Synthesis, docking and acetylcholinesterase inhibitory assessment of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives with potential anti-Alzheimer effects
© Mohammadi-Farani et al.; licensee BioMed Central Ltd. 2013
Received: 20 February 2013
Accepted: 7 May 2013
Published: 7 June 2013
Alzheimer’s disease (AD) as neurodegenerative disorder, is the most common form of dementia accounting for about 50-60% of the overall cases of dementia among persons over 65 years of age. Low acetylcholine (ACh) concentration in hippocampus and cortex areas of the brain is one of the main reasons for this disease. In recent years, acetylcholinesterase (AChE) inhibitors like donepezil with prevention of acetylcholine hydrolysis can enhance the duration of action of acetylcholine in synaptic cleft and improve the dementia associated with Alzheimer’s disease.
Design, synthesis and assessment of anticholinesterase activity of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives showed prepared compounds can function as potential acetylcholinesterase inhibitor. Among 12 synthesized derivatives, compound 4a with ortho chlorine moiety as electron withdrawing group exhibited the highest potency in these series (IC50 = 0.91 ± 0.045 μM) compared to donepezil (IC50 = 0.14 ± 0.03 μM). The results of the enzyme inhibition test (Ellman test) showed that electron withdrawing groups like Cl, F and NO2 can render the best effect at position ortho and para of the phenyl ring. But compound 4g with methoxy group at position 3(meta) afforded a favorable potency (IC50 = 5.5 ± 0.7 μM). Furthermore, docking study confirmed a same binding mode like donepezil for compound 4a.
Synthesized compounds 4a-4l could be proposed as potential anticholinesterase agents.
Alzheimer’s disease (AD), is described by Dr. Alois Alzheimer in 1907 as a neurodegenerative disorder. AD as a disease of the central nervous system (CNS) characterized especially by premature senile mental deterioration. AD patients exhibit a significant decrease in cognitive ability and severe behavioral and psychological abnormalities such as irritability, anxiety and depression . AD, one of the most diffuse neurodegenerative pathology among the elderly, causes a progressive impairment in functional performances and continuous reduction in cognitive activities and memory [2–7]. AD is the most common form of dementia accounting for about 50-60% of the overall cases of dementia among persons over 65 years of age, is a neurodegenerative alteration characterized by a low acetylcholine (ACh) in hippocampus and cortex . AD is said to be the leading cause of dementia in elderly patients. Nowadays, with increase of the elderly population, the prevalence of AD is likely to increase. AD persons exert a decrease in mental functions and performances and consequently rendering them incapacitated and unable to perform normal daily activities. Elderly persons are the most common individuals afflicted with this disease. Unfortunately, the true nature or cause of the disease is still unknown and therefore, the development of effective anti-alzheimer is one of the encouraging area in current medicinal chemistry researches .
Over two decades ago, several autopsy studies inside hippocampus revealed that the levels of the neurotransmitter acetylcholine in patients with Alzheimer’s disease are importantly decreased . Currently, the loss of cholinergic function is the only evidentiary finding responsible for cognitive decline. Hence, therapeutical development has focused on this theory. The loss of the basal forebrain cholinergic system is one of the most significant aspects of neurodegeneration in the brains of AD patients, and it is thought to play a central role in producing cognitive impairments [1, 2, 10, 11]. Alzheimer’s disease leads to a progressive decline of the cognitive function, executive function losses, memory deficits, and eventually to incapacitating dementia before death. In order to improve cholinergic neurotransmission, different strategies have been investigated including the increase of synthesis or pre-synaptic release of ACh, the stimulation of cholinergic post-synaptic muscarinic and nicotinic receptors, and the reduction of ACh synaptic degradation using AChE inhibitors (e.g., AChEIs or anticholinesterase agents) [12–19].
All chemical substances consisting starter materials, reagents and solvents were purchased from the commercial supplier like Merck and Sigma-Aldrich companies. The purity of the prepared compounds was proved by thin layer chromatography (TLC) using various solvents of different polarities. Merck silica gel 60 F254 plates were used for analytical TLC. Column chromatography was applied on Merck silica gel (70–230 mesh) for purification of intermediate and final compounds. 1H-NMR spectra were recorded using a Bruker 400 MHz spectrometer in deutrated solvents, and chemical shifts are expressed as δ (ppm) with tetramethylsilane (TMS) as internal standard. The IR spectra were obtained on a Shimadzu 470 spectrophotometer using potassium bromide (KBr) disks. Melting points were determined using Electrothermal 9001 elemental analyzer apparatus and are uncorrected. The mass spectra were run on a Finigan TSQ-70 spectrometer (Finigan, USA) at 70 eV.
Synthesis of 2-(2-(piperazin-1-yl)ethyl)isoindoline-1,3-dione (3)
In a flask 3 g (20 mmol) of Phthalic anhydride, 2.6 ml (20 mmol) N-amnioethylpiperazine and 2.9 ml (20 mmol) triethylamine (Et3N) were mixed in 40 ml of toluene solvent. The reaction mixture was refluxed for 24 hours and the termination of reaction and formation of the desired product was confirmed by thin layer chromatography. The discoloration of the reaction medium and formation of a yellow precipitate was also an indicator of the progress of the reaction. Then, toluene was evaporated under reduced pressure using rotary evaporator apparatus and the obtained yellow viscose and oily residue was washed several times by ethyl acetate (EtOAc) and diethyl ether (Et2O) .
1H NMR (CDCl3, 400 MHz) δ (ppm): 2.37 (m, 4H, Piperazine), 2.54 (m, 4H, Piperazine), 3.22 (t, 2H, phthalimide-CH2-CH2-piperazine), 3.44 (t, 2H, phthalimide-CH2-CH2-piperazine), 4.73 (NH, Piperazine), 7.35-7.85 (m, 4H, Phthalimide). IR (KBr, cm-1) ῡ: 3380, 3330, 3157, 3111, 2924, 1730, 1681, 1521, 1489, 1458, 1328, 1303, 1186, 1143, 1035, 910, 750, 710. MS (m/z, %): 259 (M+, 10), 224 (30), 174 (30), 160 (60), 149 (85), 99 (100), 70 (70), 57 (65), 41 (40).
General procedure for synthesis of compounds 4a-4l
In a flat-bottom flask equimolar quantities of compound 3 and appropriate derivative of benzyl chloride were added together in dichloromethane (CH2Cl2) solvent. The reaction mixture was stirred in room temperature overnight. Then, dichloromethane was evaporated under reduced pressure and the afforded residue was washed by diethyl ether and n-hexane. Methanol containing Hydrochloric acid gas was added to the residue to form the related hydrochloride salt of the product .
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.36 (m, 8H, Piperazine), 3.33 (t, 2H, CH2-piperazine), 3.35 (s, 2H, -CH2-2-Chlorophenyl), 3.61 (t, 2H, -CH2-Phthalimide), 7.25-7.32 (m, 2H, 2-Chlorophenyl), 7.34-7.44 (m, 2H, 2-Chlorophenyl), 7.46-7.87 (m, 4H, Phthalimide). MS (m/z, %): 385 (M++2, 2), 383 (M+, 5), 225 (50), 223 (100), 160 (50), 125 (95), 89 (15), 70 (20). IR (KBr, cm-1) ῡ: 3460, 3051, 2943, 2800, 2762, 1766, 1465, 1438, 1396, 1357, 1300, 1192, 1161, 1107, 1041, 921, 759, 717, 698.
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.34 (m, 4H, Piperazine), 3.35 (t, 2H, -CH2-piperazine), 3.51 (s, 2H, -CH 2 -phenyl), 3.7 (t, 2H, -CH2-phthalimide), 7.27-7.32 (m, H2, H5, 3-Chlorophenyl), 7.41 (d, 1H, J = 8 Hz, H6-3-Chlorophenyl), 7.45 (d, J = 8 Hz, H4-3-Chlorophenyl), 7.85 (m, 2H, H5,H6-phthalimide), 7.88 (m, 2H, H4,H7-phthalimide). IR (KBr, cm-1) ῡ: 3160, 3113, 2924, 1710, 1681, 1533, 1521, 1489, 1458, 1327, 1303, 1186, 1143, 1037, 715.
1H NMR (CDCl3, 400 MHz) δ (ppm): 2.2 (t, 2H, -N-CH2-CH2-NH-, piperazine), 2.5 (t, 2H, -N-CH2-CH2-NH-, Piperazine), 2.63 (t, 2H, phthalimide-CH2-CH2-piperazine), 3.42 (s, 2H, -CH2-phenyl), 3.8 (t, 2H, phthalimide-CH2-CH2-piperazine), 7.23 (d, 2H, J = 8 Hz, H2,6-4-chlorophenyl), 7.30 (d, 2H, J = 8 Hz, H3,5-4-chlorophenyl phenyl), 7.76 (m, 4H, Phthalimide). IR (KBr, cm-1) ῡ: 3400, 3380, 3135, 3111, 2927, 2812, 1703, 1681, 1533, 1521, 1489, 1456, 1328, 1305, 1186, 1143, 1035, 721, 707. MS (m/z, %): 384 (M+ +1, 20), 383 (M+, 18), 280 (20), 223 (100), 167 (30), 149 (90), 125 (90).
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.4 (m, 4H, piperazine), 3.1 (m, 4H, aliphatic), 3.8 (s, 2H, -CH2-phenyl), 7.35 (m, 4H, 2-Fluorophenyl), 7.88 (m, 4H, Phthalimide). IR (KBr, cm-1) ῡ: 3429, 2993, 2924, 2854, 1774, 1716, 1396, 1068, 1010, 721. MS (m/z, %): 368 (M++1, 25), 313 (40), 285 (35), 257 (40), 236 (100), 152 (40), 111 (60), 97 (95), 83 (90), 69 (90), 57 (85), 43 (50).
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 3.37-3.87 (m, aliphatic), 3.99 (s, 2H, -CH2-phenyl), 7.29 (d, 1H, J = 8 Hz, H2-3-Fluorophenyl), 7.49 (m, 1H, H6-3-Fluorophenyl), 7.66 (d, 1H, J = 8 Hz, H5-3-Fluorophenyl), 7.68 (d, 1H, J = 8 Hz, H3-3-Fluorophenyl), 7.86-7.88 (m, 4H, phthalimide). IR (KBr, cm-1) ῡ: 3371, 2993, 2958, 2924, 2854, 1774, 1712, 1546, 1462, 1404, 1056, 972, 721.
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 3.99 (m, 12H, aliphatic), 3.96 (s, -CH2-phenyl), 3.99 (t, 2H, -CH2-phthalimide), 7.3 (t, 2H, J = 8 Hz, 4-Fluorophenyl), 7.58-7.73 (m, 4-Fluorophenyl), 7.83-7.88 (m, 4H, Phthalimide). IR (KBr, cm-1) ῡ: 3367, 2997, 2854, 1774, 1716, 1604, 1512, 1462, 1400, 1056, 975, 721.
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 3.2-3.66 (m, aliphatic), 3.79 (s, 3H, -OCH3), 3.97 (s, 2H, -CH2-phenyl), 7.1-7.36 (m, 4H, 4-Methoxyphenyl), 7.58-7.66 (m, 4H, Phthalimide). IR (KBr, cm-1) ῡ: 3371, 2993, 1774, 1716, 1612, 1462, 1435, 1400, 1381, 1269, 1056, 972, 906, 798, 721. MS (m/z, %): 379 (M+, 15), 219 (100), 160 (30), 121 (80), 91 (20).
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 3.1-3.78 (m, aliphatic), 3.78 (s, 3H, -OCH3), 4.4 (s, 2H, -CH2-phenyl), 7.1 (dd, 4H, J = 8 Hz, 4-Methoxyphenyl), 7.43-7.58 (m, 4H, Phthalimide). IR (KBr, cm-1) ῡ: 3429, 2978, 2935, 1778, 1716, 1612, 1516, 1462, 1435, 1400, 1235, 1184, 1072, 1029, 802, 725.
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.25-2.35 (m, 8H, Piperazine), 3.35 (t, 2H, -CH2-piperazine), 3.66 (s, 2H, CH2-phenyl), 3.68 (t, 2H, -CH2-phthalimide), 7.4-7.66 (m, 4H, 2-Nitrophenyl), 7.83-7.89 (m, 4H, Phthalimide). IR (KBr, cm-1) ῡ: 3155, 3111, 2956, 2922, 1681, 1521, 1489, 1458, 1327, 1303, 1188, 1141, 1035, 740, 717, 705. MS (m/z, %): 394 (M+, 3), 377 (15), 259 (30), 235 (40), 234 (100), 200 (50), 160 (70), 130 (30), 99 (55), 78 (30) 56 (15).
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.51 (m, 4H, Piperazine), 3.53 (t, 2H, -CH2-piperazine), 3.79 (s, -CH2-phenyl), 3.85 (t, 2H, -CH2-phthalimide), 7.6-7.66 (m, 2H, H4,6-3-Nitrophenyl), 7.65 (s, 1H, H2-3-Nitrophenyl), 7.75 (t, J = 8 Hz, 1H, H5-3-Nitrophenyl), 7.85 (m, 2H, H5,6-phthalimide), 7.88 (m, 2H, H4,7-phthalimide). IR (KBr, cm-1) ῡ: 3425, 2924, 2854, 1774, 1716, 1531, 1435, 1400, 1350, 1060, 806, 721.
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.3 (m, 8H, Piperazine), 3.33 (t, 2H, phthalimide-CH2-CH2-piperazine), 3.56 (s, 2H, -CH2-phenyl), 3.69 (t, 2H, phthalimide-CH2-CH2-piperazine), 7.57 (d, 2H, J = 8 Hz, H2,6-4-Nitrophenyl), 7.83-7.88 (m, 4H, Phthalimide), 8.19 (d, 2H, J = 8 Hz, H3,5-4-Nitrophenyl). IR (KBr, cm-1) ῡ: 3157, 3111, 2924, 1775, 1681, 1519, 1489, 1458, 1330, 1303, 1186, 1143, 1037, 750, 710. MS (m/z, %): 395 (M++1, 10), 394 (M+, 35), 235 (85), 234 (100), 191 (60), 174 (30), 160 (85), 90 (25), 70 (40).
1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.51 (m, 4H, Piperazine), 3.55 (m, 8H, aliphatic), 3.99 (s, 2H, -CH2-phenyl), 7.45-7.68 (m, 4H, phenyl), 7.85 (m, 4H, Phthalimide). IR (KBr, cm-1) ῡ: 3414, 2997, 2924, 1774, 1712, 1635, 1431, 1396, 1064, 721. MS (m/z, %): 349 (10), 234 (20), 189 (100), 160 (35), 91 (90).
Anticholinesterase activity assay (Ellman test)
Lyophilized powder of acetylcholinesterase from electric eel source (AChE, E.C. 220.127.116.11, Type V-S, 1000 unit) was purchased from Sigma-Aldrich (Steinheim, Germany). 5,5’-Dithiobis-(2-nitrobenzoic acid), potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium hydroxide, sodium hydrogen carbonate, and acetylthiocholine iodide were purchased from Fluka (Buchs, Switzerland). Compounds 4a-4l were dissolved in a mixture of 20 ml distilled water and 5 ml methanol and then diluted in 0.1 M KH2PO4/K2HPO4 buffer (pH 8.0) to afford a final concentration range. The Ellman test was carried out for assessment of the anticholinesterase activity of intended compounds in vitro. Prior to use, all solutions were adjusted to 25°C. To achieve 20-80% inhibition of AChE activity five different concentrations of each compound were tested. The assay solution consisted of a 0.1 M potassium phosphate buffer pH 8.0, with the addition of 0.01 M 5,50-dithio-bis(2-nitrobenzoic acid), 2.5 unit/mL of enzyme solution (AChE, E.C. 18.104.22.168, Type V-S, lyophilized powder, from electric eel) (Sigma Chemical). Compounds 4a-4l were added to the assay solution and preincubated at 25°C with the enzyme for 15 min followed by adding 0.075 M substrate (acetylthiocholine iodide). After rapid and immediate mixing the change of absorption was measured at 412 nm. In order to justify non enzymatic reaction assays were carried out with a blank containing all components except AChE.
The blank reading contained 3 ml buffer, 200 μl water, 100 μl DTNB and 20 μl substrate. The reaction rates were calculated, and the percent inhibition of test compounds was determined. Each concentration was analyzed in triplicate, and IC50 values were determined graphically from inhibition curves (log inhibitor concentration vs percent of inhibition). Spectrophotometric measurements were performed on a Cecil BioAquarius CE 7250 Double Beam Spectrophotometer .
Results and discussion
Properties of synthesized compounds
C21H22 Cl N3O2
C21H22 Cl N3O2
C21H22 Cl N3O2
Different types of substituent consisted of three electron withdrawing substituents (Cl, F, NO2) and also an electron donating substituent (−OCH3) were synthesized to investigate the electronic effects of various moieties. Furthermore, compound 4l was also synthesized without any group on the phenyl ring to explore the effect of the presence of the substitution on this ring.
Melting points of intermediate and final compounds were obtained using capillary tubes by electrothermal melting point analyzer. A range in melting point was recorded for compounds 3, 4a, 4b, 4f and 4i. In other cases a sharp point was detected and presented in Table 1. 1H NMR, IR and MS spectroscopic methods were applied for characterization and identification of all compounds. Deutrated dimethyl sulfoxide (DMSO-d6) was used for 1H NMR acquisition and TMS (tetramethyl silane) was applied as internal standard. Infrared spectroscopy was performed for all compounds using KBr disk and outstanding peaks was reported. Molecular ion peak of synthesized compounds was recorded in MS spectroscopy. Furthermore, M++2 was also reported for chlorinated compounds.
Results (IC 50 , μM) of in vitro acetylcholinesterase assay of compounds 4a-4l
0.91 ± 0.045
85 ± 12
26 ± 5
23 ± 7
74 ± 11
42 ± 8
5.5 ± 0.7
72 ± 9
36 ± 5
59 ± 6
40 ± 4
9 ± 2
0.14 ± 0.03
Totally, electron withdrawing substituents are capable to enhance the anticholinestease activity of the phthalimide derivatives that synthesized in this research. Comparison of the different compounds with electron withdrawing moieties showed that ortho position is the best position for this type of substituents. Whereas, the para position was the worst position for all of the electron withdrawing moieties. Introducing of an electron donating group such as methoxy at meta position of the phenyl ring also led to the increasing of the potency. But, this change was not so effective like ortho substitution of chlorine atom. Absence of any moiety on the phenyl ring as observed about compound 4l could be an AChE inhibitor with an averaged potency. In fact, this compound exerted potency less than compound 4a with ortho chlorine as well as compound 4g with meta methoxy substituent.
All ligands 4a-4l were docked into the active site of acetylcholinesterase (PDB ID: 1EVE). For performing an accurate docking procedure, the binding site of donepezil was intended as probable binding site for all ligands especially for ligand 4a. Compound 4a as the best inhibitor of AChE in vitro was studied in silico to reveal the probable binding mode of synthesized compounds perfectly (Figure 3). Superimposed state for this ligand with donepezil was also explored. According to the Figure 4, a similar binding mode and conformation as observed for donepezil, was also seen for this ligand. In fact, the structure of synthesized compounds occupies a similar region like donepezil in the active site of AChE. As seen in Figure 4, phthalimide, piperazine and benzyl rings of compound 4a adopt a same location like indanone, piperidine and benzyl rings of the donepezil respectively.
A new series of donepezil-like analogs were synthesized based on the phthalimide structure and anticholinesterase activity was assessed using Ellman test. All compounds exhibited a μM range in IC50 value (5.5-85 μM) for inhibition of AChE except for compound 4a that exhibited a nM range in IC50 value (0.91 μM). In silico study of compound 4a by docking method was also confirmed a similar binding mode like donepezil for this ligand.
Authors are grateful from the research deputy of Kermanshah University of Medical Sciences for financial support. This work was performed in partial fulfillment of the requirement for PharmD of Mr. Aram Ahmadi.
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