Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 16  |  Issue : 2  |  Page : 71-77

Synthesis and antimicrobial activity of substituted 1,4-bis-spiro[benzocycloheptene-6(5h),3′(3h-pyrazol)-5-one]-benzene under microwave irradiation and molecular docking study


Department of the Chemistry of Natural and Microbial Products, National Research Centre, Dokki, Egypt

Date of Submission28-Apr-2016
Date of Acceptance18-May-2016
Date of Web Publication8-Sep-2017

Correspondence Address:
Fatma A.A. El-Hag
Department of the Chemistry of Natural and Microbial Products, National Research Centre, 33 El Bohoth St, PO Box 12622, Dokki, Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-4315.214206

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  Abstract 

Background and objective
Spiropyrazole derivatives are one of the most bioactive spiro compounds that play a vital role in drug discovery, such as antibacterial, anti-inflammatory, antifungal, antiviral, analgesic, and antidepressant activities. Moreover, microwave as an energy source enhances the reaction rates and improves the regioselectivity. The aim of this study was to synthesize the spiropyrazole derivative compounds. Molecular docking was performed.
Materials and methods
1,3-Dipolar cycloaddition of 6,6′-(1,4-phenylene-bis(methanylylidene))-bis(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one) to a variety of nitrilimines (generated in situ by triethylamine dehydrohalogenation of the corresponding hydrazonoyl halides) under microwave irradiation proceeded regioselectively affording spiro[benzo[7]-annulene-6,3′-pyrazol]-4′-yl)phenyl)-spiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-ones. The structure of the newly synthesized compounds was confirmed on the basis of spectral data and elemental analyses. The antimicrobial activity of the bis(spiropyrazoles) derivatives was tested for antimicrobial activity. Molecular docking was performed and analyzed with the molecular modeling environment program.
Results and conclusion
Compound 7f has high potency against all fungi (except Candida albicans) and bacterium species (except Pseudomonas aeruginosa) compared with the reference drug fungicide amphotericin B and the standard bactericides ampicillin and gentamicin. Docking of the most active antibacterial compounds 7f and 7g against the dihydropteroate synthase enzyme gave comparable scores for hydrogen bond interaction (−22.9123, −17.5995 kcal/mol(and binding mode to the reference antibiotic sulfamethoxazole (−13.00 kcal/mol).

Keywords: 1-benzosuberone, hydrazonoyl halides, microwave irradiation, regioselectivity, spiropyrazoles


How to cite this article:
El-Hag FA, Elrashedy AA. Synthesis and antimicrobial activity of substituted 1,4-bis-spiro[benzocycloheptene-6(5h),3′(3h-pyrazol)-5-one]-benzene under microwave irradiation and molecular docking study. Egypt Pharmaceut J 2017;16:71-7

How to cite this URL:
El-Hag FA, Elrashedy AA. Synthesis and antimicrobial activity of substituted 1,4-bis-spiro[benzocycloheptene-6(5h),3′(3h-pyrazol)-5-one]-benzene under microwave irradiation and molecular docking study. Egypt Pharmaceut J [serial online] 2017 [cited 2017 Sep 20];16:71-7. Available from: http://www.epj.eg.net/text.asp?2017/16/2/71/214206


  Introduction Top


Spiropyrazole derivatives belong to one of the most bioactive spiro compounds as some derivatives show antibacterial [1],[2], antifungal [3], anti-inflammatory [4],[5], analgesic [6], and herbicide activities [7]. Moreover, microwave as an energy source enhances the reaction rates and improves the regioselectivity [8],[9],[10],[11]. One of the most important methods to synthesize spiropyrazoles is 1,3-dipolar cycloaddition of the nitrilimines (generated in situ from the corresponding hydrazonoyl halides) to the exocyclic double bond [12],[13],[14],[15]. Moreover, bi-pyrazole derivatives show a wide range of antitumor [16], anti-inflammatory [17], cytotoxic [18],[19], antiallergic [20], cardiovascular [21], and diuretic [22] activities. From the above observation, the present work deals with the reaction of nitrilimines (5) (generated in situ from the corresponding hydrazonoyl halides) with 6,6′-(1,4-phenylene-bis(methanylylidene))-bis(6, 7, 8, 9-tetrahydro-5H-benzo[7]annulen-5-one) (3) under microwave irradiation to synthesize spiro[benzo[7]annulene-6,3′-pyrazol]-4′-yl-phenyl-spiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-ones.


  Materials and methods Top


Chemistry

Melting points were measured with an IA 9000-series digital melting-point apparatus (Bibby Sci. Lim. Stone, Staffordshire, UK). IR spectra were recorded in potassium bromide discs on FTIR 8101 PC infrared spectrophotometers (Shimadzu, Tokyo, Japan). NMR spectra were recorded on a Mercury VX-300 NMR spectrometer (Varian, Inc., Karlsruhe, Germany) operating at 300 MHz (1H-NMR) and run in deuterated dimethylsulfoxide (DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCeMS-QP1000 EX mass spectrometer (Tokyo, Japan) at 70 eV. Elemental analyses were measured using an ElementarVario LIII CHNS analyzer (elementar Analysensysteme GmbH, Hanau, Germany). Micro wave was carried out in an ElmaRD-7700 apparatus (Singen, German). Antimicrobial activity was evaluated by the (Elementar Analysen system Gmb H, Hanau , Germany) Regional Center for Mycology and Biotechnology, Al-Azhar University (Cairo, Egypt). Hydrazonoyl halides (4) were prepared as previously reported in the literature [23],[24].

Synthesis of 6,6′-(1,4-phenylene-bis(methanylylidene))bis(6, 7, 8, 9-tetrahydro-5H-benzo[7]annulen-5-one) (3)

A mixture of 1-benzosuberone (1) (1.6 g, 10 mmol) and terephthalaldehyde (2) (5 mmol) in absolute ethanol (25 ml) in the presence of KOH (1 g) was refluxed under pressurized microwave irradiation for 5 min. The separated solid was collected and crystallized from dimethylformamide to give compound 3 as white crystals; 85% yield; melting point (m.p.) 260262°C (DMF/ethanol); IR υmax 1693(CO)/cm; 1H NMR (DMSO-d6) 1.08–3.10 (m, 12H, 6CH2), 7.09–7.70 (m, 12H, Ar-H), 7.85 (s, 2H, olefinic CH); MS m/z (%) 419 (M+, +1, 26), 418 (M+, 88), 417 (62), 298 (100), 260 (86), 131 (48), 128 (38), 103 (52), 91 (49), 90 (39), 77 (43). Anal. calcd. for C30H26O2 (418.54): C, 86.09; H, 6.26. Found: C, 86.23; H, 6.12.

Reaction of 1,4-bis[2-(3,4-dihydro-(2H)-1-oxo-naphthalenyl)methylene]benzene 3 with hydrazonoyl halides (4)

A mixture of 3 (2.5 mmol) and the appropriate hydrazonoyl halide 4a–g (5 mmol) in dry benzene (30 ml) containing triethylamine (7.5 mmol) was irradiated in a pressurized microwave (17.2 bar, 140°C) at a power of 300 W for 15–30 min as evidenced by TLC. The reaction mixture was filtered when hot to remove the triethylamine hydrochloride, and then concentrated to 10 ml and cooled overnight. The separated solid was collected and crystallized from the suitable solvent to afford the corresponding products 7a–g.

4′-(4-(5-Oxo-2′,5′-diphenyl-2′,4′, 5, 7, 8, 9-hexahydrospiro[benzo[7]annulene-6,3′-pyrazol]-4′-yl)phenyl)-2′,5′-diphenyl-2′,4′, 8, 9-tetrahydrospiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-one (7a)

Yellow solid; yield 74%; m.p. 150–152°C (ethanol); IR υmax 1678(CO)/cm; 1H NMR (DMSO-d6) 1.17–2.86 (m, 12H, 6CH2), 5.33 (s, 2H, 2-pyrazole-H), 6.94–7.70 (m, 32H, Ar-H); MS m/z (%) 807 (M+, +1, 17), 806 (M+, 17), 613 (35), 493 (59), 167 (45), 131 (38), 91 (100), 84 (52), 77 (86). Anal. calcd. for C56H46N4O2 (806.36): C, 83.35; H, 5.75; N, 6.94. Found: C, 83.23; H, 5.56; N, 6.73.

2′-(4-Nitrophenyl)-4′-(4-(2′-(4-nitrophenyl)-5-oxo-5′-phenyl-2′,4′, 5, 7, 8, 9-hexahydrospiro[benzo[7]annulene-6,3′-pyrazol]-4′-yl)phenyl)-5′-phenyl-2′,4′, 8, 9-tetrahydrospiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-one (7b)

Yellow solid; yield 55%; m.p. 214–216°C (dioxane); IR υmax 1698(CO)/cm; 1H NMR (DMSO-d6) 1.18–2.88 (m, 12H, 6CH2), 4.75 (s, 2H, 2-pyrazole-H), 6.78–7.69 (m, 30H, Ar-H). Anal. calcd. for C56H44N6O6 (896.33): C, 74.98; H, 4.94; N, 9.37. Found: C, 74.70; H, 4.76; N, 9.21.

4′-(4-(5-Oxo-2′-phenyl-5′-((E)-styryl)-2′,4′, 5, 7, 8, 9-hexahydrospiro[benzo[7]annulene-6,3′-pyrazol]-4′-yl)phenyl)-2′-phenyl-5′-((E)-styryl)-2′,4′, 8, 9-tetrahydrospiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-one (7c)

Yellow solid; yield 64%; m.p. 222–224°C (dioxane/ethanol); IR υmax 1711(CO)/cm; 1H NMR (DMSO-d6) 0.97–2.83 (m, 12H, 6CH2), 5.18 (s, 2H, 2-pyrazole-H), 6.60–7.64 (m, 36H, Ar-H, 4CH); MS m/z (%) 859 (M+, +1, 14), 858 (M+, 12), 418 (52), 299 (100), 260 (50), 247 (36), 141 (36), 131 (48), 128 (50), 115 (57), 103 (71) 90 (41), 89 (29), 77 (31). Anal. calcd. for C60H50N4O2 (858.39): C, 83.89; H, 5.87; N, 6.52. Found: C, 83.65; H, 5.71; N, 6.40.

2′-(4-Nitrophenyl)-4′-(4-(2′-(4-nitrophenyl)-5-oxo-5′-(thiophen-2-yl)-2′,4′, 5, 7, 8, 9-hexahydrospiro[benzo[7]annulene-6,3′-pyrazol]-4′-yl)phenyl)-5′-(thiophen-2-yl)-2′,4′, 8, 9-tetrahydrospiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-one (7d)

Yellow solid; yield 54%; m.p. 200–202°C (ethanol), IR υmax 1688(CO)/cm;1H NMR (DMSO-d6) 1.08–2.98 (m, 12H, 6CH2), 5.34 (s, 2H, 2-pyrazole-H), 6.97–7.66 (m, 26H, Ar-H); MS m/z (%) 908 (M+, 2), 568 (15), 298 (39), 169 (33), 148 (85), 122 (73), 121 (39), 119 (30), 105 (88), 103 (73), 91 (61), 77 (73), 55 (100). Anal. calcd. for C52H40N6O6S2 (908.25): C, 68.71; H, 4.44; N, 9.25. Found: C, 68.54; H, 4.65; N, 9.18.

5′-(4-Chlorophenyl)-4′-(4-(5′-(4-chlorophenyl)-5-oxo-2′-phenyl-2′,4′, 5, 7, 8, 9-hexahydrospiro[benzo[7]annulene-6,3′-pyrazol]-4′-yl)phenyl)-2′-phenyl-2′,4′, 8, 9-tetrahydrospiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-one (7e)

Dark yellow solid; yield 69%; m.p.: 124–126°C (ethanol); IR υmax 1681(CO)/cm; 1H NMR (DMSO-d6) 1.05–2.90 (m, 12H, 6CH2), 5.34 (s, 2H, 2-pyrazole-H), 6.94–7.56 (m, 30H, Ar-H); MS m/z (%) 878 (M+, +4, 29), 877 (M+, +3, 54), 876 (M+, +2,42), 756 (42), 437 (33), 312 (58), 144 (42), 121 (42), 111 (33), 105 (50), 91 (67), 77 (100). Anal. calcd. for C56H44Cl2N4O2 (875.89): C, 76.79; H, 5.06; N, 6.40. Found: C, 76.58; H, 5.06; N, 6.40%.

5′-(Ethoxycarbonyl)-4′-(4-(5′-(ethoxycarbonyl)-5-oxo-2′-phenyl-2′,4′, 5, 7, 8, 9-hexahydrospiro[benzo[7]annulene-6,3′-pyrazol]-4′-yl)phenyl)-2′-phenyl-2′,4′, 8, 9-tetrahydrospiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-one (7f)

Dark orange solid; yield 64%; m.p. 210–212°C (ethanol); IR υmax 1693, 1666(2CO)/cm; 1H NMR (DMSO-d6) 1.0 (t, 6H, 2CH3), 1.08–3.09 (m, 12H, 6CH2), 4.12 (q, 4H, 2CH2), 4.85 (s, 2H, 2-pyrazole-H), 7.12–7.70 (m, 22H, Ar-H); MS m/z (%) 798 (M+, 25), 797 (15), 299 (40), 260 (35), 132 (55), 104 (70), 91 (60), 90 (45), 77 (90), 55 (100). Anal. calcd. for C50H46N4O6 (798.34): C, 75.17; H, 5.80; N, 7.01. Found: C, 75.03; H, 5.65; N, 7.23.

5′-(Ethoxycarbonyl)-4′-(4-(5′-(ethoxycarbonyl)-5-oxo-2′-(4-bromophenyl)-2′,4′, 5, 7, 8, 9-hexahydrospiro[benzo[7]annulene-6,3′-pyrazol]-4′-yl)phenyl)-2′-(4-bromo-phenyl)-2′,4′, 8, 9-tetrahydrospiro[benzo[7]annulene-6,3′-pyrazol]-5(7H)-one (7g)

Brown solid, yield 68%; m.p. 82–84°C (dioxane/ethanol); IR υmax 1732, 1699(2CO)/cm; 1H NMR (DMSO-d6) 1.01 (t, 6H, 2CH3), 1.18–3.09 (m, 12H, 6CH2), 4.15 (q, 4H, 2CH2), 4.85 (s, 2H, 2-pyrazole-H), 7.09–7.72 (m, 20H, Ar-H); MS m/z (%) 953 (M+, −1, 5), 952 (7), 454 (10), 439 (10), 316 (14), 284 (14), 239 (14), 186 (13), 156 (16), 129 (25), 98 (29), 97 (31), 91 (22), 85 (33), 77 (20), 57 (100). Anal. calcd. for C50H44Br2N4O6 (954.16): C, 62.77; H, 4.64; N, 5.86. Found: C, 62.54; H, 4.56; N, 5.71.

Antimicrobial activity

Agar diffusion well method to determine the antimicrobial activity

The microorganism inoculums were uniformly spread using a sterile cotton swab on a sterile Petri dish malt extract agar (for fungi) and nutrient agar (for bacteria). One hundred milliliter of each sample was added to each well (6-mm diameter holes cut in the agar gel, 20-mm agar from one another). The systems were incubated for 24–48 h at 37°C (for bacteria) and at 28°C (for fungi). After incubation, the growth of microorganisms was observed. Inhibition of bacterial and fungal growth was measured in millimeter. Tests were performed in triplicate [25],[26].

Determination of minimum inhibitory concentration

The minimum inhibitory concentration (MIC) of the samples was estimated for each tested organism in triplicate using concentrations of the samples (1000–0.007 μg/ml). Nutrient broth was added followed by a loopful of the test organism previously diluted to 0.5, and McFarland turbidity standard was introduced to the tubes. A tube containing only broth media was seeded with the test organism to serve as control. Tubes containing tested organism cultures were then incubated at 37°C for 24 h, whereas the other fungal cultures were incubated at 25–30°C for 48 h. Microbial growth was indicated by the presence of turbidity of the well. The lowest concentration showing no growth was taken as the MIC [27].


  Results and discussion Top


Chemistry

6,6′-(1,4-Phenylene-bis(methanylylidene))-bis(6, 7, 8, 9-tetrahydro-5H-benzo[7]annulen-5-one) (3) was prepared from condensation of two mole equivalents of benzosuberone (1) with terephthalaldehyde (2) in ethanolic potassium hydroxide solution under microwave irradiation for 5 min (Scheme 1). The 1H NMR spectrum of compound 3 showed one singlet signal at 7.85 ppm due to olefinic protons. Moreover, the mass spectrum of compound 3 showed the expected molecular ion peak at 418 (88%). The IR spectrum of the isolated product 3 revealed the carbonyl absorption bands at υ 1693/cm.



We were interested here to investigate the reaction of nitrilimines with the bis(aryledine) derivative 3 under microwave irradiation. Reaction of 3 with nitrilimines (5) [generated in situ through triethylamine dehydrohalogenation of the corresponding hydrazonoyl halides (4)] in 1 : 2 molar ratio in dry benzene under microwave irradiation for 15–30 min gave the dicyclo adduct 7 rather than 6 or 8. The IR spectra of the isolated products 7 revealed the carbonyl absorption bands in the region υ 1711–1666/cm. The appearance of one singlet signal in 1H NMR spectra at δ=5.34–4.75 assignable to the pyrazole H-4 ruled out the formation of the isomeric dicyclo adduct 6 or 8 (Scheme 2) [28],[29].



Antimicrobial activity

Screening of the newly synthesized products 7a–g was carried out using four fungal strains − namely, Aspergillus fumigatus, Penicillium italicum, Candida albicans, and Geotrichum candidum − and four bacteria species, including Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and Gram-negative bacteria, Pseudomonas aeruginosa and Escherichia coli. The results in [Table 1] indicate that compound 7f has high potency against all fungi (except C. albicans) and bacterium species (except P. aeruginosa) compared with the reference fungicide amphotericin B and the standard bactericides ampicillin and gentamicin. In addition, compounds 7g, 7d, 7c, and 7e showed significant activities against all tested microorganisms (except C. albicans and P. aeruginosa), whereas the compounds 7a and 7b have moderate activity against the same microorganisms ([Table 1]). Moreover, it was found that compound 7f exhibited the MIC against all tested microorganisms, especially fungus A. fumigatus and P. italicum (MIC=0.9 and 3.9 μg/ml, respectively) ([Table 2]). This is may be due to the presence of the ethoxycarbonyl group (COOEt) and the Ph group. Moreover, we note that compound 7g showed less activity compared with 7f. This may be related to the presence of bromine in p-position of the phenyl group.
Table 1: Preliminary antimicrobial activity of the tested compounds 7a–g

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Table 2: Minimum inhibitory concentration (μg/ml) of the most active compounds

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Molecular docking study

Drug resistance is one of the most common problems that decreases the clinical utility of virtually all marketed antibacterial agents [30]. Unfortunately, sulfonamide class was one victim of this phenomenon [31],[32]. Sulfonamide class (sulfa drugs) works by targeting the dihydropteroate synthase (DHPS) essential in the folate pathway in bacteria, which catalyzes the condensation of 6-hydroxymethyl-7,8-dihydropterin-pyrophosphate (DHPP) with p-aminobenzoic acid in the production of the folate intermediate, 7,8-dihydropteroate [33]. Sulfa drugs can target both Gram-positive and Gram-negative infection. However, resistance mutations have severely compromised the usefulness of these drugs [31]. Thus, searching for new drugs became important. The molecular docking study is performed and analyzed with the molecular modeling environment (MOE) program. The actively synthesized compounds 7f and 7g are enquired for the binding affinity of the DHPS enzyme receptor [protein data bank (PDB) code: 3TZF] [34] for the purpose of lead optimization; to study the interaction between compounds 7f and 7g and the DHPS receptor, docking calculations were carried out using standard default variables for the MOE program. The binding affinity was evaluated from the binding free energies (S-score, kcal/mol), hydrogen bonds, and root mean square deviation values. Compounds 7f and 7g were docked into the comparable groove of the binding site of the native cocrystallize ligand. Scoring in MOE software was carried out using the London dG scoring function and enhanced using two different refinement methods; the force-field and grid-min poses were updated to ensure that refined poses satisfy the specified conformations. Rotatable bonds were allowed; the best 10 poses were retained and analyzed for the binding pose’s best score. Energy was minimized through force-field MMFF94 optimization with a gradient of 0.0001 for determining low-energy conformations with the most favorable geometry (lowest energy). The crystal structures of DHPS enzyme receptor in complex with sulfamethoxazole ligand were obtained from the PDB (http://www.rcsb.org/pdb/explore.do?structureId=3TZF; PDB code: 3TZF). Partial charges and hydrogen atoms were added to the protein to assign ionization states and position of hydrogen atoms in the macromolecular structure using protonation 3D application in MOE ([Figure 1],[Figure 2],[Figure 3]).
Figure 1: The ligand interaction and the binding mode of the native ligand sulfamethaxazole (O8D) showed one H-bond donor with HOH 333 with a distance of 2.76 (black color); it bonded with one H-bond acceptor with SER 222 at a distance of 2.9 (blue color) and one H-bond acceptor with HOH 289 (black color) depicted as hatched line. It gave a score of −13.0424.

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Figure 2: The ligand interaction and the binding mode of the compound 7f. It binds with one H-bond acceptor with ASN 180 at a distance of 2.57. It gives a score of −22.9123 kcal/mol greater than that of the cocrystallized ligand.

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Figure 3: The ligand interaction and the binding mode of the compound 7g. It binds with one H-bond acceptor with ASN 180 at a distance of 2.46. It gave a score of −17.5995 kcal/mol greater than that of the cocrystallized ligand.

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  Conclusion Top


6,6′-(1,4-Phenylene-bis(methanylylidene))-bis(6, 7, 8, 9-tetrahydro-5H-benzo[7]annulen-5-one) (3) was prepared. Reaction of 3 with nitrilimines (5) [generated in situ through triethylamine dehydrohalogenation of the appropriate hydrazonoyl halides (4)] in 1 : 2 molar ratio in dry benzene under microwave irradiation for 15–30 min gave dicyclo adduct 7 rather than 6 or 8. The structure of all compounds was established based on spectral data and elemental analysis. Compounds 7g, 7d, 7c, and 7e showed significant activities against all tested microorganisms (except C. albicans and P. aeruginosa), whereas other compounds 7a and 7b have moderate activity against the same microorganisms. It was found that compound 7f exhibits the MIC against all tested microorganisms, especially fungus A. fumigatus and P. italicum (MIC=0.9 and 3.9 μg/ml, respectively). This may be due to the presence of the ethyl carboxylate group (COOEt) and the Ph group. We also noted that compound 7g shows less activity compared with 7f, which may be related to the presence of bromine in p-position of the phenyl group. Docking of the most active antibacterial compounds 7f and 7g against the dihydroperorate synthase enzyme gave comparable scores for hydrogen bond interaction (−22.9123, −17.5995 kcal/mol(and binding mode to the reference antibiotic sulfamethoxazole (−13.0424 kcal/mol).

Acknowledgements

The authors are grateful to Microanalatical Center, Faculty of Science, Cairo University, Egypt, for carrying out elemental analysis, IR, 1H NMR, and mass spectra.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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