Editor-in-Chief Hatice Kübra Elçioğlu Vice Editors Levent Kabasakal Esra Tatar Online ISSN 2630-6344 Publisher Marmara University Frequency Bimonthly (Six issues / year) Abbreviation J.Res.Pharm. Former Name Marmara Pharmaceutical Journal
Journal of Research in Pharmacy 2013 , Vol 17 , Num 3
Synthesis and antimicrobial activity of some pyrazoline derivatives bearing amide moiety
Ahmet Özdemir
Anadolu University, Faculty of Pharmacy, Deparment of Pharmaceutical Chemistry, Eskisehir, Turkey DOI : 10.12991/2013171314


Bu çalışmada, bir seri pirazolin türevi sentezlendi. Bileşiklerin kimyasal yapıları IR, 1H-NMR, 13C-NMR, FAB-MS spektral verileri ve elemental analiz ile aydınlatıldı. Sentezlenen bileşikler antimikrobiyal etkileri tarandı. Bütün bileşikler en yüksek antibakteriyel etkiyi P. aeruginosa'ya karşı gösterdiler. 1-(Kloroasetil)-3-(2-furanil)-5-(4-klorofenil)-2- pirazolin ve 1-(kloroasetil)-3-(2-tiyenil)-5-(3,4-metilendioksifenil)-2-pirazolin bileşikleri hariç bütün bileşikler C. albicans'a karşı ketokonazolden daha etkili iken, 1-(kloroasetil)-3-(2-furanil)-5-(4-klorofenil)-2-pirazolin ve 1-(kloroasetil)-3-(2-tiyenil)-5-(3,4-metilendioksifenil)-2-pirazolin bileşikleri C. albicans'a karşı ketokonazol ile aynı düzeyde antifungal etki gösterdiler.


Microbial resistance to antimicrobial agents still remains a major challenge in the medicinal chemistry, as many species of bacteria and fungi have developed resistance to currently available antimicrobial drugs. Therefore, there could be a major global healthcare problem in the clinical management of life-threatening infectious diseases caused by multi-drug resistant of Gram-positive pathogens like Staphylococcus, and Gram-negative pathogens like Escherichia, and Pseudomonas strains. In order to overcome this serious problem, the search for new antimicrobial agents have gained great importance[1-3].

Medicinal chemists have carried out considerable research for novel antimicrobial agents carrying haloacetamide moiety. Chloramphenicol and analogues, which are widely used antibiotics for the treatment of systemic bacterial infections, possess dichloroacetamide group. Dichloroacetamide group is one of the functional groups that determine antibacterial activity of chloramphenicol. Loss of this group results in significant loss of biological activity[4,5].

Bioisosteric replacement approach was used for designing the compounds. The bioisosteric replacement of benzene with a heteroaromatic ring resulted in analogues maintaining the same biological activity within a series of different pharmacological agents, lending great importance to ring-equivalent bioisosteres. Furan, and thiophene, which are structurally related to benzene, are widely used as ring equivalents in drug development[6-8]. β-lactam antibiotics, which possess thiophene ring as the side chain, play a leading role in the treatment of systemic bacterial infections. Tioconazole is also an example of antifungal agents bearing thiophene moiety[4]. Furthermore, nitrofuran derivatives represent an important class of antimicrobial agents in medicinal chemistry[9].

Pyrazolines are widely used and studied privileged pharmacophores in medicinal chemistry due to their synthetic and biological importance. Some studies have confirmed that pyrazoline derivatives possess antimicrobial activity[10-15].

In continuation of our previous work on the synthesis and antimicrobial evaluation of pyrazoline derivatives[11-15], herein we described the discovery of 2-pyrazoline derivatives bearing three important functional moieties, namely haloacetamide, furan and thiophene and focused on their potential antimicrobial effects.


All reagents were used as purchased from commercial suppliers without further purification. Melting points were determined by using an Electrothermal 9100 digital melting point apparatus and were uncorrected (Electrothermal, Essex, UK). The compounds were checked for purity by TLC on silica gel 60 F254. Spectroscopic data were recorded on the following instruments: IR, Shimadzu 435 IR spectrophotometer (Shimadzu, Tokyo, Japan); 1H-NMR, Bruker 500 MHz NMR spectrometer (Bruker Bioscience, Billerica, MA, USA) and 13CNMR, Bruker Avance II 125 MHz NMR spectrometer (Bruker Bioscience, Billerica, MA, USA) in DMSO-d6 using TMS as internal standard; MS-FAB, VG Quattro mass spectrometer (Fisons Instruments Vertriebs GmbH, Mainz, Germany), Elemental analyses were performed on a Perkin Elmer EAL 240 elemental analyser (Perkin–Elmer, Norwalk, CT, USA).

General procedure for the synthesis of the compounds 1-(2-Furanyl/thienyl)-3-aryl-2-propen-1-ones (3a-h)
A mixture of 2-acetylfuran/thiophene (0.06 mol) (1), aromatic aldehyde (0.06 mol) (2), and 10% aqueous sodium hydroxide (10 mL) in ethanol (30 mL) was stirred at room temperature for about 5 h. The resulting solid was washed, dried, and crystallized from ethanol[16,17].

5-Aryl-3-(2-furanyl/thienyl)-2-pyrazolines (4a-h)
A solution of the appropriate furanyl/thienyl chalcone (0.03 mol) and hydrazine hydrate (80%) (0.06 mol) in ethanol (30 mL) was refluxed for 3 h. The reaction mixture was cooled and kept at 0°C overnight. The resulting solid was recrystallized from ethanol[16,17].

1-(Chloroacetyl)-3-(2-furanyl/thienyl)-5-aryl-2-pyrazolines (5a-h)
5-Aryl-3-(2-furanyl/thienyl)-2-pyrazolines (0.02 mol) and triethylamine (0.02 mol) were dissolved in dry acetone (30 mL) with constant stirring. Later, the mixture was cooled in an ice bath, and chloroacetyl chloride (0.02 mol) was added dropwise with stirring. The reaction mixture thus obtained was further agitated for 2 h at room temperature. The precipitate was filtered, the solvent was evaporated to dryness under reduced pressure, and the products were recrystallized from ethanol.

1-(Chloroacetyl)-3-(2-furanyl)-5-(4-methylphenyl)-2- pyrazoline (5a)
IR (KBr) νmax (cm-1): 1662 (C=O), 1558, 1488, 1436 (C=N and C=C).

1H-NMR (500 MHz, δ ppm, DMSO-d6): 2.32 (3H, s), 3.04 (1H, dd, J = 18.02, 4.52 Hz), 3.81 (1H, dd, J = 18.04, 11.61 Hz), 4.60 (1H, d, J =13.73 Hz), 4.71 (1H, d, J = 13.74 Hz), 5.51 (1H, dd, J = 11.62, 4.51 Hz), 6.68 (1H, t, J = 3.51, 2.02 Hz), 7.04 (1H, d, J = 3.52 Hz), 7.09 (2H, d, J = 8.03 Hz), 7.15 (2H, d, J=8.01 Hz), 7.90 (1H, s).

13C-NMR (125 MHz, DMSO-d6): 21.10 (CH3), 42.33 (CH2), 42.85 (CH2), 59.69 (CH), 112.79 (CH), 115.46 (CH), 125.93 (2CH), 129.72 (2CH), 137.17 (C), 138.86 (C), 146.17 (CH), 146.62 (C), 147.39 (C), 163.46 (C).

For C16H15ClN2O2 calculated: 63.47 % C, 4.99 % H, 9.25 % N; found: 63.45 % C, 5.02 % H, 9.18 % N.

MS (FAB) [M+1]+: m/z 303

1-(Chloroacetyl)-3-(2-furanyl)-5-(3,4- methylenedioxyphenyl)-2-pyrazoline (5b)
IR (KBr) νmax (cm-1): 1658 (C=O), 1564, 1506, 1446 (C=N and C=C).

1H-NMR (500 MHz, δ ppm, DMSO-d6): 3.06 (1H, dd, J = 18.01, 4.54 Hz), 3.78 (1H, dd, J = 18.03, 11.58 Hz), 4.61 (1H, d, J = 13.74 Hz), 4.73 (1H, d, J =13.71 Hz), 5.48 (1H, dd, J = 11.57, 4.53 Hz), 6.00 (2H, s), 6.67-7.05 (5H, m), 7.93 (1H, s).

13C-NMR (125 MHz, DMSO- d6): 42.33 (CH2), 42.94 (CH2), 59.68 (CH), 101.52 (CH2), 108.79 (CH), 112.79 (CH), 115.46 (CH), 119.30 (CH), 135.69 (CH), 146.26 (CH), 146.45 (C), 146.62 (C), 147.00 (C), 147.37 (C), 148.01 (C), 163.52 (C).

For C16H13ClN2O4 calculated: 57.76 % C, 3.94 % H, 8.42 % N; found: 57.68 % C, 3.89 % H, 8.44 % N.

MS (FAB) [M+1]+: m/z 333

1-(Chloroacetyl)-3-(2-furanyl)-5-(4-methoxyphenyl)-2- pyrazoline (5c) (17)
IR (KBr) νmax (cm-1): 1662 (C=O), 1610, 1512, 1463, 1440 (C=N and C=C).

1H-NMR (500 MHz, δ ppm, DMSO-d6): 3.06 (1H, dd, J = 18.02, 4.52 Hz), 3.73 (3H, s), 3.82 (1H, dd, J = 18.03, 11.48 Hz), 4.60 (1H, d, J =13.76 Hz), 4.70 (1H, d, J = 13.77 Hz), 5.50 (1H, dd, J = 11.48, 4.52 Hz), 6.69 (1H, t, J = 3.52, 1.57 Hz), 6.89 (2H, d, J = 8.52 Hz), 7.05 (1H, d, J = 3.02 Hz), 7.13 (2H, d, J=8.51 Hz), 7.93 (1H, s).

13C-NMR (125 MHz, DMSO-d6): 42.28 (CH2), 42.87 (CH2), 55.58 (CH3), 59.43 (CH), 112.79 (CH), 114.53 (2CH), 115.43 (C), 127.32 (2CH), 128.63 (CH), 131.52 (CH), 133.89 (C), 152.62 (C), 158.60 (C), 163.28 (C).

For C16H15ClN2O3 calculated: 60.29 % C, 4.74 % H, 8.79 % N; found: 60.31 % C, 4.71 % H, 8.72 % N.

MS (FAB) [M+1]+: m/z 319

1-(Chloroacetyl)-3-(2-furanyl)-5-(4-bromophenyl)-2- pyrazoline (5d)
IR (KBr) νmax (cm-1): 1683 (C=O), 1564, 1488, 1456 (C=N and C=C).

1H-NMR (500 MHz, δ ppm, DMSO-d6): 3.09 (1H, dd, J = 18.06, 4.74 Hz), 3.84 (1H, dd, J = 18.04, 11.72 Hz), 4.62 (1H, d, J =13.85 Hz), 4.72 (1H, d, J = 13.87 Hz), 5.54 (1H, dd, J = 11.71, 4.73 Hz), 6.69 (1H, t, J = 3.52, 2.02 Hz), 7.05 (1H, d, J = 3.50 Hz), 7.19 (2H, d, J = 8.52 Hz), 7.54 (2H, d, J =8.50 Hz), 7.94 (1H, s).

For C15H12BrClN2O2 calculated: 49.01 % C, 3.29 % H, 7.62 % N; found: 49.04 % C, 3.27 % H, 7.65 % N.

MS (FAB) [M+1]+: m/z 368

1-(Chloroacetyl)-3-(2-furanyl)-5-(4-chlorophenyl)-2- pyrazoline (5e)
IR (KBr) νmax (cm-1): 1677 (C=O), 1556, 1488, 1427 (C=N and C=C).

1H-NMR (500 MHz, δ ppm, DMSO-d6): 3.03 (1H, dd, J = 18.08, 4.58 Hz), 3.82 (1H, m), 4.57 (1H, d, J =13.78 Hz), 4.67 (1H, d, J = 13.79 Hz), 5.54 (1H, dd, J = 11.68, 4.58 Hz), 6.65 (1H, t, J = 3.52, 2.01 Hz), 7.01 (1H, d, J = 3.50 Hz), 7.22 (2H, d, J = 8.02 Hz), 7.39 (2H, d, J =8.08 Hz), 7.85 (1H, s).

13C-NMR (125 MHz, DMSO-d6): 42.11 (CH2), 42.67 (CH2), 59.32 (CH), 112.88 (CH), 115.72 (CH), 127.95 (2CH), 129.18 (2CH), 132.56 (C), 140.56 (C), 145.98 (CH), 146.47 (C), 147.54 (C), 163.78 (C).

For C15H12Cl2N2O2 calculated: 55.75 % C, 3.74 % H, 8.67 % N; found: 55.83 % C, 3.76 % H, 8.61 % N.

MS (FAB) [M+1]+: m/z 323

1-(Chloroacetyl)-3-(2-furanyl)-5-(4-fluorophenyl)-2- pyrazoline (5f)
IR (KBr) νmax (cm-1): 1683 (C=O), 1564, 1510, 1463 (C=N and C=C).

1H-NMR (500 MHz, δ ppm, DMSO-d6): 3.08 (1H, dd, J = 18.08, 4.59 Hz), 3.80 (1H, dd, J = 18.06, 11.71 Hz), 4.61 (1H, d, J =13.98 Hz), 4.72 (1H, d, J = 13.92 Hz), 5.57 (1H, dd, J = 11.75, 4.58 Hz), 6.68 (1H, t, J = 3.08, 1.52 Hz), 7.05 (1H, d, J = 3.50 Hz), 7.18 (2H, d, J = 8.50 Hz), 7.27 (2H, d, J =8.49 Hz), 7.93 (1H, s).

For C15H12ClFN2O2 calculated: 58.74 % C, 3.94 % H, 9.13 % N; found: 58.65 % C, 3.87 % H, 9.21 % N.

MS (FAB) [M+1]+: m/z 307

1-(Chloroacetyl)-3-(2-thienyl)-5-(3,4- methylenedioxyphenyl)-2-pyrazoline (5g)
IR (KBr) νmax (cm-1): 1679 (C=O), 1564, 1500, 1452, 1415 (C=N and C=C).

1H-NMR (500 MHz, δ ppm, DMSO-d6): 3.19 (1H, dd, J = 18.02, 4.58 Hz), 3.86 (1H, dd, J = 18.03, 11.57 Hz), 4.60 (1H, d, J = 13.84 Hz), 4.71 (1H, d, J =13.86 Hz), 5.52 (1H, dd, J = 11.59, 4.57 Hz), 6.04 (2H, s), 6.71 (1H, dd, J = 8.05, 1.50 Hz), 6.77 (1H, d, J = 1.52 Hz), 6.87 (1H, d, J = 8.04 Hz), 7.17 (1H, t, J = 5.02, 3.50 Hz), 7.50 (1H, d, J = 3.52 Hz), 7.79 (1H, d, J = 5.01 Hz).

13C-NMR (125 MHz, DMSO-d6): 42.86 (CH2), 43.20 (CH2), 60.27 (CH), 101.52 (CH2), 106.51 (CH), 108.80 (CH), 119.32 (CH), 128.60 (CH), 130.65 (CH), 131.58 (CH), 134.07 (C), 135.78 (C), 147.00 (C), 148.01 (C), 152.04 (C), 163.33 (C).

For C16H13ClN2O3S calculated: 55.10 % C, 3.76 % H, 8.03 % N; found: 55.18 % C, 3.73 % H, 8.11 % N.

MS (FAB) [M+1]+: m/z 349

1-(Chloroacetyl)-3-(2-thienyl)-5-(4-bromophenyl)-2-pyrazoline (5h)
IR (KBr) νmax (cm-1): 1666 (C=O), 1558, 1448, 1425, 1413 (C=N and C=C).

1H-NMR (500 MHz, δ ppm, DMSO-d6): 3.22 (1H, dd, J = 18.05, 4.57 Hz), 3.91 (1H, dd, J = 18.03, 11.55 Hz), 4.61 (1H, d, J =13.86 Hz), 4.71 (1H, d, J = 13.89 Hz), 5.58 (1H, dd, J = 11.56, 4.54 Hz), 7.16 (1H, t, J = 3.51, 1.04 Hz), 7.20 (2H, d, J = 8.50 Hz), 7.50 (1H, d, J = 3.50 Hz), 7.55 (2H, d, J =8.51 Hz), 7.80 (1H, d, J = 5.03 Hz).

13C-NMR (125 MHz, DMSO-d6): 42.76 (CH2), 42.97 (CH2), 59.97 (CH), 121.01 (C), 128.41 (2CH), 128.62 (CH), 130.32 (CH), 131.71 (CH), 132.10 (2CH), 133.90 (C), 141.23 (C), 152.08 (C), 163.44 (C).

For C15H12BrClN2OS calculated: 46.96 % C, 3.15 % H, 7.30 % N; found: 46.93 % C, 3.19 % H, 7.23 % N.

MS (FAB) [M+1]+: m/z 384

Microbiology Antimicrobial activity
The in vitro antimicrobial activities of the compounds (5a-h) were tested using the microbroth dilution method[18]. Tested microorganism strains were Staphylococcus aureus (NRRL B-767), Listeria monocytogenes (ATCC-7644), Escherichia coli (ATCC-25922), Pseudomonas aeruginosa (ATCC-254992), Micrococcus luteus (NRLL B-4375), Bacillus subtilis (NRS-744) and Candida albicans (ATCC-22019). Microbroth dilution-susceptibility assay was used for antimicrobial evaluation of the compounds. Stock solutions of the samples were prepared in dimethyl sulfoxide. Dilution series using sterile distilled water were prepared from 4 mg/mL to 0.0039 mg/mL in microtest tubes that were transferred to 96-well microtiter plates. Overnight- grown bacterial and C. albicans suspensions in doublestrength Mueller-Hinton broth were standardized to 108 CFU/ mL using McFarland No: 0.5 standard solutions. Hundred microliter of each microorganism suspension was then added into the wells. The last well-chain without a microorganism was used as a negative control. Sterile distilled water and the medium served as a positive growth control. After incubation at 37 °C for 18-24 h, antimicrobial activity was detected by spraying of 0.5% TTC (triphenyltetrazolium chloride, Merck) aqueous solution. Minimum Inhibitory Concentration (MIC) was defined as the lowest concentration of compounds that inhibited visible growth, as indicated by the TTC staining. Streptomycin was used as standard antibacterial agent, whereas ketoconazole was used as an antifungal agent. Observed data on the antimicrobial activity of the compounds and control drugs are given in Table 2.


Initially, the chalcones (1-(2-furanyl/thienyl)-3-aryl-2-propen- 1-ones) (3a-h) were synthesized by literature methods as described (16,17) and treated with hydrazine hydrate (80%) to obtain 5-aryl-3-(2-furanyl/thienyl)-2-pyrazolines (4a-h) (Scheme 1).

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SCHEME 1: The synthetic protocol of the compounds (5a-h)

The desired 1-(chloroacetyl)-3-(2-furanyl/thienyl)-5-aryl- 2-pyrazolines (5a-h) were synthesized via the nucleophilic acyl substitution reactions of 5-aryl-3-(2-furanyl/thienyl)- 2-pyrazolines with chloroacetyl chloride in the presence of triethylamine. These reactions are summarized in Scheme 1 and some properties of the compounds are given in Table 1.

TABLE 1: Some properties of the synthesized compounds (5a-h)

The structures of the compounds (5a-h) were confirmed by IR, 1H-NMR, 13C-NMR and FAB+-MS spectral data and Elemental analyses.

In the IR spectra of all compounds (5a-h), all derivatives have a strong, characteristic band in the region 1658-1683 cm-1 due to the amide C=O stretching vibration. The bands due to the C=C and C=N stretching vibrations are observed in the region 1610-1413 cm-1.

The 1H-NMR spectral data were also consistent with the assigned structures. In the 500 MHz 1H-NMR spectra of compounds, the CH2 protons of the pyrazoline ring resonated as a pair of doublets of doublets at δ 3.04-3.22 ppm, 3.78-3.91 ppm. The CH proton appeared as doublet of doublets at δ 5.48-5.58 ppm due to vicinal coupling with the two magnetically nonequivalent protons of the methylene group at position 4 of the pyrazoline ring (JAM = 18.01-18.08 Hz, JAX = 4.51-4.74 Hz, JMX = 11.48-11.75 Hz). The CH2 protons of acetyl (5a-h) are observed in the region 4.57-4.73 ppm as double doublets (J = 13.73-13.98 Hz, J = 13.71-13.92 Hz). This geminal coupling result from steric structure of the compounds. These geminal protons are observed as double doublet due to possible two different conformations since rigid protons were occurred[19,20]. All the other aromatic and aliphatic protons were observed at expected regions.

In the 13C-NMR spectra of the compounds, the signal due to the carbonyl carbon appears at 163.28-163.78 ppm. 13C-NMR chemical shift values of the carbon atoms at 42.11-42.86 ppm (C-4), 59.32-60.27 ppm (C-5), and about 147.39-152.62 ppm (C- 3) corroborate the 2-pyrazoline character deduced from the 1H-NMR data. The other aromatic and aliphatic carbons were observed at expected regions.

In the mass spectra of all compounds (5a-h), the M+1 peak is observed. All compounds gave satisfactory elemental analyses.

The antimicrobial activity of the compounds was studied with seven pathogenic microorganisms. Streptomycin and ketoconazole were used as reference drugs. The results are summarized in Table 2.

TABLE 2: Antimicrobial activities of the compounds (5a-h) (μg/mL)

All compounds (5a-h) exhibited the highest antibacterial activity against P. aeruginosa with a MIC value of 250 μg/mL among the tested bacteria. The results clearly indicated that the functional groups on 2-pyrazoline ring did not have a considerable influence on the antibacterial activity against P. aeruginosa.

Compound 5a exhibited antibacterial activity against S. aureus with a MIC value of 125 μg/mL. Among all compounds (5a-h), compound 5a also displayed the highest antibacterial activity against B. subtilis. Compounds 5a, 5d and 5g showed moderate activity M. luteus with a MIC value of 125 μg/mL. All compounds (5a-h) displayed the same antibacterial activity against E. coli with a MIC value of 250 μg/mL.

All compounds except compounds 5e and 5g are more effective than ketoconazole against C. albicans, whereas compounds 5e, 5g and ketoconazole showed the same level of antifungal activity against C. albicans.


In conclusion, the synthesis of 2-pyrazoline derivatives was described and their in vitro antimicrobial effects of these compounds on various pathogenic bacteria and C. albicans were evaluated. The biological results indicate that P. aeruginosa and C. albicans are more susceptible to the synthesized compounds.

Considering all the results obtained from antimicrobial screen, in comparison with reference agents, it can be concluded that compound 5a is the most effective compound in the screen.

Based on eight compounds evaluated, it appears that 4-methyl substitution on the phenyl ring (5a) has made a good contribution to the antimicrobial activity in this series of pyrazolinehaloacetamide combination.

The author would like to thank Anadolu University Medicinal Plants, Drugs and Scientific Research Center (AUBIBAM) for spectroscopic analyses and biological activity tests.


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