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Bis (Diamines) Cu and Zn Complexes of Flurbiprofen as Potential Cholinesterase Inhibitors: In Vitro Studies and Docking Simulations

Department of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
Institute of Chemistry, University of Sargodha, Sargodha 40100, Pakistan
Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
Department of Psychiatry, Lahore General Hospital, Lahore 54000, Pakistan
Department of Critical Care Medicine, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
Authors to whom correspondence should be addressed.
Crystals 2021, 11(2), 208;
Submission received: 27 January 2021 / Revised: 12 February 2021 / Accepted: 14 February 2021 / Published: 20 February 2021


Alzheimer’s disease (AD) causes dementia and continuous damage to brain cells. Cholinesterase inhibitors can alleviate the condition by increasing communication between the nerve cells and reducing the risk of dementia. In an effort to treat Alzheimer’s disease, we synthesized flurbiprofen-based diamines (1,2 diaminoethane and 1,3 diaminopropane) Zn(II), Cu(II) metal complexes and characterized them by single-crystal X-ray analysis, NMR, (FT)-IR, UV-Vis, magnetic susceptibility, elemental analysis and conductivities measurements. Synthesized diamine metal complexes appeared in ionic forms and have distorted octahedral geometry based on conductivity studies, magnetic susceptibility and electronic studies. Single crystal X-ray diffraction analysis confirmed (2b) Cu(H2O)2(L1)2(L2)2 complex formation. Moreover, we tested all synthesized metal complexes against the cholinesterase enzyme that showed higher inhibition potential. In general, copper metal complexes showed higher inhibitory activities than simple metal complexes with flurbiprofen. These synthesized metal complexes may derive more effective and safe inhibitors for cholinesterases.

1. Introduction

Around the globe, 2.5 to 4.0 million elderly people suffer from Alzheimer’s disease (AD), manifested by long-term neurodegeneration, loss of neural functions and cognitive abilities that ultimately lead to death [1]. Studies show that numerous disorders, including AD, correlate with high cholinesterase activity. Cholinesterase belongs to the serine hydrolases family, consisting of acetylcholinesterase (AChE) and butyryl-cholinesterase (BChE) [2,3]. Many physiological processes have been controlled by cholinesterase in either a direct or indirect way. Cholesterol overexpression may lead to numerous disorders like ataxia, myasthenia gravis and Parkinson’s disease [4,5]. To combat and treat these disorders, researchers have been looking for synthetic and natural inhibitors of cholinesterase. Physostigmine existed as the first cholinesterase inhibitor (ChEI) explored for the cure of AD [6]. Tacrine was the first approved drug for treating AD. Donepezil was permitted in 1996 for the treatment of mild-to-moderate AD. All these compounds, rivastigmine, galantamine, metrifonate, phenserine, physostigmine and tacrine, showed effective inhibition of human AChE and BuChE [7,8,9,10,11,12,13]. To target neuroinflammation and vesicant-induced inflammation, studies have focused on NSAID-AChEI complexes [14,15,16,17]. Current “second-generation” AChEIs also demonstrate some side effects such as diarrhoea, nausea, anorexia and vomiting [18]. So far, no proper treatment exists for these neurodegenerative disorders like Alzheimer’s disease; hence, researchers have been avidly seeking a proper cure for these neurodegenerative problems.
Currently, several potent inhibitors for cholinesterase exist in the market as first-line treatment for these neurodegenerative problems. However, effective treatment requires more effective inhibitors with safe and extraordinary potential for cholinesterase control, which demands further exploration of anticholinesterase compounds. Recently, organic metal complexes have shown positive effects on these neurodegenerative disorders [19]. For example, Pt(II) complexes with 1,10-phenanthroline ligands can inhibit cholinesterase and reduce Aβ aggregation and Aβ-induced synaptotoxicity [20]. Similarly, previous studies have prepared and analyzed metal complexes of bis (thiosemicarbazone) for cholinesterase inhibition along with a reduction in levels of Aβ aggregations [21].
Some studies showed that Cu or Zn complexes with 8-hydroxyquinoline ligands could induce metal-dependent metalloprotease activity, which degrades Aβ aggregations and ultimately reduces the risk of AD [22,23,24]. Mono-, bis- and tris-diamine conjugated ligands have been found more water-soluble with an enhanced H-bonding network. By using this property, various ligand-metal complexes have been designed with anti-cancer properties [25,26,27,28]. Flurbiprofen-tacrine conjugates and tris-diamine conjugates of flurbiprofen have been reported as cholinesterase inhibitors, where flurbiprofen backbone was found to augment the inhibitory activity [17,29]. Here, we present synthesis and characterization of a relatively new class of flurbiprofen (a propionic acid carboxylate) and its transition metal complexes with diamines (1,2-diaminoethane and 1,3-diaminopropane) as effective cholinesterase inhibitors.

2. Materials and Methods

Analytical grade reagents and chemicals including metal salts (copper acetate, zinc acetate), 1,2-diaminoethane, 1,3-diaminopropane, flurbiprofen acid and solvents were purchased from Merck Millipore and Sigma Aldrich, England. Reagent for cholinesterase assay including electric eel acetyl cholinesterase (AChE), equine serum autyrylcholinesterase (BChE), 5,5-dithio-bis-(2-nitrobenzoic acid), acetylthiocholine iodide (ATChI), butyryl thiocholine Iodide (BChI), galantamine hydrobromide and donepezil were obtained from Sigma Aldrich, England, while a μQuant microplate spectrophotometer (MQX200, BioTek, Winooski, VT, USA) was used for assay monitoring. Aluminum-backed TLC plates were used to analyse the products. UV/visible, infrared spectra and 1H-/13C-NMR spectra were obtained using Jenway 6505 (Keison Products, Chelmsford, UK), Shimadzu (FT)IR-8400S (Shimadzu Scientific Instruments Inc. Kyoto, Japan), and Bruker AM 300/400 (Bruker’s AVANCE Tech, Billerica, MA, USA) spectrometers, respectively, as described in [30]. Stanton SM12/S Gouy’s balance was used to to determine magnetic susceptibility. The Elemental Analyzer (Perkin Elmer, USA) and Inolab Conductivity Bridge 720 were used to determine the percentage of C, H, N, M and molar conductance.

2.1. Synthesis of Flurbiprofen Metal Complexes (1a-b)

The potassium salt of flurbiprofen (FLP-K) was prepared by adding 20 mL of 0.01 mol flurbiprofen acid (2.44 g) solution in de-ionized water to 0.01 mol KOH (0.56 g). A dropwise addition of 0.005 mol metal acetate solution (10 mL) to the FLP-K solution with continuous stirring for 20 min in a round bottom flask at room temperature resulted in the formation of the metal-flurbiprofen complex (1a-b) with the characteristic colored precipitates. The precipitates were filtered, followed by subsequent washings with de-ionized water and ethanol. After washing, precipitates were dried at the room temperature.

2.1.1. Zn(H2O)2(L)2 (1a)

C30H28F2O6Zn (1a) was synthesized by the method given in Section 2.1 using 0.005 moles zinc acetate (0.971 g). A white solid product with 83%, yield was obtained showing a melting point of 183 °C. Analytical calculations for C30H28F2O6Zn (%) was found to be: C, 61.29; H, 4.80, found: C, 61.22; H, 4.82. Selected FT-IR data (KBr, cm−1) show: ῡ(M←H2O) 3653 cm−1, ῡ(M←O) 484 cm−1, (CO)1650–1730 cm−1, (Ar C = C)1500–1590 cm−1, (C-H) 2700–2900 cm−1 and disappearance of the broad (OH) peak at 3200–3400, λmax (cm−1) = 29543, Ω−1cm2mol−1 = 18, µeff = diamagnetic, 1H NMR (400.13 MHz, [d6]DMSO, 25 °C): δ = 6.64 (d, 3J = 8 Hz, 4H, H-9, H-13, H-9′, H-13′), 6.58 (t, 3J = 7 Hz, 4H, H-10, H-12, H-10′, H-12′), 6.55–6.51 (m, 4H, H-5, H-11, H-5′, H-11′), 6.36 (d, 3J = 8 Hz, 2H, H-4, H-4′), 6.33 (s, 2H, H-8, H-8′), 2.78–2.71 (m, 2H, H-2, H-2′), 0.49 (d, 3J = 8 Hz, 6H, H-1, H-1′) ppm. 13C NMR (100.61 MHz, [d6] DMSO, 25 °C): δ = 178.7, 160.0, 157.6, 135.2, 130, 128.7, 128.6, 127.6, 125.8, 124.2, 115.1, 45.8, 19.7.

2.1.2. Cu(H2O)2(L)2 (1b)

Copper acetate 0.908 g (0.005 moles) was used to synthesize Cu(H2O)2(C15H12FO2)2 (1b) using the method given in Section 2.1. A light green solid product with a yield of 76% was obtained showing a melting point of 174–176 °C. Analytical calculations show (%): C, 61.48; H, 4.82, found: C, 61.44; H, 4.82. Selected FT-IR data (KBr, cm−1): ῡ(M←H2O) 3690 cm−1, ῡ(M←O) 453 cm−1, (CO)1650–1730 cm−1, (Ar C = C)1500–1590 cm−1, (C-H) 2700–2900 cm−1 and disappearance of the broad (OH) peak near 3200–3400, λmax (cm−1) = 15,219–15,412, Ω−1cm2mol−1 = 21, µeff = 1.7.

2.2. Synthesis of Bis (1,2-diaminoethane) Metal Flurbiprofen Complexes (2a-b)

Diaminoethane and flurbiprofen-metal complex conjugates were obtained by adding 1.42 mL of 0.02 moles 1,2-diaminoethane in flurbiprofen-metal complex (1a-b) solutions in 10 mL of ethanol/water (1:1). The mixture was stirred at room temperature for 25 min to obtain a clear blue solution. Crystals for diaminoethane and flurbiprofen-metal complexes were obtained by slow evaporation (2a-b).

2.2.1. Zn(H2O)2 (C2H8N2)2 (C15H12FO2)2 (2a)

A white solid product, C34H44F2N4O6Zn (2a), with a yield of 88% was obtained using the method given in Section 2.2. The melting point was found to be 222–224 °C. Analytical calculations for C34H44F2N4O6Zn (%): C, 57.67; H, 6.26; N, 7.91, found: C, 57.60; H, 6.29; N, 7.90. Selected FT-IR data (KBr, cm−1): ῡ(M←H2O) 3623 cm−1, ῡ(M←N) 509 cm−1, (CO)1650–1730 cm−1, (Ar C=C)1500–1590 cm−1, (CH) 2700–2900 cm−1 and disappearance of the broad (OH) peak at 3200–3400 and ῡ(M←O)peak, λmax (cm−1) = 30,816, Ω−1 cm2mol−1 = 164, µeff = diamagnetic, 1H NMR (400.13 MHz, [d6]DMSO, 25 °C): δ = 7.51 (d, 3J = 8 Hz, 4H, ArH), 7.45 (t, 3J = 7 Hz, 4H, ArH), 7.40–7.35 (m, 4H, ArH), 7.21–7.17 (m, 4H, ArH), 3.59–3.53 (m, 2H, 2 × CH), 3.24–3.19 (m, 8H, 4×NH2), 3.12–3.09 (m, 8H, 4×CH2), 1.35 (d, 3J = 8 Hz, 6H, 2×CH3) ppm. 13C NMR (100.61 MHz, [d6] DMSO, 25 °C): δ = 177.8, 159.6, 157.3, 135.0, 129.9, 128.4, 128.2, 127.4, 125.2, 124.1, 114.9, 46.7, 46.2, 19.6.

2.2.2. Cu(H2O)2 (L1)2 (L)2 (2b)

C34H44F2N4O6Cu (2b) was synthesized as mentioned in Section 2.2 using 1.42 mL 1,2-diaminoethane (0.02 moles). Blue crystals with a yield of 84(%) were obtained. A melting point of 215–217 oC was observed. Analytical calculations for C34H44F2N4O6Cu (%): C, 57.82; H, 6.28; N, 7.93, found: C, 57.79; H, 6.24; N, 7.95. Selected FT-IR data (KBr, cm−1): ῡ(M←H2O) 3598 cm−1, ῡ(M←N) 516 cm−1, (CO)1650–1730 cm−1, (Ar C = C)1500–1590 cm−1, (CH) 2700–2900 cm−1 and disappearance of the broad (O-H) peak at 3200–3400 and ῡ(M←O) peak, λmax (cm−1) = 16,749–16,810, Ω−1cm2mol−1 = 158, µeff = 1.9.

2.3. Synthesis of Bis (1,3-diaminopropane) Metal Flurbiprofen Complexes (3a-b)

To the ethanol/water (1:1) solution (10 mL) of flurbiprofen metal complexes (1a-b), 1.68 mL of 1,3-diaminopropane (0.02 mol) was added to obtain 1,3-diaminopropane diamines and flurbiprofen mixed ligand complexes. After 25 min stirring at room temperature, a clear blue solution was obtained that crystalized upon slow evaporation to give bis (1,3-diaminopropane) metal flurbiprofen complex crystals (3a-b).

2.3.1. Zn(H2O)2 (L1)2 (L)2 (3a)

A white solid product, C36H48F2N4O6Zn (3a), with a yield of 80%, was synthesized using the method mentioned in Section 2.3. The melting point was observed as 218–220 °C. Analytical calculations show (%): C, 58.73; H, 6.57; N, 7.61, found: C, 57.64; H, 6.55; N, 7.96. Selected FT-IR data (KBr, cm−1): ῡ(M←H2O) 3623 cm−1, ῡ(M←N) 509 cm−1, (CO)1650–1730 cm−1, (Ar C = C)1500–1590 cm−1, (CH) 2700–2900 cm−1 and disappearance of broad (O-H) at 3200–3400 cm−1 and ῡ(M←O) peak, λmax (cm−1) = 20,842, ε cm2mol−1 = 160, µeff = diamagnetic, 1H NMR (400.13 MHz, [d6]DMSO, 25 °C): δ = 7.50 (d, 3J = 8 Hz, 4H, ArH), 7.45 (t, 3J = 7 Hz, 4H, ArH), 7.40–7.35 (m, 4H, ArH), 7.22 (d, 3J = 8 Hz, 2H, ArH), 7.20 (s, 2H, ArH), 3.59–3.53 (m, 2H, 2 × CH), 3.47–3.42 (m, 8H, 4×NH2), 2.68–2.64 (m, 8H, 4×CH2), 2.01–1.95 (m, 4H, 2×CH2), 1.35 (d, 3J = 8 Hz, 6H, 2×CH3) ppm. 13C NMR (100.61 MHz, [d6] DMSO, 25 °C): δ = 177.8, 159.6, 157.3, 135.0, 129.9, 128.4, 128.2, 127.4, 125.2, 124.1, 114.9, 46.2, 39.2, 38.6, 19.6.

2.3.2. Cu(H2O)2 (L1)2 (CL)2 (3b)

The general method given in Section 2.3 was used to obtain the compound C36H48F2N4O6Zn (3b) with a yield of 80(%); melting point of 210–212 °C; analytical calculations (%) of C, 58.88; H, 6.59; N, 7.63, found: C, 58.80; H, 6.49; N, 7.79. Selected FT-IR data (KBr, cm−1): ῡ(M←H2O) 3598 cm−1, ῡ(M←N) 516 cm−1, (CO)1650–1730 cm−1, (Ar C = C)1500–1590 cm−1, (CH) 2700–2900 cm−1 and disappearance ῡ(M←O) peak and broad (O-H) peak at 3200–3400 cm−1, λmax (cm−1) = 16,735–16,788, Ω−1cm2mol−1 = 150, µeff = 1.9.

2.4. Molecular Docking Simulations

The Three-dimensional structures of human AChE and BChE were obtained from the Protein Data Bank (PDB) with PDB IDs of 4EY4 (X-ray structure with 2.15 Å resolution) and 6ESY (X-ray structure with 2.80 Å resolution), respectively, and attached ligands/water molecules were removed. The Cu-bisdiamine-flurbiprofen complex, 2b (C34H44F2N4O6Cu), was docked against the human AChE and BChE enzymes to map the protein–ligand interactions and binding energies. Cu-bisdiamines and flurbiprofen were also docked individually to calculate the efficacy of 2b. The crystal structure of 2b was used in the docking where the AMBER03 force field and a modified AutoDock-LGA algorithm module were used in YASARA software [31] to perform molecular docking simulations. Binding energies and dissociation constants were obtained by running the 100 simulations for each ligand, where the seed value was set to 1000 [32]. Protein–ligand interactions were extracted and mapped using PyMol (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC. New York, NY, USA) and LigPlus

2.5. Determination of AChE and BChE Inhibitory Activity

A modified Ellman’s method [33] was used to determine the AChE and BChE inhibitory activity of metal complexes [34]. Phosphate buffer (0.1 M KH2PO4/K2HPO4, pH 8.0) was used to prepare metal complex samples, enzymes and standard solutions. 0.03 U/mL of AChE and BChE were added to a 10 µL metal complex solution (0–50 µM), and the mixture was incubated for 10 min at room temperature. Then, 25 µL of 1 mM of either ATChI or BTChI was added, and the sample mixture was incubated for the next 15 min followed by the addition of 25 μL of 3 mM DTNB before taking absorbance at 412 nm using a μQuant microplate spectrophotometer. Microwells with DTNB were used as blank. All reactions were made in triplicate, and the IC50 values were calculated for each sample. Galantamine and donepezil are well-known cholinesterase inhibitors and were used as reference drugs.

3. Results

3.1. Synthesis

In this study, we synthesized transition metal complexes of flurbiprofen with propane-diamine (1,3-diaminopropane) and ethylene-diamine (1,2-diaminoethane). Next, we evaluated these metal complexes using magnetic susceptibility, elemental analysis and FT-IR, UV-VIS spectroscopy, conductivity measurements and X-ray analysis, 1H-NMR, 13C-NMR. These metal complexes are ionic based on conductivity rearmaments and have distorted octahedral geometry based on electronic studies and magnetic susceptibility studies. Synthesis of these metal complexes caused little to no pollution (green synthesis) because we used harmless solvents like water and ethanol. These metal complexes can only be obtained in water, but for precise crystals, ethanol was also used. Figure 1 illustrates the scheme of synthesis for these metal complexes.

3.2. X-ray Crystallography

Among all the simple and bis (1,2-diaminoethan and 1,3-diaminoprpane)-derived metal complexes of flurbiprofen, only Cu(H2O)2(L1)2 (L)2 (2b) yielded blue crystals which were suitable for X-ray analysis. The coordination sphere appears octahedral with a basal plane A (N1/N2/N1i/N2i i = 1 − x, − y, 1 − z) around the copper cation in (2b) with two apical O-atoms from two water and four nitrogen atoms from two 1,2-diaminoethane. In the equatorial plane, the copper atom appears in the centre. The Cu-N bonds fall within the experimental error [1.998(4)-2.011(4) Å], and the Cu-O bond is 2.605(5) Å. Two symmetry operations relate flurbiprofen anions. In the flurbiprofen anion, the terminal benzene ring (C10-C15) is planar with r.m.s deviations of 0.0032, 0.0084 and 0.0023 Å with acetyl moiety (O1/O2/C1/C2) and the fluorophenyl ring (C4-C9/F1).
The crystal contains an infinite polymeric network due to hydrogen bonding of N-H⋅⋅⋅O, O-H⋅⋅⋅O and C-H⋅⋅⋅F with two-dimensional crystallographic base vectors [100], [1] in the plane (0 1 0). The ORTEP diagram of 2b with a 50% probability level and the two-dimensional polymeric network are displayed in Figure 2.

3.3. NMR Analysis

Next, we characterize zinc complexes of flurbiprofen by 1H NMR and 13C NMR in d6DMSO. The 1H NMR of zinc complex of flurbiprofen (1a) indicates the complex formation. Singlet, duplet and multiplet with chemical shift values of 6.64, 6.58, 6.55–6.51, 6.36 and 6.33 ppm indicate aromatic protons. A shielded signal for the methyl group at 0.49 ppm is observed, and a multiplet near 2.78–2.71 ppm reflects tertiary carbon attached to the aromatic ring. A characteristic downfield signal in 13C-NMR at 178.5 ppm indicates that aromatic carbon is directly attached with a tertiary carbon. Up-field signals at 160.0, 157.6, 135.2, 130.2, 128.7, 128.6, 127.6, 125.8, 124.2 ppm show other aromatic carbons. A chemical shift value at 45.8 ppm indicates a tertiary carbon.
The zinc flurbiprofen complex (2a) complex was synthesized showing the 1H NMR peak shifting at 7.51, 7.45, 7.40–7.35, 7.21–7.17 ppm for aromatic protons and multiplet (3.59–3.53) ppm for hydrogen of tertiary methyl groups shift downfield. This indicates a decrease in (M-O) interaction and an increase in (M-N) interaction, which reflects the formation of (2a).
Chemical shifts at 3.12–3.09 ppm (4×CH2) and 3.24–3.19 ppm (4×NH2) confirm the synthesis of (2a). Two new peaks at 46.7 ppm (2×CH2) and 46.2 ppm (2×CH2) in 13C NMR of (2a) indicate that 4×CH2 of 1,2-diaminoethane are interacting with zinc metal, which suggest a synthesis of (2a). Similarly, for the synthesis of bis (1,3-diaminopropane) zinc flurbiprofen complex (3a), 1,3-diaminopropane was added to (1a). The 1H NMR and 13C NMR chemical shifts values of 1H NMR at (7.50, 7.45, 7.40–7.35, 7.22, 7.20 ppm) for aromatic protons and multiplet (3.59–3.53) ppm for tertiary methyl groups shift towards the downfield region. New signals of multiplet at 3.47–3.42 ppm (4×NH2), 2.68–2.64 ppm (4×CH2) and 2.01–1.95 ppm (2×CH2) confirm the formation of (3a). The 13C NMR of (3a) shows three new peaks at 46.2 ppm (2×CH2), 39.2 ppm (2×CH2) and 38.6 ppm (2×CH2), indicating the (6×CH2) of (1,3-diaminopropane) are interacting with zinc metal, which suggests a synthesis of (3a).

3.4. FT-IR Analysis

We also performed an FT-IR analysis of metal complexes for the structural confirmation of metal complexes. IR peaks near 1419–1476 cm−1 suggest that these peaks belong to (aromatic–CH) functional groups. The peaks appearing near the 461–479 cm−1 range reflect (M←O) metal–oxygen bonds formation and peaks near 523–572 cm−1 show the formation of (M←N) metal–nitrogen bonds. IR analysis of the complexes does not show the (M-N) metal–nitrogen peaks for (1a-b) due to synthesis from transition metals and flurbiprofen acid. However, if the addition of (1,3-diaminopropane) and (1,2-diaminoethane) to simple flurbiprofen complexes (1a-b) leads to the formation of (2a-b) and (3a-b), the (M-N) metal peaks appear near 514–580 cm−1, suggesting the formation of a metal–ligand chelating bond between the nitrogen of 1,2-diaminoethane and 1,3-diaminopropane and metal.

3.5. UV/vis and Magnetic Susceptibility

In addition to other spectroscopic techniques, UV-visible analysis was performed to support the complex formation and confirm the symmetry of metal complexes. The symmetry of transition metal complexes was deduced from several peaks observed. For each metal complex, the electronic spectra of 3d-transition metals were recorded in 10−3 to 10−5 M solutions in the range of 200–800 nm in DMSO. Only one peak at 29,543 cm−1 in Zn(II) complexes appears for (1a), 30,816 cm−1 in (2a) and 30,842 cm−1 in (3a), for metal to ligand charge transfer. The B.M. values were recorded as zero, suggesting the diamagnetic nature of these complexes. Only a single low-intensity broadband in the range of 15,219–15,412 cm−1 was observed for Cu(II) complexes for (1b), 16,749–16,810 cm−1 for (2b) and 16,735–16,788 cm−1 in (3b). The spectrum of these metal complexes indicates that the 2Eg2T2g transition leads to distorted octahedral geometry of the metal complexes. The difference in the position of peaks is due to the difference in the size of ligands in (1b), (2b) and (3b) for copper complexes. Because different ligands possess different splitting in d-orbitals of metal, B.M. values for copper complexes are measured near 1.7, 1.9 and 1.9, which suggests distorted octahedral geometry of copper complexes.

3.6. Elemental Analysis

Percentage analysis of C, H, N and all synthesized transition metal (II) complexes of flurbiprofen agreed with the calculated percentage values of their suggested molecular structures (Supplementary Materials). Both values fall under acceptable ranges (±0.03–0.95), which confirms the formation of suggested diamine-based transition metal (II) complexes.

3.7. Conductivity Measurements

Synthesized metal complexes were subjected to molar conductivities at room temperature. Conductivity measurements were performed to check the ionic and non-ionic nature of the metal complexes. All the metal complex solutions were prepared with a molar concentration of (1 × 10−3 M). Molar conductivities of synthesized flurbiprofen metal complexes (1a-b) measure 18 and 21 Ω−1cm2mol−1, indicating their non-ionic nature. However, as ethylene-diamine (1,2-diaminoethane) and propane-diamine (1,3-diaminopropane) were added to (1a-b) for the formation of bis (1,2-diaminoethane) metal flurbiprofen complexes (2a-b) and bis (1,3-diaminopropane) metal flurbiprofen complexes (3a-b), the conductance increased one order of magnitude to 164 and 158 Ω−1cm2mol−1 for (2a-b) and 160 and 150 Ω−1cm2mol−1 for (3a-b). This increase in conductivity of these bis (1,3-diaminopropane and 1,3-diaminopropane) flurbiprofen transition metal complexes indicates their electrolytic or ionic character.

3.8. Anticholinesterase Activity

Anti-cholinesterase activities of transition metal complexes of diamines (1,2-diaminoethane, 1,3-diaminopropane) with flurbiprofen (1a-b, 2a-b and 3a-b) are shown in Table 1. We observed that metal complexes of flurbiprofen derived from 1,2-diaminoethane (2a-b) show most potency as a cholinesterase inhibitor, with the lowest IC50 values compare to other series (1a-b and 3a-b). In general, the trend in cholinesterase inhibition follows the order 2a-b >3a-b >1a-b. This sequence indicates that nitrogen-containing transition metal complexes possess more cholinesterase inhibitory potency as compared to simple transition metal complexes. Table 2 shows the inhibitory activities of diamine-based metal in vitro.
Moreover, copper complexes exhibit higher activity and have the lowest IC50 values in our study. Among all the metal complexes, Cu(H2O)2 (L1)2 (L)2 (2b) showed inhibitory activities against AChE and BChE, with the lowest IC50 values, 3.0 ± 0.24 and 12.3 ± 0.21.

3.9. Molecular Docking Studies

Molecular docking results are in agreement with in vitro choline esterase activities for the metal complex Cu(H2O)2 (C2H8N2)2 (C15H12FO2)2. FLP docking with hAChE shows π–π stacking with Trp86 and Tyr124, while Tyr337 forms a hydrogen bond (Figure 3a). These interactions look similar to donepezil binding to the PAS (Peripheral Anionic Site), but interestingly Trp286 does not seem to be involved in FLP binding. Tyr337 is considered an entry point for the CAS (Catalytic Binding Site) [35,36] and it seems here FLP-Tyr337 interactions hinder the FLP entry deep into the CAS. The bis-diamine metal complex was found to interact with Glu81, Trp86 and Asp131. Bound water molecules were found to interact with Glu81 and Trp86. Met85 interacts with metal ion, while one of the amines from each bis-diamine complex forms H-bonds with Asp131 (Figure 3b).
The FLP-bis-diamine complex reached the entrance at the gorge of CAS while interacting with Tyr341. Non-polar interactions to Tyr337, Phe338 and Phe295 in the CAS gorge stabilize the complex interactions within the active site (Figure 3c). The complex cannot enter entirely into the CAS gorge; it also loses the interactions with Trp286. The bis-diamine metal complex interacts with Glu392 viz bound water molecule. The interactions within the CAS gorge account for high binding energy and stabilized ligand binding. The Phe295 interactions, seen here, are also responsible for donepezil inhibition towards hAChE [35,37]. Zephycandidine A and galanthamine have been shown to interact with AChE via Tyr337 and Trp286.
In the case of hBChE, the bis-diamine metal complex shows backbone interactions with Gln119, Ser287, Leu286 and Val288 (Figure 4b). The metal complex is stabilized by Gly116, Gly117, Gln119, Phe329 and Tyr332. FLP interacts with hBChE via π–π stacking to Trp82 and Phe329, while Asp70, Ser79, Gly115, Gly116, Ser198, Ala328, Tyr332, Trp430 and His438 stabilize the ligand binding (Figure 4a). Here it seems that a highly electronegative fluorine atom in FLP was the reason for its strong interactions with Gly115 and Gly116. Tarcine, an inhibitor of hBChE, has also been found to share the same binding site [38] and its binding is stabilized by π–π stacking with Trp82.
The FLP-bis-diamine complex was found to perfectly occupy the position in the hBChE PAS and CAS gorge. The metal ion was found to coordinate with Glu238. Here, interactions with hBChE show that FLP-bis-diamine complex enters the gorge fully, where Phe357, Phe358 and Tyr396 are involved in π–π stacking. While FLP loses the π–π stacking to Trp82, its binding is stabilized by Leu286, Val293 and Asn396 (Figure 4c). The results suggest that the FLP-bis-diamine complex may be an ideal hAChE and hBuChE inhibitor due to the presence of extensive π–π stacking and hydrogen and hydrophobic interactions. The metal-bound FLP-bis-diamine complex shows stable interactions in comparison to individual the FLP or bis-diamine metal complex.

4. Conclusions

Since no proper cure for AD exists, cholinesterase inhibitors such as Donepezil have delayed the progression of AD therapeutically. Second-generation cholinesterase inhibitors, such as rivastigmine and galantamine, have entered the treatment of AD. This study aims to develop novel inhibitors to further advance AD treatment by utilizing the fascinating properties of transition metal complexes [39,40,41]. We have synthesized and characterized Zn(II) and Cu(II) transition metal complexes with flurbiprofen and diamines. All the metal complexes demonstrated distorted octahedral geometry on the basis of electronic spectra and B.M values. Metal complexes, along with 1,2-diaminoethane, 1,3-diaminopropane, and flurbiprofen, show an electrolytic nature, while simple metal flurbiprofen complexes are non-electrolytic. Among all synthesized metal complexes, most of the synthesized metal complexes exhibited elevated cholinesterase inhibitory activity. Copper complexes exhibit the highest activity against the cholinesterase enzyme as compared to zinc metal complexes. Furthermore, bis (1,2-diaminoethane) metal flurbiprofen complexes and bis (1,3-diaminopropane) metal flurbiprofen complexes show better cholinesterase inhibition as compared to simple metal flurbiprofen complexes. In conclusion, the diamines synthesized in this study show potential in AD treatment as novel cholinesterase inhibitors.

Supplementary Materials

The following are available online at, Figure S1: ORTEP diagram of 2b with thermal ellipsoids drawn at 100% probability level. The H-atoms are shown as small circles of arbitrary radii. Symmetry code i = 1 − x, − y, 1 − z, Table S1: UV/VIS, IR and Molar conductivities of the metal complexes, Table S2: Elemental analysis and magnetic susceptibility data of the complexes, Table S3: Bond lengths [Å] and angles [°] for 2b.

Author Contributions

Conceptualization, C.L. and M.I.T.; methodology, M.J., W.X.Z. and R.A.; software, M.F.u.R.; validation, M.J. and N.S. and F.K.; formal analysis, W.X.Z.; investigation, M.I.T., M.J., H.E., and F.K.; data curation, M.F.u.R.; writing—original draft preparation, C.L, M.J., M.B. and F.K.; writing—review and editing, M.F.u.R., M.J., and F.K.; visualization, W.X.Z.; supervision, W.X.Z.; project administration, W.X.Z., C.L.; funding acquisition, C.L. and M.I.T. All authors have read and agreed to the published version of the manuscript.


Funding in the Lu lab was provided by the Fundamental Research Funds for the Central Universities (2232021G-04), Shanghai Science and Technology Committee (19ZR1471100), the National College Student Innovation Experiment Program (105-03-0178028, 105-03-0178029, 105-03-0178229, 105-03-0178139).

Conflicts of Interest

The authors declare no conflict of interest.


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Figure 1. Scheme for the synthesis of bis (1,2-diaminoethan and 1,3-diaminoprpane) metal flurbiprofen complexes. (Flurbiprofen (C15H12FO2) = L, 1,2-diaminoethane (C2H8N2) = L1, 1,3-diaminpropane (C3H10N2) = L2.).
Figure 1. Scheme for the synthesis of bis (1,2-diaminoethan and 1,3-diaminoprpane) metal flurbiprofen complexes. (Flurbiprofen (C15H12FO2) = L, 1,2-diaminoethane (C2H8N2) = L1, 1,3-diaminpropane (C3H10N2) = L2.).
Crystals 11 00208 g001
Figure 2. ORTEP diagram of 2b with thermal ellipsoids drawn at 50% probability level. The H-atoms are shown as small circles of arbitrary radii. Symmetry code i = 1 − x, − y, 1 − z (a,b). The two-dimensional polymeric network due to various H-bonding of 2b (c) (CCDC# 1965852).
Figure 2. ORTEP diagram of 2b with thermal ellipsoids drawn at 50% probability level. The H-atoms are shown as small circles of arbitrary radii. Symmetry code i = 1 − x, − y, 1 − z (a,b). The two-dimensional polymeric network due to various H-bonding of 2b (c) (CCDC# 1965852).
Crystals 11 00208 g002
Figure 3. Binding mode of flurbiprofen (FLP) (a), bis-diamine metal complex (b), FLP-bis-diamine metal complex (c) in the catalytic and peripheral pocket of hAChE. The figures on the left show electrostatic potential surface (generated with PyMol) and ligand binding cavities (gorge).
Figure 3. Binding mode of flurbiprofen (FLP) (a), bis-diamine metal complex (b), FLP-bis-diamine metal complex (c) in the catalytic and peripheral pocket of hAChE. The figures on the left show electrostatic potential surface (generated with PyMol) and ligand binding cavities (gorge).
Crystals 11 00208 g003
Figure 4. Binding mode of FLP (a), bis-diamine metal complex (b), FLP-bis-diamine metal complex (c) in the catalytic and peripheral pocket of hBChE. The figures on the left show electrostatic potential surface (generated with PyMol) and ligand binding cavities (gorge).
Figure 4. Binding mode of FLP (a), bis-diamine metal complex (b), FLP-bis-diamine metal complex (c) in the catalytic and peripheral pocket of hBChE. The figures on the left show electrostatic potential surface (generated with PyMol) and ligand binding cavities (gorge).
Crystals 11 00208 g004aCrystals 11 00208 g004b
Table 1. Crystal data and structure refinement for 2b.
Table 1. Crystal data and structure refinement for 2b.
Identification Code Shelx
Empirical formula C34 H44 Cu F2 N4 O6
Formula weight 706.27
Temperature 296(2) K
Wavelength0.71073 Å
Crystal systemMonoclinic
Space groupP 21/n
Unit cell dimensions
a = 6.6291(8) Åα = 90°
b = 40.392(5) Åβ = 112.243(6)°
c = 6.8061(9) Åγ = 90°
Volume1686.8(4) Å3
Density (calculated)1.391 Mg/m3
Absorption coefficient0.708 mm−1
Crystal size0.420 × 0.280 × 0.200 mm3
Theta range for data collection1.008 to 27.356°.
Index ranges−8 ≤ h≤ 7, −51 ≤ k ≤ 49, −5 ≤ l ≤ 8
Reflections collected10,124
Independent reflections3611 [R(int) = 0.0400]
Completeness to theta = 25.242°98.4%
Refinement methodFull-matrix least-squares on F2
Goodness-of-fit on F21.172
Final R indices [I > 2sigma(I)]R1 = 0.0884, wR2 = 0.2301
R indices (all data)R1 = 0.1181, wR2 = 0.2532
Extinction coefficientn/a
Largest diff. peak and hole1.684 and −0.713 e.Å−3
Table 2. In vitro AChE and BChE inhibitory activities of compounds.
Table 2. In vitro AChE and BChE inhibitory activities of compounds.
(1a-b, 2a-b and 3a-b)
Sample CodeCompoundsAnticholinesterase Activity * (IC50 µM)
eeAChE eqBChE SI
1aZn(H2O)2(L)232.3 ± 1.443.2 ± 1.231.3
2aZn(H2O)2(L1)2(L)23.5 ± 0.1413.6 ± 0.385.4
3aZn(H2O)2(L2)2(L)29.3 ± 0.2221.3 ± 2.312.2
1bCu(H2O)2(L)222.5 ± 0.6245.4 ± 1.452.0
2bCu(H2O)2(L1)2(L)23.0 ± 0.2412.3 ± 0.214.1
3bCu(H2O)2(L2)2(L)23.4 ± 0.1714.5 ± 0.274.2
A *Galantamine4.0 ± 0.1015.0 ± 0.673.7
LFlurbiprofen45 ± 0.13443 ± 30.739.5
* Experiments were performed thrice at 0.5 mM substrates.
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Jamil, M.; Sultana, N.; Ashraf, R.; Bashir, M.; Rehman, M.F.u.; Kanwal, F.; Ellahi, H.; Lu, C.; Zhang, W.X.; Tariq, M.I. Bis (Diamines) Cu and Zn Complexes of Flurbiprofen as Potential Cholinesterase Inhibitors: In Vitro Studies and Docking Simulations. Crystals 2021, 11, 208.

AMA Style

Jamil M, Sultana N, Ashraf R, Bashir M, Rehman MFu, Kanwal F, Ellahi H, Lu C, Zhang WX, Tariq MI. Bis (Diamines) Cu and Zn Complexes of Flurbiprofen as Potential Cholinesterase Inhibitors: In Vitro Studies and Docking Simulations. Crystals. 2021; 11(2):208.

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Jamil, Muhammad, Nargis Sultana, Rizwan Ashraf, Maryam Bashir, Muhammad Fayyaz ur Rehman, Fariha Kanwal, Humna Ellahi, Changrui Lu, Wei Xing Zhang, and Muhammad Ilyas Tariq. 2021. "Bis (Diamines) Cu and Zn Complexes of Flurbiprofen as Potential Cholinesterase Inhibitors: In Vitro Studies and Docking Simulations" Crystals 11, no. 2: 208.

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