|Year : 2009 | Volume
| Issue : 1 | Page : 32-36
Synthesis and antimicrobial activity of 2-chloroquinoline incorporated pyrazoline derivatives
Sandhya Bawa1, Suresh Kumar1, Sushma Drabu1, Bibhu P Panda2, Rajiv Kumar1
1 Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University), New Delhi - 110 062, India
2 Pharmaceutical Biotechnology Laboratory, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi - 110 062, India
|Date of Submission||14-Nov-2009|
|Date of Decision||28-Nov-2009|
|Date of Acceptance||04-Dec-2009|
|Date of Web Publication||23-Apr-2010|
Department of Pharmaceutical Chemistry, Jamia Hamdard (Hamdard University), New Delhi - 110 062
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Purpose : A series of 2-chloroquinoline containing pyrazoline derivatives having 3,4-dichloro/ 3,4-dimethoxy in the phenyl ring were synthesized and screened for their antimicrobial activity against a panel of bacterial and fungal strains. Materials and Methods : The structures of the newly synthesized compounds were established on the basis of spectral data obtained from the FTIR, 1H and 13C-NMR, and mass spectrometry. All the compounds were evaluated for their antibacterial activity against Escherichia coli (NCTC, 10418), Staphylococcus aureus (NCTC, 65710), and Pseudomonas aeruginosa (NCTC, 10662). The compounds were also tested for antifungal activity aganist Aspergillus niger (MTCC, 281), Aspergillus flavus (MTCC, 277), Monascus purpureus (MTCC, 369) and Penicillium citrinum (NCIM, 768) by the cup-plate method. Results : Among the compounds tested, 3,4-dichloro derivatives were comparatively more active in antimicrobial screening with respect to their 3,4-dimethoxy analog. Conclusion : A careful analysis of the antimicrobial activity data of the compounds revealed that compounds 3a, 3b, 3c, and 3e exhibited potent antibacterial
Keywords: Pyrazoline, 2-chloroquinoline, antimicrobial activity
|How to cite this article:|
Bawa S, Kumar S, Drabu S, Panda BP, Kumar R. Synthesis and antimicrobial activity of 2-chloroquinoline incorporated pyrazoline derivatives. J Pharm Bioall Sci 2009;1:32-6
|How to cite this URL:|
Bawa S, Kumar S, Drabu S, Panda BP, Kumar R. Synthesis and antimicrobial activity of 2-chloroquinoline incorporated pyrazoline derivatives. J Pharm Bioall Sci [serial online] 2009 [cited 2022 Dec 6];1:32-6. Available from: https://www.jpbsonline.org/text.asp?2009/1/1/32/62684
The recent literature is enriched with progressive findings about the synthesis and pharmacological activities of pyrazoline and substituted pyrazolines. Pyrazolines have been found to possess antimicrobial, antitubercular, antiamoebic, antidepressant, anticonvulsant, anti-inflammatory, anti-tumor, and antiviral activities, among others. ,,,,,,,, In addition, quinoline derivatives are also known to possess antibacterial, antifungal, anticonvulsant, and antimalarial activities, and the medicinal utility of quinoline as a heterocyclic ring has moved from the antimalarial to almost every branch of medicinal chemistry. ,, Various functional groups, such as, chloro, fluoro, nitro, methoxy, and so on, have an important significance in medicinal chemistry. Especially the dihalogen-like dichloro, as in antifungal azoles, provides a potent antifungal activity for drugs such as Oxiconazole, Ketoconazole, Terconazole, Itraconazole, and so on.  Moreover, the 3,4-dichloro function has been regarded as an equivalent to the naphthalene ring as reported for the compound pronethalol, an adrenergic blocker, which was formed by replacing the 3,4-dichlorophenyl group in Dichloroisoproterenol (DCI) with the 2-naphthyl group.  Similarly, the 3,4-dimethoxy group has also been associated with potent biological activity. Prompted by these observations it was envisaged to synthesize some new pyrazoline derivatives bearing a 2-chloroquinoline nucleus as well as bifunctional groups, such as, 3,4-dichloro and 3,4-dimethoxy in a single matrix, and also to screen for their antifungal, antibacterial activities.
| Materials and Methods|| |
Melting points were determined by the open capillary method using the electrical melting point apparatus and were uncorrected. The IR spectra were recorded as KBr (pallet) on Bio Rad FT-IR spectrophotometer. 1 H and 13 C-NMR spectra were recorded on Bruker DPX 300 MHz spectrophotometer using TMS as the internal standard. The mass spectra were recorded on JEOL SX102/DA-6000 mass spectrometer and elemental analysis was carried out on the Vario-EL III CHNOS-Elemantar analyzer. The lipophilicity of the compounds was calculated using the Chemsketch 12.0 software of the Advanced Chemistry Development (ACD) Laboratory. Thin Layer Chromatography (TLC) was performed to check the purity of the compounds, the spot being located under iodine vapors.
General procedure for the synthesis of chalcones (1a-e, 2a-e)
3,4-Dichloro acetophenone (1) or 3,4-dimethoxy acetophenone (2) (0.01 mol) was added to the mixture of substituted 2-chloroquinoline-3-carboxaldehyde (a-e) (0.01 mol), and aq. sodium hydroxide solution (30%, 1 ml), in ethanol 30 ml. The reaction mixture was stirred overnight at room temperature. Subsequently, this reaction mixture was poured over crushed ice and neutralized to pH 7 with dilute HCl. The yellow solid thus obtained was filtered, washed with water, and dried. The crude product was crystallized with a chloroform-ethanol mixture to afford pure chalcones.
3-(2-chloroquinolin-3-yl)-1-(3,4-dichlorophenyl)prop-2-en-1-one. (1a-e, 2a-e)
IR (KBr) cm -1 ; 1698 (C=O), 1627 (C=N), 1579 (C=C), 747 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 7.59-7.64 (m, 2H, Ar-H and CH=CH), 7.73-7.92 (m, 4H, Ar-H and CH=CH), 7.98-8.09 (m, 3H, Ar-H), 8.48 (s, 1H, H-4).
General procedure for the synthesis of Pyrazolines (3a-e, 4a-e)
To a solution of chalcones (1a-e, 2a-e) (0.01 mol) in absolute ethanol (25 ml) containing 1-1.5 ml of acetic acid, an equimolar amount of hydrazine hydrate (0.01 mol) was added and the reaction mixture was refluxed for 12 to 16 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure and then allowed to cool. A solid product separated out, which was filtered, washed with aqueous ethanol, and dried. This product was further purified by crystallization from the ethanol-DMF mixture. The physicochemical data of the synthesized pyrazolines is given in [Table 1]. Spectral data of compounds (3a-e and 4a-e) are given below.
IR (KBr) cm -1 ; 3279 (N-H), 1615 (C=N), 1583 (C=C), 756 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 3.19 (dd, 1H, H A , J = 18.09, 4.57 Hz), 3.78 (dd, 1H, H B , J = 17.32, 12.57, Hz), 5.56 (dd, 1H, H X , J = 11.51, 4.33 Hz), 7.08 (d, 1H, Ar-H, J = 6.99 Hz), 7.31 (d, 1H, Ar-H, J = 6.12 Hz), 7.53-7.73 (m, 5H, Ar-H), 7.95 (s, 1H, Ar-H), 11.13 (s, 1H, NH, D 2 O-exchangeble). 13 C-NMR (75 MHz, DMSO-d 6); δ 41.35 (CH 2 ), 60.13 (CH), 112.84, 115.88, 126.43, 128.86, 130.03, 132.47, 133.62, 135.18, 137.41, 141.83, 144.71, 147.91, 149.26, 151.38. DEPT-135; 41.35 (-ve peak, CH 2 ), 60.13 (+ve peak CH). FAB -MS : m/z 377 (M + ), 379 (M+2) [Figure 1].
IR (KBr) cm -1 ; 3271 (N-H), 1617 (C=N), 1583 (C=C), 751 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 2.50 (s, 3H, CH 3 ), 3.20 (dd, 1H, H A , J = 18.12, 4.50 Hz), 3.89 (dd, 1H, H B , J = 18.00, 12.17, Hz), 5.52 (dd, 1H, H X , J = 11.63, 4.28 Hz), 7.20-7.33 (m, 2H, Ar-H), 7.48-7.53 (m, 2H, Ar-H), 7.73-7.80 (m, 2H, Ar-H), 7.97 (s, 1H, Ar-H), 11.86 (s, 1H, NH, D 2 O-exchangeble). 13 C-NMR (75 MHz, DMSO-d 6); δ 21.07 (CH 3 ), 40.87 (CH 2 ), 61.28 (CH), 113.05, 115.93, 126.85, 128.47, 130.14, 131.64, 133.72, 136.23, 137.57, 141.68, 145.71, 147.98, 149.84, 151.37. DEPT-135; 40.87 (-ve peak, CH 2 ), 61.28 (+ve peak CH). FAB -MS : m/z 391 (M + ), 393 (M+2).
IR (KBr) cm -1 ; 3258 (N-H), 1625 (C=N), 1579 (C=C), 758 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 2.51 (s, 3H, CH 3 ), 3.17 (dd, 1H, H A , J = 18.08, 4.77 Hz), 3.75 (dd, 1H, H B , J = 18.07, 12.16, Hz), 5.53 (dd, 1H, H X , J = 11.74, 4.66 Hz), 6.99 (d, 1H, Ar-H, J = 7.90 Hz), 7.10 (s, 1H, Ar-H), 7.49-7.57 (m, 2H, Ar-H), 7.70-7.77 (m, 2H, Ar-H), 7.95 (s, 1H, Ar-H), 11.86 (s, 1H, NH, D 2 O-exchangeble).
IR (KBr) cm -1 ; 3247 (N-H), 1621 (C=N), 1584 (C=C), 762 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 2.76 (s, 3H, CH 3 ), 3.18 (dd, 1H, H A , J = 18.10, 4.52 Hz), 3.76 (dd, 1H, H B , J = 17.89, 12.21 Hz), 5.54 (dd, 1H, H X , J = 11.67, 4.45 Hz), 7.20-7.36 (m, 2H, Ar-H), 7.46-7.54 (m, 2H, Ar-H), 7.69-7.80 (m, 2H, Ar-H), 7.94 (s, 1H, Ar-H), 11.87 (s, 1H, NH, D 2 O-exchangeble).
IR (KBr) cm -1 ; 3263 (N-H), 1622 (C=N), 1583 (C=C), 756 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 3.19 (dd, 1H, H A , J = 18.19, 4.53 Hz), 3.75 (dd, 1H, H B , J = 17.93, 12.23, Hz), 3.96 (s, 3H, OCH 3 ), 5.53 (dd, 1H, H X , J = 11.65, 4.21 Hz), 7.29 (d, 1H, Ar-H, J = 7.77 Hz), 7.46-7.54 (m, 3H, Ar-H), 7.69-7.80 (m, 2H, Ar-H), 7.96 (s, 1H, Ar-H), 11.82 (s, 1H, NH, D 2 O-exchangeble).
IR (KBr) cm -1 ; 3279 (N-H), 1615 (C=N), 1583 (C=C), 756 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 3.21 (dd, 1H, H A , J = 18.31, 4.50 Hz), 3.80 (s, 6H, OCH 3 ), 3.99 (dd, 1H, H B , J = 16.82, 12.22, Hz), 5.87 (dd, 1H, H X , J = 11.72, 4.23 Hz), 7.04-7.10 (m, 3H, Ar-H), 7.64-7.66 (m, 2H, Ar-H), 7.80 (t, 1H, Ar-H, J = 7.68), 7.95-7.98 (m, 2H, Ar-H), 11.19 (s, 1H, NH, D 2 O-exchangeble).
IR (KBr) cm -1 ; 3273 (N-H), 1620 (C=N), 1587 (C=C), 756 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 2.51 (s, 3H, CH 3 ), 3.16 (dd, 1H, H A , J = 18.13, 4.60 Hz), 3.77 (s, 6H, 2xOCH 3 ), 3.94 (dd, 1H, H B , J = 18.01, 12.11, Hz), 5.57 (dd, 1H, H X , J = 11.89, 4.59 Hz), 7.03-7.10 (m, 3H, Ar-H), 7.49-7.57 (m, 2H, Ar-H), 7.70-7.73 (m, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 11.86 (s, 1H, NH, D 2 O-exchangeble).
IR (KBr) cm -1 ; 3326 (N-H), 1626 (C=N), 1581 (C=C), 748 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 2.52 (s, 3H, CH 3 ), 3.18 (dd, 1H, H A , J = 18.07, 4.57 Hz), 3.76 (s, 6H, 2xOCH 3 ), 3.93 (dd, 1H, H B , J = 18.14, 12.23, Hz), 5.58 (dd, 1H, H X , J = 11.76, 4.63 Hz), 7.07-7.12 (m, 3H, Ar-H), 7.39-7.43 (m, 2H, Ar-H), 7.73 (d, 1H, Ar-H, J = 7.68 Hz), 7.98 (s, 1H, Ar-H), 11.53 (s, 1H, NH, D 2 O-exchangeble).
IR (KBr) cm -1 ; 3267 (N-H), 1630 (C=N), 1574 (C=C), 752 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 2.71 (s, 3H, CH 3 ), 3.16 (dd, 1H, H A , J = 18.06, 4.63 Hz), 3.73 (s, 6H, 2xOCH 3 ), 3.91 (dd, 1H, H B , J = 18.08, 12.17 Hz), 5.57 (dd, 1H, H X , J = 11.59, 4.61 Hz), 7.03-7.08 (m, 3H, Ar-H), 7.47-7.52 (m, 2H, Ar-H), 7.82 (d, 1H, Ar-H, J = 7.72 Hz), 8.03 (s, 1H, Ar-H), 11.49 (s, 1H, NH, D 2 O-exchangeble).
IR (KBr) cm -1 ; 3283 (N-H), 1634 (C=N), 1582 (C=C), 760 (C-Cl). 1 H-NMR (300 MHz, DMSO-d 6); δ 3.17 (dd, 1H, H A , J = 18.13, 4.69 Hz), 3.76 (s, 6H, 2xOCH 3 ), 3.86-3.96 (m, 4H, H B and OCH 3 ), 5.54 (dd, 1H, H X , J = 11.65, 4.71 Hz), 7.04-7.09 (m, 3H, Ar-H), 7.19 (s, 1H, Ar-H), 7.50 (d, 1H, Ar-H, J = 8.09 Hz), 7.89-7.95 (m, 2H, Ar-H), 8.02 (s, 1H, Ar-H), 11.73 (s, 1H, NH, D 2 O-exchangeble).
The newly synthesized compounds were tested for their growth inhibitory effect against bacterial strains, Escherichia More Details coli NCTC 10418, Staphylococcus aureus NCTC 65710, and Pseudomonas aeruginosa NCTC 10662, and also against fungal strains Aspergillus niger MTCC 281, Aspergillus flavus MTCC 277, Monascus purpureus MTCC 369, and Penicillium citrinum NCIM 768, by using the cup plate method. , Nutrient agar and potato dextrose agar were used as culture mediums for the antibacterial and antifungal activity, respectively. Using an agar punch, wells were made on these seeded agar plates and dilution of 200 μg/ml of test compounds, in DMSO, were added into each well, labeled previously. A control was also prepared using the DMSO solvent. The petri plate were prepared in triplicate and maintained at 30° for 72 hours for fungi and at 37°C for 24 hours for bacteria. Antimicrobial activity was determined by measuring the zone of inhibition and results have been reported in [Table 2] as the mean zone of inhibition in Millimeter ± Standard Deviation. Fluconazole and Ciprofloxacin at concentrations of 200 g/ml were used as reference drugs for the antifungal and antibacterial activities, respectively.
| Results and Discussion|| |
The synthesis of the new derivatives of pyrazoline were carried out as outlined in scheme 1. The chalcones were prepared by reacting 3,4-dichloro/3,4-dimethoxy acetophenone (1,2), with the appropriately substituted 2-chloro-3-formylquinoline (a-e), in the presence of base NaOH, by the conventional Claisen-Schmidt condensation. For this purpose the required substituted 2-chloro-3-formyl-quinoline was prepared from the substituted N-aryl acetamide by the action of DMF / POCl 3 using Meth-Cohn and Narine procedures.  The reaction of 3-(2-chloro-substituted-quinolin-3-yl)-1-(3,4-dichlorophenyl)prop-2-en-1-one (1a-e) and 3-(2-chloro-substituted-quinolin-3-yl)-1-(3,4 dimethoxyphenyl) prop-2-en-1-one (2a-e) with hydrazine hydrate was carried out by refluxing it in absolute ethanol in the presence of glacial acetic acid, which gave 2-chloro-3-[3-(3,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-5-yl]-substituted-quinoline (3a-e) and 2-chloro-3-[3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-5-yl]-substituted-quinoline (4a-e). The reaction time varied from 12 to 16 hours, and an yield ranging from 45 to 67% was obtained. The physicochemical data of pyrazolines have been mentioned in [Table 1].
The 1 H-NMR spectra of pyrazolines (3a-e, 4a-e) displayed three characteristic signals due to the diastereotopic proton , (H A , H B and H X ). The H A proton, was cis to H X resonated upfield in the range δ 3.16 - 3.21 as doublet of doublet (dd, J = ~ 18.07 and 4.60 Hz), while the H B proton was trans to H X resonated downfield in the range of 3.75 - 3.99 (dd, J =17.89 and 12.21 Hz). The H X proton which was vicinal to two methylene protons (H A and H B ) was also observed as doublet of doublet at d values ranging from 5.52 to 5.87 (dd, J = 11.74 and 4.66 Hz).
The cyclization of chalcone into pyrazolines was further supported by the 13 C-NMR of two prototype compounds 3a and 3b, in which the C-4 and C-5 carbon resonated at d 41.35 and 60.13 and 40.87 and 61.28, respectively. These values are in close agreement with the reported values for pyrazolines carbon C-4 and C-5. , DEPT-135 is an important tool of 13 C-NMR spectroscopy in which only the primary, secondary, and tertiary carbons, which have an attached proton, give a signal, but the phases of the signals are different, depending on whether the number of the attached hydrogen is an odd or even number. Signals arising from the CH or CH 3 group will give positive peaks, while signals arising from the CH 2 group will give negative (inverse) peaks.  DEPT-135 spectra of two compounds 3a and 3b revealed positive peaks at d 60.13 and 61.28, due to the CH of pyrazoline, that is, (C-5), and negative (inverse) peaks at 41.35 and 40.87, due to CH 2 of pyrazoline (C-4), respectively. The combination of 1 H-NMR, 13 C-NMR, and DEPT-135, provides a strong evidence in support of structures assigned to pyrazoline derivatives.
The FAB-MS spectra of two selected compounds, that is, 3a and 3b showed molecular ion peaks at m/z 377 and m/z 391. The (M+2) appeared at peaks m/z 379 and 393, respectively. These data were found to be satisfactory for the structures assigned to compounds (3a-e, 4a-e).
The newly synthesized compounds were screened for their antibacterial and antifungal activities against organisms Escherichia coli 10418, Staphylococus aureus NCTC 6571, Pseudomonas aeruginosa i>NCTC 10662, Aspergillus niger MTCC 281, Aspergillus flavus MTCC 277, Monascus purpureus MTCC 369, and Penicillium citrinum NCIM 768, in DMSO, by the cup plate method. On the basis of the observed zone of inhibition values, it appears that there are significant differences in the antibacterial and antifungal potentials of prepared quinolinyl pyrazolines. Although the difference among the responses of different compounds was not significant, with regard to the antimicrobial activity of pyrazolines, these compounds were comparatively more active against the bacterial and fungal strains. Pyrazoline derivatives showed 6.83 - 12.16 mm zone of inhibition against the fungal strains and compounds 3a, 3b, 3c, 3d, and 3e, exhibited the highest antifungal activity against Aspergillus niger MTCC 281 (10.58 - 12.16 mm). The pyrazoline derivatives exhibited very good antibacterial activity against the test organism (8.24 - 14.07 mm). Compounds 3a, 3b, 3c, and 3e exhibited potent antibacterial activity. A careful analysis of the antimicrobial activity data of the compounds [Table 2] suggested that 3,4-dichloro derivatives were comparatively more active in antimicrobial screening, with respect to their 3,4-dimethoxy analog, which may be attributed to the high C log P values.
| Acknowledgments|| |
The authors are thankful to the Department of Pharmaceutical Chemistry, Faculty of the Pharmacy, and Jamia Hamdard for providing the necessary facility, and also CDRI, Lucknow, India for recording the FAB-MS spectral data.
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[Table 1], [Table 2]