining acute toxicity in animal models. Toxicol Int 20:224. https://doi.org/10.4103/0971-6580.121674 View ArticlePubMedPubMed CentralGoogle Scholar
- Lorke D (1983) A new approach to practical acute toxicity testing. Arch Toxicol 54:275–287. https://doi.org/10.1007/BF01234480 View ArticlePubMedGoogle Scholar