{Microwave-assisted synthesis and antimicrobial evaluation of 6-(3'-(aryl)-1'-phenyl-3,4-dihydro-1'h,2H-[3,4'-bipyra- zol]-5-yl)-2H-chromen-5-ols} J. Serb. Chem. Soc. 84 (3) 237–244 (2019) UDC 547.772.2+537.5–962:615.28 JSCS–5179 Original scientific paper 237 Microwave-assisted synthesis and antimicrobial evaluation of 6-[3-aryl-1-phenyl-4′,5′-dihydro[4,5′-bi-1H-pyrazol]-3′-yl]- -2H-chromen-5-ols DONGAMANTI ASHOK1*, RANGU KAVITHA1, SRINIVAS GUNDU1 and MADDERLA SARASIJA2 1Green and Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad- 500 007, India and 2Department of Chemistry, Satavahana University, Karimnagar- 505001, India (Received 6 December 2017, revised 7 December, accepted 21 December 2018) Abstract: A new series of 6-[3-aryl-1-phenyl-4′,5′-dihydro[4,5′-bi-1H-pyrazol]-3′- -yl]-2H-chromen-5-ol derivatives was synthesized by Michael addition of chal- cones 5a–j with hydrazine hydrate in presence of sodium acetate under con- ventional heating and microwave irradiation. Structural assignment of the products was confirmed based on IR, 1H-NMR, 13C-NMR, MS and analytical data. All the synthesized compounds 6a–j were screened for their antimicrobial activity against various bacterial and fungal strains. Most of the compounds exhibited variable range of antimicrobial activity and compounds 6c–f and 6i showed promising antimicrobial potency. Keywords: pyrazole; pyrazoline; microwave irradiation; antimicrobial activity. INTRODUCTION Heterocyclic compounds containing nitrogen and oxygen play important roles in agrochemical and pharmaceuticals. Heterocyclic compounds have great applicability in pharmaceutics because they have specific chemical reactivity and provide false synthons in biosynthetic processes or block the normal functioning of biological receptors. The interesting biological activities of heterocycles have stimulated considerable research work in recent years, including the synthetic utility. Pyrazoles, an important member of heterocyclic compounds, are widely found as the core structure in a large variety of compounds that possess important agrochemical and pharmaceutical activities. Many pyrazole derivatives are rep- orted to have a broad spectrum of biological activities, such as anti-inflammat- ory,1,2 antifungal,3 herbicidal,4 insecticidal,5 anti-HIV,6 antiviral,7 anticonvul- sant8 and anticancer9 activities. Some of the drugs possessing a pyrazole scaf- *Corresponding author E-mail: ashokdou@gmail.com https://doi.org/10.2298/JSC171206113A 238 ASHOK et al. fold, such as celecoxib,10 rimonabant,11 deracoxib,12 and phenylbutazone, exhi- biting anti-inflammatory, analgesic and antipyretic activities, are already on the market (Fig. 1). Fig. 1. Commercially available pyrazole and pyrazoline drugs. Pyrazolines are partially reduced form of pyrazoles that contain five-mem- bered ring system with two adjacent nitrogens. Pyrazolines are one of the emer- ging classes of compounds associated with a broad spectrum of biological activi- ties. Many compounds bearing pyrazoles and their reduced forms pyrazolines constitute an interesting class of heterocycles due to their synthetic versatility and effective biological activities, such as antiviral,13 anti-inflammatory,14,15 antitub- ercular,16 anti-amoebic,17 analgesic,18 antibacterial,19 analgesic,20 antifungal,21 anti-arthritic,22 cerebroprotective23 and antidepressant24 activities. They are also useful as biodegradable agrochemicals.25 A literature survey revealed several synthetic protocols for the synthesis of these compounds and the presence of this core in any molecule plays a key role in enhancing activity. Prompted by the above-mentioned biological properties of pyrazole and pyrazoline incorporated heterocycles, it was contemplated to syn- thesize a novel series of pyrazole–chromene containing pyrazolines. In continuat- ion to ongoing research, herein, the synthesis of 6-[3-aryl-1-phenyl-4′,5′- -dihydro[4,5′-bi-1H-pyrazol]-3′-yl]-2H-chromen-5-ol derivatives in excellent yields is reported. EXPERIMENTAL Materials All used materials were obtained commercially, mostly from Sigma–Aldrich, and were used without further purification. Equipment All the microwave irradiation experiments were performed in a CEM Discover micro- wave system equipped with an IR sensor, with which the reaction temperatures were moni- tored. All the reactions were monitored on silica gel percolated TLC plates, 60 F254 from Merck and the spots were visualized with UV light. Melting points were determined by the open capillary method and are uncorrected. The 1H-NMR and 13C-NMR spectra were run on a Bruker Avance-400 spectrometer at 400 and 100 MHz, respectively, using tetramethylsilane (TMS) as an internal reference. Mass spectra were recorded on a Shimadzu LCMS 2020 mass spectrometer. Elemental microanalysis was performed on a Perkin Elmer CHN-2400 analyzer. SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF BIPYRAZOLYL CHROMEN-5-OLS 239 Spectral and analytical data of the synthesized compounds are given in Supplementary mat- erial to this paper. General procedure for the synthesis of 6-[3-aryl-1-phenyl-4′,5′-dihydro[4,5′-bi-1H-pyrazol]-3′- -yl]-2H-chromen-5-ol derivatives (6a–j) Conventional heating method. To a solution of 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1- (5-hydroxy-2H-chromen-6-yl)prop-2-en-1-ones 5a–j (0.23 mmol) in DMF (5 mL) containing sodium acetate (0.23 mmol) and hydrazine hydrate (0.23 mmol), few drops of acetic acid was added and the reaction mixture heated at 80–90 °C for 1–3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, ice-cold water was added. The solid product that separated was filtered, washed with water and dried. Recrystallisation from MeOH:CHCl3 (1:1) afforded 6-[3-aryl-1-phenyl-4′,5′-dihydro[4,5′-bi-1H-pyrazol]-3′-yl]-2H- -chromen-5-ols 6a–j. Yield: 57–62 %. Microwave irradiation method. A mixture of 3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-(5- -hydroxy-2H-chromen-6-yl)prop-2-en-1-ones 5a–j (0.23 mmol), hydrazine hydrate (0.23 mmol), sodium acetate (0.23 mmol) and few drops of acetic acid in DMF (2 mL) was taken in a glass vessel and then placed into a teflon vial with screw cap and the mixture was subjected to microwave irradiation at 100 W for 1–3 min. After completion of the reaction, indicated by TLC, the vial was cooled and the reaction mixture was poured into ice cold water. The solid product that separated was filtered, washed with water and dried. Recrystallisation from MeOH:CHCl3 (1:1) furnished 6-[3-aryl-1-phenyl-4′,5′-dihydro[4,5′-bi-1H-pyrazol]-3′-yl]-2H- -chromen-5-ol derivatives 6a–j. Yield: 86–96 %. Biological assays Antibacterial activity. The synthesized novel compounds 6a–j were screened for their antibacterial activity against different types of bacterial strains, viz. Gram-positive bacterial strains Staphylococcus aureus and Bacillus subtilis, and Gram-negative bacterial strains Escherichia coli and Proteus vulgaris at concentrations of 10 and 20 μg mL-1. The cultures were diluted with 5 % saline, autoclaved, and the final volume was made with a concentration approximately 105–106 CFU mL-1. The synthesized compounds were diluted in acetone for the antibacterial biological assays. For agar disk diffusion method,26 the solution form of a test compound was allowed to air-dry, such that the disk became completely saturated with the test compound. The saturated chemical disks were introduced onto the upper layer of the medium evenly floated with the bacteria. The disks were dipped in different chemical samples and placed over the evenly spread bacterial nutrient media and incubated at 37 °C for 24–48 h for better inhibition of the bacteria. The zones of inhibition were measured after 24–48 h. All the experiments were performed in triplicate, and the results are expressed as zone of inhi- bition in mm. The zones of inhibition of synthesized compounds were compared with the zone of inhibition of the standard antibiotic gatifloxacin at concentrations of 10 and 20 μg mL-1. Antifungal activity. The antifungal activities of the synthesized compounds 6a–j were tested against three pathogenic fungi, namely Fusarium oxysporum, Aspergillus niger and A. flavus by the poison plate technique at a concentration of 100 μg/mL. Three kinds of fungi were incubated in potato dextrose agar (PDA) at 25±1 °C for 5 days to obtain new mycelium for the antifungal assay; then the mycelia as disks of approximately 0.45 cm diameter cut from the culture medium were picked up with a sterilized inoculation needle and inoculated in the centre of a PDA plate. The test compounds were dissolved in acetone (10 mL) and then added to the potato dextrose agar medium (PDA, 90 mL). The final concentration of the compounds in the medium was adjusted to 100 μg mL-1. The inoculated plates were incubated at 25±1 °C for 5 240 ASHOK et al. days. Acetone was diluted with sterilized distilled water and used as the control, while clotri- mazole (100 μg mL-1) was used as the standard. For each treatment, three replicates of the expe- riments were performed. The radial growth of the fungal colonies was measured on the sixth day. RESULTS AND DISCUSSION The synthetic route for 6-[3-aryl-1-phenyl-4′,5′-dihydro[4,5′-bi-1H-pyrazol]- -3′-yl]-2H-chromen-5-ols is illustrated in Schemes 1 and 2. The synthesis of title compounds involved the preliminary preparation of 1-(5-hydroxy-2H-chromen- -6-yl)ethanone (3). Starting from resacetophenone (1) upon treating with pro- pargyl bromide in the presence of anhydrous K2CO3 in dry acetone yielded 1-(2- -hydroxy-4-(prop-2-yn-1-yloxy)phenyl)ethanone (2), which was further refluxed in N,N-dimethylaniline at 180 °C for 3 h to give compound 327 (Scheme 1). Clai- sen–Schmidt condensation between 1-(5-hydroxy-2H-chromen-6-yl)ethanone (3) and substituted pyrazole aldehydes (4a–j) in the presence of powdered KOH under microwave irradiation for 4–7 min (Scheme 2) gave 3-(3-aryl-1-phenyl-1H- -pyrazol-4-yl)-1-(5-hydroxy-2H-chromen-6-yl)prop-2-en-1-ones27 5a–j. These chal- cones were then cyclised by means of hydrazine hydrate and few drops of glacial acetic acid under conventional heating and microwave irradiation to furnish the title compounds 6a–j in excellent yields. Scheme 1. Synthesis of 1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)ethanone (3). Scheme 2. Synthesis of 6-[3-aryl-1-phenyl-4′,5′-dihydro[4,5′-bi-1H-pyrazol]-3′-yl]-2H- -chromen-5-ols (6a–j). Preliminarily, the synthesis of compounds 6a–j was carried out under con- ventional heating method, but this method suffered from poor yields (57–62 %). SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF BIPYRAZOLYL CHROMEN-5-OLS 241 In order to improve the yields and reduce the reaction time, the synthesis approach was changed to the microwave irradiation method. Microwave-assisted synthesis of title compounds 6a–j is advantageous over conventional method in terms of higher yields in shorter reaction times. A comparison of the yields of the title compounds prepared by the conventional and microwave irradiation methods is demonstrated in Table I. TABLE I. Comparison of yields (isolated) of compounds 6a–j under different synthetic con- ditions Compound Melting point, °C Conventional MWI Time, h Yield, %a Time, min Yield, %a 6 a 98–100 2 61 1 95 6 b 102–104 2 59 1 93 6 c 101–103 2 60 1 94 6 d 94–96 2 60 1 96 6 e 104–106 2 58 2 86 6 f 99–101 2 62 2 96 6 g 108–110 1 62 1 96 6 h 103–105 2 60 2 92 6 i 90–92 2 60 2 90 6 j 136–138 2 57 2 89 aIsolated yields Formation of the 6-[3-aryl-1-phenyl-4′,5′-dihydro[4,5′-bi-1H-pyrazol]-3′-yl]- -2H-chromen-5-ols (6a–j) were confirmed by IR, 1H-NMR, 13C-NMR, MS and elemental analyses. The IR spectrum of compound 6h showed absorption bands at 3464, 3268 and 1596 cm–1 due to OH, NH and C=N groups, respectively. The 1H-NMR spectrum of 6h displayed two characteristic signals due to the dias- tereotopic protons (HA, HB). The HA proton, which is cis to HX resonated upfield at δ 3.09 ppm as a doublet of doublets (dd) with J values of 8.87 and 16.24 Hz, while the HB proton which is trans to HX resonated downfield at δ 3.48 ppm (dd) with J values 10.19, 16.24 Hz. The HX proton which is vicinal to two methylene protons (HA and HB) was observed as doublet of doublets (dd) at δ 5.08 ppm with J values of of 8.87 and 10.19 Hz. A triplet appeared at δ 1.43 ppm was due to aliphatic CH3 proton and quartet at δ 4.09 ppm due to Ar–O–CH2. The NH pro- ton appeared at δ 5.90 ppm as a broad singlet. The pyrazole proton appeared as a singlet at δ 7.98 ppm and a broad singlet was observed at δ 11.38 ppm due to the OH proton. In the 13C-NMR spectrum of 6h, CH3, pyrazoline-CH2, pyrazoline CH and Ar-OCH2 carbons appeared at δ 14.8, 40.9, 54.1 and 63.5 ppm, respect- ively. The mass spectra of 6h showed the molecular ion peak at m/z 479 [M+H]+. Antimicrobial activity Antibacterial activity. The synthesized compounds were screened in vitro for antibacterial activity against different types of bacterial strains viz. Gram-positive 242 ASHOK et al. bacterial strains Staphylococcus aureus (ATCC 9144) and Bacillus subtilis (ATCC 6633), and Gram-negative bacterial strains Escherichia coli (ATCC 25922) and Proteus vulgaris at concentrations of 10 and 20 μg mL–1. The inhi- bitory efficiency of the synthesized compounds was measured through the zone of inhibition (in mm) compared with the standard drug gatifloxacin and the results are presented in Table II. The study of the antibacterial efficiency of the synthesized compounds revealed that most of the tested compounds displayed variable inhibitory effects on the growth of the tested Gram-positive and Gram- -negative bacterial strains compared to the standard drug gatifloxacin at concen- trations of 10 and 20 μg mL–1. The compounds 6d (Ar = 4-methylphenyl), 6e (Ar = 4-hydroxyphenyl), 6f (Ar = 4-methoxyphenyl) and 6i (Ar = 3,4-dimethoxy- phenyl) showed the equipotent activity through the zone of inhibition (Table II) against S. aureus, B. subtilis, E. coli and P. vulgaris, respectively. Compound 6e exhibited the most potent antibacterial activity against Gram-positive and Gram- -negative bacterial strains. The remaining compounds showed moderate activity compared to the standard. An analysis of the antibacterial activity results indi- cated that compound with electron-donating groups, such as methyl, hydroxy and methoxy, on the phenyl ring were more potent as compared to the control drug gatifloxacin. TABLE II. Antimicrobial activity of synthesized compounds (zone of inhibition, mm) Compound Gram-positive bacteria Gram-negative bacteria Fungal strains S. aureus B. subtilis E. coli P. vulgaris A. flavus A. niger F. oxysporum 6a 15a 26 12 22 12 19 09 12 13.3 13.6 13.9 6b 15 25 15 25 13 17 08 14 11.5 14.1 12.4 6c 13 23 14 21 10 16 09 11 17.2 17.5 18.1 6d 19 31 18 35 16 23 10 17 12.9 14.1 15.6 6e 21 34 19 36 18 25 11 18 08.7 13.4 15.3 6f 20 32 18 33 16 23 11 17 16.9 15.2 17.7 6g 17 28 16 30 16 20 10 16 15.1 14.7 16.1 6h 13 21 10 23 12 17 08 12 14.4 12.1 15.7 6i 21 33 19 34 17 25 11 16 17.0 17.3 18.0 6j 14 21 10 19 09 16 08 12 12.4 13.1 13.7 Gatifloxacin 21 33 20 36 18 25 12 18 – – – Clotrimazole – – – – – – – – 17.3 17.7 18.4 Antifungal activity The antifungal activity of the synthesized compounds was tested against three pathogenic fungi, viz. Aspergillus flavus, A. niger (ATCC 9029) and Fusarium oxysporum by the poison plate technique at a concentration of 100 μg mL–1. Most of the synthesized compounds showed promising antifungal activity com- pared to standard drug clotrimazole (Table II). The compounds 6c, 6f and 6i SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF BIPYRAZOLYL CHROMEN-5-OLS 243 showed equipotent inhibition compared to the standard drug against the tested fungi, whereas the remaining compounds showed moderate activity against the pathogenic fungi. CONCLUSION In summary, a new series of compounds 6a–j was synthesized under con- ventional and microwave irradiation conditions. Using the microwave irradiation method, the reactions were completed in short reaction times under mild reaction conditions, in high yields and convenient operation. All the titled compounds were screened for their in vitro antimicrobial activity. Compound 6e was found to be the most potent and compounds 6d, 6f and 6i were found to be equipotent compared to the standard drug gatifloxacin against the pathogenic bacteria whereas compounds 6c, 6f and 6i exhibited potent activity against the pathogenic fungi compared to the standard drug clotrimazole at their respective concentra- tions. The antifungal screening results revealed that compounds 6f and 6i could be considered as promising antifungal drug candidates. SUPPLEMENTARY MATERIAL Spectral and analytical data of the synthesized compounds are available electronically at the pages of journal website: http://www.shd.org.rs/JSCS/, or from the corresponding author on request. Acknowledgement. The authors are thankful to The Head of Department of Chemistry, Osmania University, for providing laboratory facilities and the Director of Central Facilities for Research and Development (CFRD), Osmania University, for providing IR and NMR spec- tral analysis. Financial support from UGC, New Delhi, India, for RK is gratefully acknowledged. И З В О Д СИНТЕЗА УПОТРЕБОМ МИКРОТАЛАСА И ИСПИТИВАЊЕ АНТИМИКРОБНЕ АКТИВНОСТИ СЕРИЈЕ 6-[3-АРИЛ-1-ФЕНИЛ-[4,5′-БИ-1H-ПИРАЗОЛ]-3′-ИЛ]ДИХИДРО- -2H-ХРОМЕН-5-ОЛА DONGAMANTI ASHOK1, RANGU KAVITHA1, SRINIVAS GUNDU1 и MADDERLA SARASIJA2 1Green and Medicinal Chemistry Laboratory, Department of Chemistry, Osmania University, Hyderabad 500 007, India и 2Department of Chemistry, Satavahana University, Karimnagar-505001, India Синтетисана је серија деривата 6-[3-арил-1-фенил-[4,5′-би-1H-пиразол]-3′-ил]дихидро- -2H-хромен-5-ола применом реакције Мајклове адиције чалкона (5a–j) и хидразин-хидрата уз присуство натријум-ацетата, под условима традиционалног загревања и применом микроталасног зрачења. Структура добијених једињења одређена је на основу IR, 1H-NMR, 13C-NMR, MS и аналитичких података. Испитана је антимикробна активност свих синте- тисаних једињења 6a–j према различитим сојевима бактерија и гљива. 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Res. 25 (2016) 501. << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /None /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Error /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /CMYK /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness true /PreserveHalftoneInfo false /PreserveOPIComments true /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages true /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ARA /BGR /CHS /CHT /CZE /DAN /DEU /ESP /ETI /FRA /GRE /HEB /HRV (Za stvaranje Adobe PDF dokumenata najpogodnijih za visokokvalitetni ispis prije tiskanja koristite ove postavke. Stvoreni PDF dokumenti mogu se otvoriti Acrobat i Adobe Reader 5.0 i kasnijim verzijama.) /HUN /ITA /JPN /KOR /LTH /LVI /NLD (Gebruik deze instellingen om Adobe PDF-documenten te maken die zijn geoptimaliseerd voor prepress-afdrukken van hoge kwaliteit. De gemaakte PDF-documenten kunnen worden geopend met Acrobat en Adobe Reader 5.0 en hoger.) /NOR /POL /PTB /RUM /RUS /SKY /SLV /SUO /SVE /TUR /UKR /ENU (Use these settings to create Adobe PDF documents best suited for high-quality prepress printing. Created PDF documents can be opened with Acrobat and Adobe Reader 5.0 and later.) >> /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ << /AsReaderSpreads false /CropImagesToFrames true /ErrorControl /WarnAndContinue /FlattenerIgnoreSpreadOverrides false /IncludeGuidesGrids false /IncludeNonPrinting false /IncludeSlug false /Namespace [ (Adobe) (InDesign) (4.0) ] /OmitPlacedBitmaps false /OmitPlacedEPS false /OmitPlacedPDF false /SimulateOverprint /Legacy >> << /AddBleedMarks false /AddColorBars false /AddCropMarks false /AddPageInfo false /AddRegMarks false /ConvertColors /ConvertToCMYK /DestinationProfileName () /DestinationProfileSelector /DocumentCMYK /Downsample16BitImages true /FlattenerPreset << /PresetSelector /MediumResolution >> /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ] >> setdistillerparams << /HWResolution [2400 2400] /PageSize [612.000 792.000] >> setpagedevice