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This is an early electronic version of an as-received manuscript that has been accepted for publication in the Journal of the Serbian Chemical Society but has not yet been subjected to the editing process and publishing procedure applied by the JSCS Editorial Office. Please cite this article as: C. B. Sangani, N. M. Shah, M. P. Patel, R. G. Patel, J. Serb. Chem. Soc. (2011), doi: 10.2298/JSC120102030S This "raw" version of the manuscript is being provided to the authors and readers for their technical service. It must be stressed that the manuscript still has to be subjected to copyediting, typesetting, English grammar and syntax corrections, professional editing and authors' review of the galley proof before it is published in its final form. Please note that during these publishing processes, many errors may emerge which could affect the final content of the manuscript and all legal disclaimers applied according to the policies of the Journal.

J. Serb. Chem. Soc. 77 (0) 1­17 (2012) JSCS­5283

UDC Original scientific paper

Department of Chemistry, Sardar Patel University, Vallabh vidyanagar-388120, Gujarat, India (Received 2 January, revised 27 March 2012) Abstarct: A new series of 4H-chromene derivatives 4(a-p) bearing 5phenoxypyrazole nucleus has been synthesized under microwave irradiation by reaction of 5-phenoxypyrazole-4-carbaldehyde 1(a-h), malononitrile 2 and compounds (Cyclohexanedione, Dimedon) 3(a-b) in presence of NaOH as basic catalyst. All the compounds were screened against three Gram positive bacteria (Streptococcus pneumoniae, Clostridium tetani, Bacillus subtilis), three Gram negative bacteria (Salmonella typhi, Vibrio cholerae, Escherichia coli) and two fungi (Aspergillus fumigatus, Candida albicans) using broth microdilution MIC (Minimum Inhibitory Concentration) method. Upon study of antimicrobial screening, it has been observed that, majority of the compounds were found to be active against Clostridium tetani and Bacillus subtilis as well as against Candida albicans as compared to standard drugs.

The steadily increasing microbial resistance to existing first line drugs is a serious problem in antimicrobial cure and necessitates continuing research into new classes of antimicrobials1. Moreover, the progression of drug-resistant strains has contributed to the inefficiency of the straight antimicrobial therapy. This issue has an enormous interest in antimicrobial research and we strongly believe that there is an urgent call for development of new drugs with divergent and unique structure and with a probably unusual mechanism of action from that of existing first line drugs. The chromene ring system is considered to be one of the most imperative heterocycle in nature as it has the distinction of being the parent ring in countless derivatives of biological relevance. The current interest in 4H and 2H-chromene derivatives arises from their potential application as antimicrobial2 anti-HIV3, anti

* Corresponding author. E-mail: [email protected] doi: 10.2298/JSC120102030S

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Keywords: phenoxypyrazole; 4H-chromene; microwave irradiation; antimicrobial activity. INTRODUCTION

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multi-component

CHETAN B. SANGANI, NIMESH M. SHAH, MANISH P. PATEL and RANJAN G. PATEL*

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Microwave assisted synthesis of novel 4H-chromene derivatives bearing phenoxypyrazole and their antimicrobial activity assess

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tubercular4, antioxidant5, anticancer6, antitumor7, cytotoxic agent8, antidyslipidemic agent9, antileishmanial10, anti-inflammatory11, anti-helicobacter pylori agent12 and TNF- inhibitor13. On the other hand, pyrazole derivatives are also known for their well-known biological properties including antimicrobial14-16, anti-inflammatory (COX-2 inhibitor and ulcerogenic activity)15, antitubercular16, antitumor17, antiangiogenesis18, anti-parasitic19, antiviral 20, analgesic and anxiolytic activity21. Moreover, the most suitable protocol for the synthesis of functionalized organic compounds would be a multicomponent reaction due to the fact that the synthesis can be performed without the isolation of the intermediates, without discharging any functional groups and within short reaction time 22. Also the conventional procedures are not found to be satisfactory with regard to operational simplicity, effectiveness and yield. An alternative synthetic approach is microwave irradiation23. In recent years, microwave irradiation has been demonstrated not only to dramatically accelerate many organic reactions, but also to improve yields and selectivity. Thus, in view of biological significance of 4H-chromene, a modification on the 4-position on pyrane by 5-phenoxypyrazole is undertaken to check whether it may bring significant changes in bioactivities of 4H-chromene derivatives. As a part of our current studies in developing new antimicrobial agents via combination of two therapeutically active moieties24, we report herein 4Hchromene 4(a-p) derivatives by MCR. All the compounds were characterized using elemental analysis, FT-IR, 1HNMR, 13C-NMR as well as molecular weight of some selected compounds were confirmed by mass spectroscopy. All compounds were screened for in vitro antimicrobial activity against eight human pathogens, of which three Gram positive bacteria (Streptococcus pneumoniae, Clostridium tetani, Bacillus subtilis), three Gram negative bacteria (Salmonella typhi, Vibrio cholerae, Escherichia coli) and two fungal pathogens (Aspergillus fumigatus, Candida albicans) using broth microdilution MIC (Minimum Inhibitory Concentration) method25.

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The key intermediate, 3-methyl-5-aryloxy-1-arylpyrazole-4-carbaldehyde 1(a-h) was prepared by refluxing 1-Aryl-5-chloro-3-methyl-1H-pyrazole-4carbaldehyde and various phenol in presence of anhydrous potassium carbonate in dry DMF for 3.5 h.26. The required 1-Aryl-5-chloro-3-methyl-1H-pyrazole-4carbaldehyde was prepared by Vilsmeier-Haack reaction according to literature procedure27.

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RESULTS AND DISCUSSION

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In the present study, 4H-chromene derivatives 4(a-p) have been synthesized in moderate to good yield i.e. 68-90% by reaction of 5-aryl-3-carbaldehyde 1(ah), malononitrile 2 and compounds 3(a-b) under microwave irradiation in the presence of NaOH as a basic catalyst (Scheme 1). Convenient electrochemical processes, organic basic catalysts like piperidine and triethylamine have been used in the synthesis of many 4H-chromene derivatives28 but in the present study, we have used NaOH as a basic catalyst to avoid use of hazardous organic bases. Further, we attempted the conventional method for the synthesis of title compounds. However, some shortcomings were observed in this method such as, longer reaction time, drastic reaction conditions and poor yield. Consequently, to overcome these drawbacks, we employed microwave irradiation method for the synthesis of title compounds. In accordance with the mechanism suggested in literature29, the first step of this process may involve Knoevenagel condensation of aldehyde and malononitrile to gives heterylidenenitrile derivatives followed by Michael addition of 3(a-b) to heterylidenenitrile to afford title compounds 4(a-p) (Scheme 2). The structures of all the newly synthesized compounds were confirmed by FTIR, 1H NMR, 13C NMR, mass and elemental analysis. The IR spectrum of title compounds 4(a-p) revealed the presence of amino, cyano, carbonyl and ether groups due to the appearance of absorption bands at around 3370-3430 & 31703350, 2190-2220, 1630-1710 and 1190-1230 cm-1 respectively. Its 1H NMR spectrum indicated the presence of one singlet in the range 4.12-4.38 ppm of CH proton and the disappearance of a singlet from 9.57-9.63 ppm of -CHO clearly confirmed the cyclization of Knoevenagel intermediate. Moreover, multiplets in the range 6.59-7.55 ppm appeared for aromatic protons. In the 13C NMR spectral data of the title compounds 4(a-p), most characteristic signal around 24.50-25.25 ppm indicated the formation of pyrane ring. The signal at around 56.20-60.64 ppm is assigned to carbon attached with carbonitrile while signals around 110.20-164.50 and 196.10-196.35 ppm are attributed to all the aromatic and carbonyl carbons respectively of compounds 4(a-p). The obtained elemental analysis values are in good agreement with theoretical data. Further, the molecular weight of selected compounds such as 4c, 4i and 4o were confirmed by its mass spectral studies. Mass Spectroscopy of above mentioned compounds showed molecular ion peak [M+1]+ corresponding to exact mass. All physical, analytical data as well as spectroscopic characterization data of the synthesized compounds 4(a-p) are given in experimental section. All the compounds were screened for their antibacterial and antifungal activity and results are expressed in the form of MIC g/mL.

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Antimicrobial activity. The examination of the data prescribed in (Table I) reveal that among the present series many of the compounds are more potent or equipotent to the standard drug against the Gram positive bacteria Clostridium tetani and few against Streptococcus pneumoniae and Bacillus subtilis. Against Gram-positive bacteria B. subtilis, compound 4n (MIC=62.5 g/mL) is found to be more potent whereas 4b, 4e, 4i, 4l, and 4p (MIC=250 g/mL) shows comparable activity to Ampicillin (MIC=250 g/mL), while compound 4n (MIC=62.5 µg/mL) have found to more active as compared to norfloxacin (MIC=100 µg/mL). Against C. tetani compounds 4d, 4j, 4n, 4o (MIC = 100 g/mL), 4e, 4f, 4h, 4l (MIC=200 g/mL) are found to be more potent whereas 4g, 4k, and 4p (MIC=250 g/mL) shows comparable activity to Ampicillin (MIC=250 g/mL), while compounds 4d, 4j, 4n, 4o (MIC=100 µg/mL) have found to be equally potent as compared to ciprofloxacin (MIC=100 µg/mL). Against S. pneumonia compounds 4m (MIC=50 g/mL) shows comparable activity to chlormphenicol & ciprofloxacine (MIC=50 µg/mL). Towards Gram-negative strain E. coli compounds 4h, 4i, 4n, and 4p (MIC=100 g/mL) show comparable activity to Ampicillin (MIC=100 g/mL). Compounds 4j, 4n, 4p (MIC=62.5 g/mL) are found to be more potent where as 4i (MIC=100 g/mL) shows comparable activity to Ampicillin (MIC=100 g/mL) towards S. typhi. Also the compounds 4b and 4g (MIC=100 g/mL) show comparable activity, to Ampicillin (MIC=100 g/mL) towards V. cholerae. Comparision of the data of compounds 4a-d with 4e-h it has been observed that replacement of H with CH3 the poorly active compound 4a, 4b and 4c (MIC=500 g/mL) against C. tetani have been converted to highly potent 4e, 4f and 4g respectively compared to the standard drug ampicilin while in one of compound 4d where R2=Cl the compound is found to be active against the C. tetani but with the introduction of CH3 at R1 the activity decreases. Against the B. subtilis it has been observed that comparing compound 4f with 4n the poorly active compound 4f (MIC=500 g/mL) is showing excellent activity 4n (MIC=62.5 g/mL) compared to ampicillin as well as norfloxacin. Similarly against the Gram negative bacteria S. typhi it has been observed that comparing compound 4b with 4j and 4f with 4n the poorly active compounds were converted to highly active (MIC=62.5 g/mL) as compared with ampicillin (MIC=100 g/mL) i.e. compound having gem dimethyl group on the benzopyran ring shows increased antimicrobial activity. Against fungal pathogen C. albicans, compounds 4d (MIC=100 g/mL), 4g (MIC=200 g/mL) 4c, 4e, 4h, 4k, 4l, and 4p (MIC=250 g/mL) show better to excellent activity, where as 4b, 4f, 4i, 4m and 4o (MIC=500 g/mL) are found to be equipotent to Griseofulvin (MIC=500 g/mL). The compound 4d (MIC=100 g/mL) was found equipotent to Nystatin towards C. albicans. The remaining

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compounds show moderate to good activity to inhibit the growth of bacterial pathogens and are all less effective than standard drugs. From the antimicrobial study of the title derivatives, it is interesting to note that a minor alteration in the molecular configuration of the investigated compounds may have a pronounced effect on antimicrobial activity.

EXPERIMENTAL Materials, instruments and methods Required acetic anhydride, substituted anilines, acetic acid, malononitrile, phosphorous oxychloride, sodium hydroxide, were obtained from S. D. fine chem ltd., Vadodara, Gujarat, India. Cyclohexanedione, and dimedone were obtained from Sigma-Aldrich. Solvents were purified and dried before being used. The microwave assisted reactions are conducted in a "RAGA's Modified Electromagnetic Microwave System" whereby microwaves are generated by magnetron at a frequency of 2450 MHz having an adjustable output power levels i.e. 10 levels from 140 to 700 Watts and with an individual sensor for temperature control (fiber optic is used as a individual sensor for temperature control) with attachment of reflux condenser with constant stirring (thus avoiding the risk of high pressure development). All melting points were taken in open capillaries and are uncorrected. Thin-layer chromatography (TLC, on aluminium plates precoated with silica gel, 60F254, 0.25 mm thickness) (Merck, Darmstadt, Germany) was used for monitoring the progress of all reactions, purity and homogeneity of the synthesized compounds. UV radiation and/or iodine were used as the visualizing agents. Elemental analysis (% C, H, N) was carried out by Perkin-Elmer 2400 series-II elemental analyzer (Perkin-Elmer, USA) and all compounds are within ±0.4% of theory specified. The IR spectra were recorded in KBr on a Perkin-Elmer Spectrum GX FT-IR Spectrophotometer (Perkin-Elmer, USA) and only the characteristic peaks are reported in cm1 1 . H-NMR and 13C-NMR spectra were recorded in DMSO-d6 on a Bruker Avance 400F (MHz) spectrometer (Bruker Scientific Corporation Ltd., Switzerland) using solvent peak as internal standard at 400 MHz and 100 MHz respectively. Chemical shifts are reported in parts per million (ppm). Mass spectra were scanned on a Shimadzu LCMS 2010 spectrometer. Conventional synthesis of compounds 4(a-p) Phenoxypyrazole-4-carbaldehyde 1(a-h) (10 mmol), malononitrile 2 (10 mmol) and Cyclohexanedione/Dimedon 3(a-b) (10 mmol) were thoroughly mixed in ethanolic NaOH (5 mmol, 10 mL) and charged in round bottom flask. Then the reaction mixture was refluxed for 3-3.5 hr. The completion of reaction was monitored by the TLC. The solid product 4(a-p) separated was filtered off washed well with ethanol (10 mL), dried and crystallized from chloroform to get the pure solid sample 4(a-p). Microwave-induced synthesis of compounds 4(a-p) Phenoxypyrazole-4-carbaldehyde 1(a-h) (10 mmol), malononitrile 2 (10 mmol) and Cyclohexanedione/Dimedon 3(a-b) (10 mmol) were thoroughly mixed in ethanolic NaOH (5 mmol, 10 mL) and irradiated in microwave oven at 350 W (50% of output power) for 140-170 sec. After the completion of reaction (checked by TLC), the solution was cooled to room temperature, the solid separated was filtered, washed well with ethanol (10 mL), dried and crystallized from chloroform to get the pure solid sample 4(a-p). Analytical and spectroscopic characterization data of the synthesized compounds are given below:

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2-Amino-4-[3-methyl-5-phenoxy-1-phenyl-1H-pyrazol-4-yl]-5-oxo-5,6,7,8-tetrahydro4H-chromene-3-carbonitrile (4a): Yield 78%, m.p.159-160°C, Anal. Calcd. for C26H22N4O3 (438.48 g/mol): C 71.22, H 5.06, N 12.78 % Found: C 71.13, H 5.13, N 12.69 %. IR (KBr, cm-1): 3395 and 3310 (asym. and sym. stretching of -NH2), 2200 (-CN stretching), 1680 (C=O str.), 1230 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.68-2.17 (m, 6H, CH2), 2.37 (s, 3H, CH3), 4.20 (s, 1H, CH), 6.68-7.41 (m, 12H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.10 (CH3), 19.45 (CH2), 25.00 (CH), 26.48 (CH2), 36.49 (CH2), 56.30 (C-CN), 111.20, 112.54, 115.26, 115.53, 120.50, 121.49, 126.85, 129.61, 138.34, 145.63, 147.80, 150.20, 155.43, 159.00, 164.30 (Ar-C), 196.19 (C=O). MS: 439.2 (M+1). 2-Amino-4-[3-methyl-1-phenyl-5-(4-methylphenoxy)-1H-pyrazol-4-yl]-5-oxo-5,6,7,8tetrahydro-4H-chromene-3-carbonitrile (4b): Yield 90%, m.p.217-218°C, Anal. Calcd. for C27H24N4O3 (452.50 g/mol): C 71.67, H 5.35, N 12.38 % Found: C 71.83, H 5.45, N 12.21 %. IR (KBr, cm-1): 3405 and 3200 (asym. and sym. stretching of -NH2), 2190 (-CN stretching), 1700 (-C=O str.), 1210 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.71-2.24 (m, 6H, CH2), 2.23, 2.25 (s, 3H, 2×CH3), 4.29 (s, 1H, CH), 6.75-7.51 (m, 11H, Ar-H + NH2). 13 C NMR (100 MHz, DMSO-d6) : 12.95 (CH3), 19.72 (CH2), 20.50 (CH3), 24.98 (CH), 26.55 (CH2), 36.60 (CH2), 57.25 (C-CN), 110.72, 112.22, 115.20, 115.75, 120.18, 121.39, 126.54, 129.60, 138.12, 145.57, 147.69, 150.14, 155.15, 159.17, 164.36 (Ar-C), 196.11 (C=O). MS: 453.2 (M+1). 2-Amino-4-[3-methyl-5-(4-methoxyphenoxy)-1-phenyl-1H-pyrazol-4-yl]-5-oxo-5,6,7,8tetrahydro-4H-chromene-3-carbonitrile (4c): Yield 84%, m.p.143-145°C, Anal. Calcd. for C27H24N4O4 (468.50 g/mol): C 69.22, H 5.16, N 11.96 % Found: C 69.09, H 5.33, N 12.03 %.IR (KBr, cm-1): 3410 and 3340 (asym. and sym. stretching of -NH2), 2200 (-CN stretching), 1640 (-C=O str.), 1205 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.73-2.13 (m, 6H, CH2), 2.33 (s, 3H, CH3), 3.65 (s, 3H, OCH3), 4.15 (s, 1H, CH), 6.60-7.53 (m, 11H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.19 (CH3), 19.59 (CH2), 25.20 (CH), 26.68 (CH2), 36.45 (CH2), 55.90 (OCH3), 56.37 (C-CN), 111.57, 112.28, 115.26, 115.71, 120.47, 121.49, 126.84, 129.60, 138.26, 145.65, 147.73, 150.19, 155.34, 159.13, 164.36 (Ar-C), 196.27 (C=O). MS: 469.2 (M+1). 2-Amino-4-[3-methyl-5-(4-chlorophenoxy)-1-phenyl-1H-pyrazol-4-yl]-5-oxo-5,6,7,8tetrahydro-4H-chromene-3-carbonitrile (4d): Yield 69%, m.p. 173-174°C, Anal. Calcd. for C26H21ClN4O3 (472.92 g/mol): C 66.03, H 4.48, N 11.85 % Found: C 65.90, H 4.63, N 12.00 %. IR (KBr, cm-1): 3375 and 3320 (asym. and sym. stretching of -NH2), 2190 (-CN stretching), 1695 (-C=O str.), 1215 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.65-2.19 (m, 6H, CH2), 2.43 (s, 3H, CH3), 4.38 (s, 1H, CH), 6.73-7.50 (m, 11H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.14 (CH3), 19.55 (CH2), 25.15 (CH), 26.58 (CH2), 36.54 (CH2), 57.25 (C-CN), 110.42, 112.01, 115.13, 115.65, 120.55, 121.11, 126.80, 129.13, 138.24, 145.18, 147.12, 150.00, 155.66, 159.18, 163.98 (Ar-C), 196.14 (C=O). MS: 473.1 (M+1). 2-Amino-4-[3-methyl-5-phenoxy-1-(4-methylphenyl)-1H-pyrazol-4-yl]-5-oxo-5,6,7,8tetrahydro-4H-chromene-3-carbonitrile (4e): Yield 80%, m.p. 189-190°C, Anal. Calcd. for C27H24N4O3 (452.50 g/mol): C 71.67, H 5.35, N 12.38 % Found: C 71.75, H 5.44, N 12.25 %. IR (KBr, cm-1): 3410 and 3240 (asym. and sym. stretching of -NH2), 2210 (-CN stretching), 1665 (-C=O str.), 1215 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.70-2.10 (m, 6H, CH2), 2.35 (s, 3H, CH3), 4.18 (s, 1H, CH), 6.69-7.44 (m, 11H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.01 (CH3), 19.40 (CH2), 20.55 (CH3), 25.23 (CH), 26.42

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2-Amino-4-[3-methyl-5-(4-chlorophenoxy)-1-(4-methylphenyl)-1H-pyrazol-4-yl]-5-oxo5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4h): Yield 64%, m.p.153-154°C, Anal. Calcd. for C27H23ClN4O3 (486.95 g/mol): C 66.60, H 4.75, N 11.51 % Found: C 66.45, H 4.94, N 11.73 %. IR (KBr, cm-1): 3370 and 3330 (asym. and sym. stretching of -NH2), 2215 (-CN stretching), 1685 (-C=O str.), 1210 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.74-2.20 (m, 6H, CH2), 2.49 (s, 3H, CH3), 4.22 (s, 1H, CH), 6.72-7.55 (m, 10H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.20 (CH3), 19.60 (CH2), 20.63 (CH3), 24.92 (CH), 26.70 (CH2), 36.38 (CH2), 56.25 (C-CN), 111.60, 111.99, 114.17, 119.12, 121.70, 123.02, 126.67, 128.72, 129.71, 138.01, 145.53, 148.27, 155.95, 158.04, 164.35 (Ar-C), 196.26 (C=O). MS: 487.1 (M+1). 2-Amino-4-[3-methyl-5-phenoxy-1-phenyl-1H-pyrazol-4-yl]-7,7-dimethyl-5-oxo-5,6,7,8tetrahydro-4H-chromene-3-carbonitrile (4i): Yield 90%, m.p.249-250°C, Anal. Calcd. for C28H26N4O3 (466.53 g/mol): C 72.09, H 5.62, N 12.01 % Found: C 71.84, H 5.52, N 12.17 %.IR (KBr, cm-1): 3380 and 3180 (asym. and sym. stretching of -NH2), 2200 (-CN stretching), 1680 (-C=O str.), 1220 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.02, 1.04 (s, 3H, 2×CH3) 1.95, 2.13 (s, 2H, 2×CH2), 2.50 (s, 3H, CH3), 4.36 (s, 1H, CH), 6.76-7.55 (m, 12H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 12.86 (CH3), 24.60 (CH), 27.68, 28.77 (2×CH3), 32.01 (C), 40.25, 50.43 (2×CH2), 60.64 (C-CN), 110.20, 111.80, 114.79, 119.00, 121.81, 122.92, 126.51, 128.92, 129.76, 138.01, 145.50, 148.21, 156.45, 157.94, 161.64 (Ar-C), 196.17 (C=O) MS: 467.2 (M+1). 2-Amino-4-[3-methyl-1-phenyl-5-(4-methylphenoxy)-1H-pyrazol-4-yl]-7,7-dimethyl-5oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4j): Yield 75%, m.p.136-137°C, Anal. Calcd. for C29H28N4O3 (480.56 g/mol): C 72.48, H 5.87, N 11.66 % Found: C 72.45, H 5.98, N

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(CH2), 36.38 (CH2), 56.18 (C-CN), 111.40, 112.22, 115.17, 116.01, 120.53, 121.19, 126.11, 129.61, 138.27, 145.60, 147.73, 150.19, 155.16, 160.00, 164.10 (Ar-C), 196.15 (C=O). MS: 453.2 (M+1). 2-Amino-4-[3-methyl-1-(4-methylphenyl)-5-(4-methylphenoxy)-1H-pyrazol-4-yl]-5-oxo5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4f): Yield 84%, m.p.129-130°C, Anal. Calcd. for C28H26N4O3 (466.53 g/mol): C 71.09, H 5.62, N 12.01 % Found: C 71.14, H 5.70, N 11.87 %. IR (KBr, cm-1): 3400 and 3225 (asym. and sym. stretching of -NH2), 2200 (-CN stretching), 1700 (-C=O str.), 1200 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.73-2.22 (m, 6H, CH2), 2.20, 2.26 (s, 3H, CH3), 4.17 (s, 1H, CH), 6.63-7.40 (m, 10H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 12.90 (CH3), 19.80 (CH2), 20.54, 20.65 (2×CH3), 24.70 (CH), 26.62 (CH2), 36.57 (CH2), 56.35 (C-CN), 110.35, 111.94, 115.20, 115.45, 120.59, 121.50, 126.84, 129.61, 138.11, 145.70, 147.84, 150.20, 155.55, 159.95, 163.28 (Ar-C), 196.29 (C=O). MS: 467.2 (M+1). 2-Amino-4-[3-methyl-5-(4-methoxyphenoxy)-1-(4-methylphenyl)-1H-pyrazol-4-yl]-5oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4g): Yield 72%, m.p.244-246°C, Anal. Calcd. for C28H26N4O4 (482.53 g/mol): C 69.70, H 5.43, N 11.61 % Found: C 70.00, H 5.19, N 11.80 %.IR (KBr, cm-1): 3425and 3195 (asym. and sym. stretching of -NH2), 2200 (-CN stretching), 1690 (-C=O str.), 1190 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.66-2.14 (m, 6H, CH2), 2.31 (s, 3H, CH3), 3.66 (s, 3H, OCH3), 4.20 (s, 1H, CH), 6.75-7.46 (m, 10H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.11 (CH3), 19.47 (CH2), 20.72 (CH3), 25.62 (CH), 26.65 (CH2), 36.30 (CH2), 55.88 (OCH3), 58.20 (C-CN), 110.98, 112.03, 115.30, 115.74, 120.20, 121.67, 126.89, 129.62, 137.88, 145.12, 147.98, 149. 91, 155.35, 159.12, 164.50 (Ar-C), 196.31 (C=O). MS: 483.2 (M+1).

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11.88 %.IR (KBr, cm-1): 3415 and 3265 (asym. and sym. stretching of -NH2), 2220 (-CN stretching), 1660 (-C=O str.), 1205 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 0.95, 0.98 (s, 3H, 2×CH3) 1.98, 2.08 (s, 2H, 2×CH2), 2.28, 2.55 (s, 3H, 2×CH3), 4.23 (s, 1H, CH), 6.74-7.46 (m, 11H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.25 (CH3), 20.58 (CH3), 25.08 (CH), 27.27, 28.89 (2×CH3), 32.00 (C), 40.00 50.34 (2×CH2), 58.69 (C-CN), 110.54, 111.48, 115.36, 115.70, 120.48, 121.51, 129.98, 135.85, 136.27, 145.54, 147.43, 150.23, 155.52, 159.00, 162.05 (Ar-C), 196.22 (C=O). MS: 481.2 (M+1). 2-Amino-4-[3-methyl-5-(4-methoxyphenoxy)-1-phenyl-1H-pyrazol-4-yl]-7,7-dimethyl-5oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4k): Yield 87%, m.p.179-180°C, Anal. Calcd. for C29H28N4O4 (496.56 g/mol): C 70.15, H 5.68, N 11.28 % Found: C 70.24, H 5.78, N 11.01 %.IR (KBr, cm-1): 3380 and 3210 (asym. and sym. stretching of -NH2), 2195 (-CN stretching), 1645 (-C=O str.), 1200 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.05, 1.07 (s, 3H, 2×CH3) 1.90, 2.01 (s, 2H, 2×CH2), 2.25 (s, 3H, CH3), 3.64 (s, 3H, OCH3), 4.17 (s, 1H, CH), 6.70-7.48 (m, 11H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.00 (CH3) 25.24 (CH), 27.42, 28.80 (2×CH3), 32.07 (C), 40.15 50.40 (2×CH2), 55.89 (OCH3), 57.31 (C-CN), 111.25, 112.02, 114.81, 119.06, 121.94, 123.11, 126.52, 128.62, 129.86, 138.19, 145.84, 148.28, 156.45, 157.90, 161.50 (Ar-C), 196.35 (C=O). MS: 497.2 (M+1). 2-Amino-4-[3-methyl-5-(4-chlorophenoxy)-1-phenyl-1H-pyrazol-4-yl]-7,7-dimethyl-5oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4l): Yield 65%, m.p.203-205° Anal. Calcd. for C28H25ClN4O3 (500.98 g/mol): C 67.13, H 5.03, N 11.18 % Found: C 67.02, H 5.25, N 11.37 %. IR (KBr, cm-1): 3430 and 3190 (asym. and sym. stretching of -NH2), 2210 (-CN stretching), 1690 (-C=O str.), 1220 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 0.88, 0.93 (s, 3H, 2×CH3) 1.81, 2.11 (s, 2H, 2×CH2), 2.39 (s, 3H, CH3), 4.12 (s, 1H, CH), 6.64-7.50 (m, 11H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 12.80 (CH3), 24.50 (CH), 27.25, 28.94 (2×CH3), 31.90 (C), 39.92, 50.30 (2×CH2), 60.64 (C-CN), 110.27, 111.18, 115.52, 115.71, 120.55, 121.87, 130.00, 135.86, 136.20, 145.54, 147.17, 150.33, 155.51, 159.17, 162.10 (Ar-C), 196.13 (C=O). MS: 501.2 (M+1). 2-Amino-4-[3-methyl-5-phenoxy-1-(4-methylphenyl)-1H-pyrazol-4-yl]-7,7-dimethyl-5oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4m): Yield 88%, m.p.240-241°C, Anal. Calcd. for C29H28N4O3 (480.56 g/mol): C 72.48, H 5.87, N 11.66 % Found: C 72.63, H 6.00, N 11.80 %.IR (KBr, cm-1): 3400 and 3340 (asym. and sym. stretching of -NH2), 2200 (-CN stretching), 1705 (-C=O str.), 1200 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 0.97, 1.01 (s, 3H, 2×CH3) 1.92, 2.04 (s, 2H, 2×CH2), 2.25, 2.50 (s, 3H, 2×CH3), 4.30 (s, 1H, CH), 6.76-7.45 (m, 11H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.18 (CH3), 20.75 (CH3), 25.25 (CH), 27.48, 28.91 (2×CH3), 32.10 (C), 40.20 50.45 (2×CH2), 57.91 (C-CN), 110.94, 111.81, 114.78, 118.79, 121.75, 122.88, 126.44, 128.90, 129.70, 138.00, 145.51, 148.12, 156.51, 157.88, 162.25 (Ar-C), 196.28 (C=O). MS: 481.2 (M+1). 2-Amino-4-[3-methyl-1-(4-methylphenyl)-5-(4-methylphenoxy)-1H-pyrazol-4-yl]-7,7dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4n): Yield 90%, m.p. 223224°C, Anal. Calcd. for C30H30N4O3 (494.58 g/mol): C 72.85, H 6.11, N 11.33 % Found: C 72.70, H 6.20, N 11.45 %. IR (KBr, cm-1): 3420 and 3300 (asym. and sym. stretching of NH2), 2205 (-CN stretching), 1680 (-C=O str.), 1225 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.01, 1.03 (s, 3H, 2×CH3) 1.97, 2.09 (s, 2H, 2×CH2), 2.25, 2.27, 2.32 (s, 3H, 3×CH3), 4.18 (s, 1H, CH), 6.71-7.43 (m, 10H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 12.92 (CH3), 20.60, 20.90 (CH3), 25.03 (CH), 27.32, 28.75 (2×CH3), 31.94 (C), 40.10 50.37 (2×CH2), 57.91 (C-CN), 110.94, 111.24, 115.38, 115.64, 120.23, 121.94, 130.56,

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A series of some new 4H-chromene derivatives 4(a-p) bearing phenoxypyrazole nuclei has been synthesized through a facile one pot multicomponent reaction by microwave irradiation method. This synthetic strategy allows the construction of relatively complicated nitrogen and oxygen containing heterocyclic system as well as the introduction of various aromatic and heteroaromatic substitutions into 4-positions of pyrane. From the studied compounds it is noticed that the most affective antimicrobial members are having methyl group on N-phenyl ring of the pyrazole moiety as well as gem dimethyl group on the benzopyrane ring with either Cl or methyl substituent on the OPhenyl ring of pyrazole moiety. Antifungal activity of the compounds shows that most of the compounds found to be potent against Candida albicans compared to Aspergillus fumigatus. It is worth mentioning that minor change in molecular configuration of these compounds profoundly influences the activity. The present study throws light on the identification of this new structural class as antimicrobials which can be of interest for further detailed preclinical investigations.

Acknowledgements. The authors are thankful to Department of Chemistry, Sardar Patel University for providing 1H-NMR and 13C-NMR spectroscopy and research facilities. Mr. C.

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135.84, 136.20, 145.55, 147.39, 150.21, 155.30, 159.18, 162.25 (Ar-C), 196.28 (C=O). MS: 495.2 (M+1). 2-Amino-4-[3-methyl-5-(4-methoxyphenoxy)-1-(4-methylphenyl)-1H-pyrazol-4-yl]-7,7dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4o): Yield 92%, m.p. 149150°C, Anal. Calcd. for C30H30N4O4 (510.58 g/mol): C 70.57, H 5.92, N 10.97 % Found: C 70.69, H 6.04, N 11.13 %. IR (KBr, cm-1): 3385 and 3230 (asym. and sym. stretching of NH2), 2205 (-CN stretching), 1710 (-C=O str.), 1195 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 0.90, 0.93 (s, 3H, 2×CH3) 1.85, 2.07 (s, 2H, 2×CH2), 2.23, 2.30 (s, 3H, 2×CH3), 3.66 (s, 3H, OCH3), 4.16 (s, 1H, CH), 6.59-7.40 (m, 10H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.10 (CH3), 20.86 (CH3), 25.03 (CH), 27.29, 28.95 (2×CH3), 31.98 (C), 39.90 50.31 (2×CH2), 55.88 (OCH3), 56.20 (C-CN), 111.18, 111.24, 115.36, 115.69, 120.43, 121.44, 130.04, 135.91, 136.21, 145.50, 147.40, 150.16, 155.26, 159.08, 162.24 (Ar-C), 196.14 (C=O). MS: 511.2 (M+1). 2-Amino-4-[3-methyl-5-(4-chlorophenoxy)-1-(4-methylphenyl)-1H-pyrazol-4-yl]-7,7dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4p): Yield 73%, m.p. 168169°C, Anal. Calcd. for C29H27ClN4O3 (515.00 g/mol): C 67.63, H 5.28, N 10.88 % Found: C 67.76, H 5.44, N 10.92 %. IR (KBr, cm-1): 3390 and 3300 (asym. and sym. stretching of NH2), 2200 (-CN stretching), 1685 (-C=O str.), 1200 (C-O-C ether stretching). 1H NMR (400 MHz, DMSO-d6): 1.03, 1.06 (s, 3H, 2×CH3) 1.83, 2.15 (s, 2H, 2×CH2), 2.28, 2.45 (s, 3H, 2×CH3), 4.14 (s, 1H, CH), 6.67-7.53 (m, 10H, Ar-H + NH2). 13C NMR (100 MHz, DMSO-d6) : 13.07 (CH3), 20.80 (CH3), 25.11 (CH), 27.50, 28.93 (2×CH3), 32.05 (C), 40.25 50.41 (2×CH2), 59.11 (C-CN), 111.15, 111.39, 115.40, 115.70, 120.73, 121.60, 130.11, 135.85, 136.17, 145.44, 147.35, 150.00, 155.15, 159.08, 161.50 (Ar-C), 196.20 (C=O). MS: 515.2 (M+1). CONCLUSIONS

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B. Sangani is grateful to UGC, New Delhi for a Research Fellowship in Sciences for Meritorious Students.

-4H-

Department of Chemistry, Sardar Patel University, Vallabh vidyanagar-388120, Gujarat, India

1. N. Woodford, Expert Opin. Investig. Drugs. 12 (2003) 117 2. (a) B. S. Kuarm, Y. T. Reddy, J. V. Madhav, P. A. Crooks, B. Rajitha Bioorg Med Chem Lett 21 (2011) 524 (b) U. S. Rai, A. M. Isloor, P. Shetty, A. M. Vijesh, N. Prabhu, S. Isloor, M. Thiageeswaran, H. K. Fun Eur J Med Chem 45 (2010) 2695 3. (a) D. Bhavsar, J. Trivedi, S. Parekh, M. Savant, S. Thakrar, A. Bavishi, A. Radadiya, H. Vala, J. Lunagariya, M. Parmar, L. Paresh, R. Loddo, A. Shah Bioorg Med Chem Lett 21 (2011) 3443 (b) J. H. Park, S. U. Lee, S. H. Kim, S. Y. Shin, J. Y. Lee, C. G. Shin, K. H. Yoo and Y. S. Lee Arch Pharm Res 31 (2008) 1 4. N. R. Kamdar, D. D. Haveliwala, P. T. Mistry, S. K. Patel Med Chem Res (2010) doi: 10.1007/s00044-010-9399-x 5. O. M. Singh, N. S. Devi, D. S. Thokchom, G. J. Sharma Eur J Med Chem 45 (2010) 2250 6. B. C. Raju, R. N. Rao, P. Suman, P. Yogeeswari, D. Sriram, T. B. Shaik, S.V. Kalivendi Bioorg Med Chem Lett 21 (2011) 2855 7. W. Huang, Y. Ding, Y. Miao, M. Liu, Y. Li, G. Yang Eur J Med Chem 44 (2009) 3687 8. (a) T. Raj, R. K. Bhatia, A. kapur, M. Sharma, A. K. Saxena, M. P. S. Ishar Eur J Med Chem 45 (2010) 790 (b) N. M. Sabry, H. M. Mohamedc, E. Shawky, A. E. H. Khattab, S. S. Motlaq, A. M. El-Agrody Eur J Med Chem 46 (2011) 765 9. K. V. Sashidhara, J. N. Rosaiah, G. Bhatia, J. K. Saxena Eur J Med Chem 43 (2008) 2592 10. Z. Nazarian, S. Emami, S. Heydari, S. K. Ardestani, M. Nakhjiri, F. Poorrajab, A. Shafiee, A. Foroumadi Eur J Med Chem 45 (2010) 1424

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4H- 4(a-p) 5- , 5--4- 1(ah), 2 (, ) 3(a-b) NaOH . 3 (Streptococcus pneumoniae, Clostridium tetani, Bacillus subtilis), 3 - (Salmonella typhi, Vibrio cholerae, Escherichia coli) (Aspergillus fumigatus, Candida albicans) ( ). C. tetani B. subtilis, C. albicans .

( 2. , 27. 2012)

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SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 4H-CHROMENE

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11. P. Gebhardt, K. Dornberger, F. A. Gollmick, U. Grafe, A. Hartl, H. Gorls, B. Schlegela, C. Hertwecka Bioorg Med Chem Lett 17 (2007) 2558 12. F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, S. Carradori, A. Granese, D. Rivanera, D. Lilli, A. Zicari, M. M. Scaltrito, F. Sisto Bioorg Med Chem Lett 17 (2007) 3065 13. J. Cheng, A. Ishikawa, Y. Ono, T. Arrhenius, A. Nadzan Bioorg Med Chem Lett 13 (2003) 3647 14. (a) I. Damljanovic, M. Colovic, M. Vukicevic, D. Manojlovic, N. Radulovic, K. Wurst, G. Laus, Z. Ratkovic, M. D. Joksovic, R. D. Vukicevic, J. Organomet. Chem. 694 (2009) 1575 (b) I. Damljanovic, M. Vukicevic, N. Radulovic, R. Palic, E. Ellmerer, Z. Ratkovic, M. D. Joksovic, R.D. Vukicevic, Bioorg. Med. Chem. Lett. 19 (2009) 1093 (c) O. Prakash, R. Kumar, V. Parkash, Eur. J. Med. Chem. 43 (2008) 435 (d) O. Prakash, R. Kumar, R. Sehrawat, Eur. J. Med. Chem., 44 (2009) 1763 15. A. A Bekhit, H. M. A. Ashour, Y. S. A. Ghany, A. E. A. Bekhit, A. M. Baraka, Eur. J. Med. Chem. 43 (2008) 456 16. A. R. Trivedi, V. R. Bhuva, B. H. Dholariya, D. K. Dodiya, V. B. Kataria, V. H. Shah, Bioorg. Med. Chem. Lett. 20 (2010) 6100 17. M. D. Joksovic, V. Markovic, Z. D. Juranic, T. Stanojkovic, L. S. Jovanovic, I. S. Damljanovic, K. M. Szecsenyi, N. Todorovic, S. Trifunovic, R.D. Vukicevic, J. Organomet. Chem. 694 (2009) 3935 18. A. H. Abadi, A. A. H. Eissa, G. S. Hassan, Chem. Pharm. Bull. 51 (2003) 838 19. P. Rathelot, N. Azas, H. El-Kashef, F. Delmas, C. D. Giorgio, P. Timon-David, J. Maldonado, P. Vanelle, Eur. J. Med. Chem. 37 (2002) 671 20. (a) A. I. Hashem, A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-Elmagd, Eur. J. Med. Chem. 42 (2007) 934 (b) A. Farghaly, H. El-Kashef, ARKIVOC XI (2006) 76 (c) A. Farghaly, E. De Clercq, H. El-Kashef, ARKIVOC X (2006) 137 21. S. C. Shetty, V. C. Bhagat, Asian J. Chem. 20 (2008) 5037 22. L. Boulard, S. BouzBouz, J. Cossy, X. Franck, B. Figadere, Tetrahedron Lett. 45 (2004) 6603. 23. M. A. Pasha, V. P. Jayshankara, Indian J. Chem. 46B (2007) 1328 24. (a) C. B. Sangani, M. P. Patel, R. G. Patel, Cent. Eur. J. Chem. 9 (2011) 635 (b) C. B. Sangani, D. C. Mungra, M. P. Patel, R. G. Patel, Chines chem.letters 23 (2012) 57 (c) N. M. Shah, M. P. Patel, R. G. Patel, J. Het. Chem. (2011) DOI 10.1002/jhet.918 (d) N. M. Shah, M. P. Patel, R. G. Patel, J. Chem. Sci Accepted (e) D. C. Mungra, M. P. Patel, D. P. Rajani, R. G. Patel, Eur. J. Med. Chem. 46 (2011) 4192 (e) J. A. Makawana, M. P. Patel, R. G. Patel, Med. Chem. Res. (2011) DOI 10.1007/s00044-010-9568-6 (f) J. A. Makawana, M.P. Patel, R.G. Patel, Arch. Pharm. Pharm. Med. Chem. (g) N. J. Thumar, M. P. Patel, Arch. Pharm. 344 (2011) 91 (h) N. K. Shah, N. M. Shah, M. P. Patel, R. G. Patel, J. Serb. Chem. Soc. (2011) DOI 10.2298/JSC110630197S (i) H. G. Kathrotiya, M. P. Patel, R. G. Patel, J. Serb. Chem. Soc.(in press) 25. NCCLS (National Committee for Clinical Laboratory Standards), 2002. Performance standards for antimicrobial susceptibility testing: Twelfth informational supplement. ISBN 1-56238-454-6, M100-S12 (M7) 26. C. B. Sangani, D. C. Mungra, M. P. Patel, R. G. Patel, Central Eur. J. Chem. 9 (2011) 635 27. R. A. Pawar, A. A. Patil, Indian J. Chem. 33B (1994) 156

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Captions for Tables: Table I: Antimicrobial activity of the compounds 4(a-p)

Minimum inhibitory concentration (MIC) expressed in µg/ml Gram-positive bacteria Compd Bs. Ct. Sp. Gram-negative bacteria Ec. St. Vc. Fungal species Af. Ca.

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4a 500 500 500 250 500 500 >1000 >1000 4b 250 500 250 500 500 100 500 500 4c 500 500 500 200 500 500 250 250 4d 1000 100 500 250 500 200 250 100 4e 250 200 250 500 250 200 500 250 4f 500 200 500 250 250 200 500 500 4g 500 250 500 250 500 100 500 200 4h 500 200 500 100 500 250 250 250 4i 250 500 250 100 100 250 1000 500 4j 500 100 500 250 62.5 250 1000 1000 4k 500 250 500 500 500 200 500 250 4l 250 200 250 250 250 200 500 250 4m 500 500 50 250 500 500 1000 500 4n 62.5 100 250 100 62.5 200 >1000 >1000 4o 500 100 500 200 500 200 500 500 4p 250 250 500 100 62.5 250 250 250 A 250 250 100 100 100 100 B 50 100 50 25 25 25 C 100 50 10 10 10 10 D 50 50 50 50 50 50 E 100 100 F 100 500 Bs.: Bacillus subtilis; Ct.: Clostridium tetani; Sp.: Streptococcus pneumoniae; Ec.: Escherichia coli; St.: Salmonella typhi; Vc.: Vibrio cholerae; Af.: Aspergillus fumigatus; Ca.: Candida albicans; MTCC: Microbial Type Culture Collection A: Ampicillin; B: Ciprofloxacine; C: Norfloxacine. D: Chloramphenicol; E: Nystatin; F: Griseofulvin. `-' represents `not tested'

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MTCC MTCC MTCC 441 449 1936

MTCC MTCC MTCC 443 98 3906

MTCC MTCC 3008 227

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Captions for Schemes: 1. Scheme 1. Synthetic pathway for the synthesis of 4H-chromene derivatives bearing the phenoxypyrazole core 4(a-p) 2. Scheme 2. Plausible mechanistic pathway of the synthesis of 4Hchromene derivatives 4(a-p)

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Yielda % 78 90 84 69 80 84 72 64

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Comp. 4a 4b 4c 4d 4e 4f 4g 4h

a

R1 H H H H CH3 CH3 CH3 CH3

R2 H CH3 OCH3 Cl H CH3 OCH3 Cl

R3 H H H H H H H H

Comp. 4i 4j 4k 4l 4m 4n 4o 4p

R1 H H H H CH3 CH3 CH3 CH3

R2 H CH3 OCH3 Cl H CH3 OCH3 Cl

All the yields are on isolated basis.

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R3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 Yielda % 90 75 87 65 88 90 92 73

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 4H-CHROMENE

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O Pyz NC -H2O CN

Hetarylidene -nitrile

R3 HO

3(a-b)

Pyz C

O R3

Pyz CHO

1(a-h)

CN CN

2

R3 NC N HO

R3

NC 3

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4 5 R3 NC R3 HN C

Pyz O

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O H

Pyz O R3 R3

H2N 2 O 6

4(a-p)

Pyz-CHO = 3-Methyl-5-aryloxy-1-aryl-1H -pyrazole-4-carbaldehyde R3 = H, CH3

Scheme 2. Plausible mechanistic pathway f or the compounds 4(a-p).

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