Synthesis and antibacterial activity of some new (2E)-1-(8-hydroxyquinolin-7-yl)-3-(Aryl) prop-2-en-1-one, Derivatives of Chalcone.
Anuruddha R. Chabukswar1*, Bhanudas S. Kuchekar1, Pradeep D. Lokhande2, Archana S. More3, Neha S. Ojha1, Ashwini M. Londhe1.
1Maharashtra Academy of Engineering And Educational Research’s , Maharashtra Institute of Pharmacy S.No.124, MIT Campus, Paud Road, Pune- 411038,M.S.,India.
2Department of Chemistry, University of Pune, Pune- 411007, M.S., India.
3J.S.P.M.’s Jayawantrao Sawant College of Pharmacy & Research Hadapsar Pune-411028, M.S., India.
*Corresponding Author E-mail: anichem18@gmail.com
ABSTRACT:
Present work describes the synthesis of (2E)-1-(8-hydroxyquinolin-7-yl)-3-(Aryl) prop-2-en-1-one, derivatives of Chalcones. Starting material 8- hydroxy quinoline was acetylated and subjected to fries rearrangement reaction to yield 7-acetaldehyde-8-hydroxy quinoline which on aldol condensation with various derivatives of benzaldehyde yields 13 compounds. The compounds have been characterized and evaluated for anti-bacterial activity. MIC values of the compounds showing higher zone of inhibition was found to be 100 µg/ml. The activity of the compounds can be attributed to the substitution of electronegative groups in the synthesized compounds.
KEY WORDS: anti-bacterial activity, benzaldehyde, Chalcone, electronegative, 8-hydroxyquinoline
INTRODUCTION:
Chalcones are α, β -unsaturated ketones which constitute an important group of natural products that serve as precursors for the synthesis of various heterocyclic compounds. Chalcones, analogs of 1,3-diarylprop-2-en-1- one, form a wide class of compounds containing two aromatic rings bound with vinyl ketone fragment. Chalcones, either natural or synthetic, are known to exhibit various biological activities like antimalarial1, antibacterial2, antifibrogenic3, anticancer4, antitrichomonal5, anti-inflammatory6, antileishmanial7, cytotoxic and anti trypanosome cruzi8.
The quinoline nucleus is an important structural moiety in a number of complex chemotherapeutic agents. Substituted quinoline and their benzo and hetero fused analogues represent an important class of heterocyclic compounds due to their presences in numerous biologically active natural products. Quinoline analogues have a wide variety of medicinal properties including antitumor, antiviral and antibacterial activities 9-11.
Literature survey reveals that 4-chloro-2-phenyl quinolin-3-ol derivatives are pharmacologically active units. Prompted by the therapeutic importance of these two bioactive moieties it was decided to develop novel, simple, economical method for synthesis of variety of chalcone derivatives starting from 8-hydroxy quinoline and various substituted benzaldehydes. The compounds have been subjected for evaluation of anti-bacterial activity.
MATERIALS AND METHODS:
All chemicals used were of analytical grade from, SD Fine. Melting point (MP) of all the synthesized compounds were determined by open capillary tube method. These are uncorrected. The purity of all compounds was checked by TLC. TLC was run on Silica Gel G plates using Chloroform and Methanol (9:1). Spots were visualized using iodine vapor chamber. IR spectra were recorded on Shimadzu IR spectrophotometer by using KBr pellets technique.1H-NMR was recorded on Burke AMX 60 MHz spectrophotometer by using DMSO as solvent.
Synthesis
Experimental procedure
Step I: Synthesis of 8- acetate quinoline from 8- hydroxy quinoline.
7.250 gm (0.05mol) of 8- hydroxy quinoline was taken in 250 ml RBF and kept in ice bath, to this 4.42 ml (0.05 mol) of acetyl chloride and 25ml of methylene di chloride were added. The reaction mixture was stirred for 2 hr. The completion of reaction was monitored by TLC using n – hexane: acetone (3:2) as a mobile phase. Slight yellowish white colored precipitate was obtained which was filtered, washed with methylene dichloride, dried and recrystalized from hot water.
Step II: Synthesis of 7- acetaldehyde-8-hydroxy quinoline from 8- acetate quinoline.
6.54 gm. of 8- acetate quinoline and 16.65 gm. of Aluminum tri chloride (1: 2.5) were refluxed in RBF at 1600C for 1.5 hr. A orange colored mass was obtained. Dilute hydrochloric acid was added to break the Aluminium – Quinoline complex. Para and Ortho isomers formed were separated by steam distillation. Separation of isomer was monitored by TLC method using n-heptane:ethylacetate as mobile phase.
Step III: Synthesis of Quinoline derivative of piperine.
1 mole of 7-acetal-8- hydroxyl Quinoline was dissolved in 5ml of 20%NaOH. 1 mole of benzaldehyde derivative was added to this reaction mixture and the reaction mixture was kept at room temperature for 5 min. 20 ml of ethanol was added as solvent. Reaction mixture was kept for stirring for 6 - 8 hr. Product formed was poured in ice cold water PH was adjusted to 4 with 10% HCl. Product was Filtered and washed, and dried.
All the synthesized compounds were characterized by TLC, IR, NMR and elemental analysis (Table 1).
Antibacterial activity:
The in vitro anti-bacterial activity was evaluated by using the agar plate diffusion method12, 13 by measuring the zone of inhibition in mm. All the compounds screened in vitro for their anti-bacterial activity against bacterial strains such as gram positive (Bacillus subtilis NCIM 3251, Staphylococcus aureus NCIM 4200) and gram negative (P. aeurigenosa NCIM 4321, Escherichia coli NCIM 8900, Salmonela typhi NCIM 3782). All the microbial strains were standardized by McFarland Standard method and 108 cfu/ml concentration of microbial culture was used. Ciprofloxacin (10 μg/ml) was used as standard. The compounds were prepared in DMSO (10-100μg/ml). The results of the in vitro anti-bacterial activities are summarized in Table 2.
RESULT AND DISCUSSION:
We have synthesized 13 Quinoline derivatives of Chalcone. In the first step 8-hydroxy quinoline was acetylated and in second step fries rearrangement was used to synthesize of 7- acetaldehyde-8-hydroxy quinoline. In the final step various substituted benzaldehyde were subjected for aldol condensation to yield chalcone derivatives. The FTIR spectra of final derivatives showed the expected bands for the characteristic groups which are present in the compounds expressed in cm-1.1H NMR spectra of final derivatives obtained in CDCl3 showed the expected chemical shift values in ppm using TMS (δ=0) as internal standard.
General Structure of quinoline derivatives of chalcone
Synthesized compounds shows characteristic IR ranges NH stretching (3300-3500 cm-1), C=O (1750-1705 cm-1), OH Streching (3500-3200 cm-1), C=C aliphatic (1695-1587 cm-1). 1H NMR spectrum of synthesized derivatives shows δ (ppm) ranges in between 7-8 ppm for aromatic nucleus and 5ppm for hydroxyl group.
QP1: (2E)-1-(8-hydroxyquinolin-7-yl)-3-(3-nitrophenyl) prop-2-en-1-one.
Yd: 81%. Rf: 0.54. Mp: 79 °C. IR shows the peaks at 3387 cm-1 (NH Str.); 3085 cm-1 (C-H Str.) ; 1665 cm-1 (C=C Str.); 1605 cm-1 (C=C str.Aromatic ring); 1726 cm-1 (C=O). 1H NMR ( CDCl3) shows δ ppm value at 8.19 δ (d, 2H) ; 7.88 δ (m, 4H) ;7.49 δ (m, 3H) ; 7.29 δ (d, 2H) ; 5 δ (s, 1H) ; Anal. Calcd. for C18H12N2O4: C, 67.5; H, 3.75; N,8.75; O, 19.981, found : C,65; H,4; N,7.65; O,18.75
QP2: (2E)-3-(3-ethoxy-2-hydroxyphenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd: 71.25%. Rf: 0.76. Mp: 58 °C. IR shows the peaks at 3565 cm-1(NH Str.); 1069 cm-1 (-OH Str.); 1592 cm-1 (C=C Str.); 1463 cm-1 (C=C str.ring); 1767 cm-1 (C=O). 1H NMR ( CDCl3) shows δ ppm value at 8.80 δ (d, 1H) ; 7.48 δ (d, 2H) ;7.69 δ (t,1H) ; 7.78 δ (t,1H) ; 5 δ (s, 1H) ; 6.47 δ (d, 2H) ;6.19 δ (t,1H) ; 8.46 δ (d,2H) ; 3.98 δ (s, 5H) ; Anal. Calcd. for C20H17NO4 : C,71.566; H,5.069; N,4.175; O,19.084, found: C,72; H, 4.957; N,7.85; O,20
QP3: (2E)-3-(3-chlorophenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one
Yd: 60%. Rf: 0.68. Mp: 72 °C. IR shows the peaks at 3218 cm-1(NH Str.); 1123 cm-1 (C-OStr.); 1687 cm-1 (C=C Str.); 1487 cm-1 (C=C str.ring); 1761 cm-1 (C=O). 1H NMR ( CDCl3) shows δ ppm value at 8.08 δ (d, 2H) ; 7.61 δ (t, 1H) ;7.57 δ (t,1H) ; 5.0 δ (s,1H) ; 7.35 δ (t,2H) ; 7.99 δ (d, 2H) ;7.28 δ (t,1H) ; Anal. Calcd. For C18H12ClNO2: C,69.735; H,3.874; N,4.52; O,10.331; Cl,11.461, found: C,70; H,3.75; N,5.07; O,9.851; Cl,12.081
QP4: (2E)-3-(2,4-dichloro-1-hydroxyphenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd:75%. Rf:0.74. Mp:97 °C. IR shows the peak at 3474 cm-1(NHStr); 1015 cm-1 (C-OStr.);
1661cm-1 (C=C Str.); 1568 cm-1 (C=C str.ring); 1728 cm-1 (C=O); 3651 cm-1(OH); 732 cm-1(Ortho); 709 cm-1(C-Cl). Anal. Calcd. . for C18H11Cl2NO3: C,59.968; H,3.054; N,3.887; O,13.326; Cl,19.712, found: C,58.897; H,4; N,9.05; O,20.09; Cl,20.086
QP5: (2E)-3-(1-hydroxy-4-methylphenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd:68%. Rf:0.81. Mp:154 °C. IR shows the peak at 3436 cm-1(NHStr); 1041 cm-1 (C-OStr.); 1642cm-1 (C=C Str.); 1564 cm-1 (C=C str.ring); 1762cm-1 (C=O); 3556 cm-1(OH); 739 cm-1(Ortho); Anal. Calcd. . for C19H15NO3: C,74.674; H,4.913; N,4.585; O,15.721, found: C,75; H5.06; N,5.86; O,16.02
QP6: (2E)-3-(4-chloro-1-hydroxyphenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd;65%. Rf :0.59. Mp:94 °C. IR shows the peak at 3537cm-1(NHStr); 1655cm-1 (C=C Str.); 1475 cm-1 (C=C str.ring); 1770 cm-1 (C=O); 3318 cm-1(OH); 739 cm-1(Ortho); Anal. Calcd. for C18H12ClNO3: C,66.309; H,3.684; N,4.298; O,14.735; Cl,1.067 found: C,67; H,3.75; N,4.267; O,13.981; Cl,2.083.
Table 1: Physical data of synthesized Derivatives:
|
Prod. Code |
R1 |
R2 |
R3 |
R4 |
R5 |
% Yield |
M.P. (0C) |
R.F. Value |
|
QP1 |
H |
No2 |
H |
H |
H |
81% |
79 |
0.54 |
|
QP2 |
OH |
OC2H5 |
H |
H |
H |
71.25% |
58 |
0.76 |
|
QP3 |
H |
Cl |
H |
H |
H |
60% |
72 |
0.68 |
|
QP4 |
OH |
Cl |
H |
Cl |
H |
75% |
97 |
0.74 |
|
QP5 |
OH |
H |
H |
CH3 |
H |
68% |
154 |
0.81 |
|
QP6 |
OH |
H |
H |
Cl |
H |
65% |
94 |
0.59 |
|
QP7 |
OH |
H |
H |
Br |
H |
45% |
115 |
0.63 |
|
QP8 |
H |
H |
H |
H |
H |
70% |
124 |
0.54 |
|
QP9 |
H |
OC2H5 |
OC2H5 |
H |
H |
40% |
67 |
0.74 |
|
QP10 |
H |
H |
Cl |
H |
H |
55% |
75 |
0.65 |
|
QP11 |
H |
H |
OCH3 |
H |
H |
42% |
82 |
0.75 |
|
QP12 |
Cl |
H |
H |
H |
H |
58% |
68 |
0.69 |
|
QP13 |
Br |
H |
H |
H |
H |
47% |
76 |
0.72 |
QP7: (2E)-3-(4-bromo-1-hydroxyphenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd:45%. Rf:0.63. Mp:115 °C. IR shows the peak at 3241 cm-1(NHStr); 1070cm-1 (C-OStr.); 1674cm-1 (C=C Str.); 1456 cm-1 (C=C str.ring); 1762 cm-1 (C=O); 3664 cm-1(OH); 538cm-1(C-Br); Anal. Calcd.for C18H12BrNO3: C,58.347; H,3.242; N,3.782; O,12.966; Br,21.584; found: C,59; H,3.21; N,4; O,12.898; Br,22.345
QP8: (2E)-1-(8-hydroxyquinolin-7-yl)-3-phenylprop-2-en-1-one
Yd: 70%. Rf: 0.54. Mp: 124 °C. IR shows the peaks at 3060 cm-1(NH Str.); 1071 cm-1 (C-OStr.); 1694 cm-1 (C=C Str.); 1495 cm-1 (C=C str.ring); 1706 cm-1 (C=O);3559 cm-1 (-OH); 1H NMR ( CDCl3) shows δ ppm value at 8.65 δ (d, 1H) ; 8.19 δ (d, 1H) ;7.68 δ (d,2H) ; 7.48 δ (d,2H) ; 7.27 δ (m,6H) ; 5.00 δ (s,1H); Anal. Calcd. for C18H13NO2 : C,78.46; H,4.722; N,5.085; O,11.624 found: C,79; H,4.223; N,6.025; O,12.876
QP9: (2E)-3-(2,3-diethoxyphenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd:40%. Rf:0.74. Mp:67 °C. IR shows the peak at 3228 cm-1(NHStr); 1130 cm-1 (C-OStr.); 1685cm-1 (C=C Str.); 1584 cm-1 (C=C str.ring); 1716 cm-1 (C=O); 3617 cm-1(OH); 2825 cm-1(C-OC); 762 cm-1 (Ortho)Anal. Calcd. for C22H21NO4: C,72.646; H,5.779; N,3.852; O,17.611 found: C,73; H,5.678; N,4.08; O,18
QP10: (2E)-3-(3-chlorophenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd:55%. Rf:0.65 Mp:75 °C. IR shows the peak at 3554 cm-1(NHStr); 1621cm-1 (C=C Str.); 1469 cm-1 (C=C str.ring); 1729cm-1 (C=O); 3644 cm-1(OH); 2359 cm-1(C-N Str); 754 cm-1(C-Cl). Anal. Calcd. for C18H12ClNO2: C,69.735; H,3.874; N,4.52; O,10.331; Cl,11.461 found: C,70.04; H,3.97; N,5.08; O,12.098; Cl,12.03
QP11: (2E)-3-(3-methoxyphenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one .
Yd:42%. Rf:0.75. Mp:82 °C. IR shows the peak at 3310 cm-1(NHStr); 1026 cm-1 (C-OStr.); 1684cm-1 (C=C Str.); 1516 cm-1 (C=C str.ring); 1745 cm-1 (C=O); 3620 cm-1(OH); 771 cm-1(Ortho); 2838cm-1(C-CH3). Anal. Calcd. for C19H15NO3: C,74.674; H,4.913; N,4.585; O,15.721 found: C,75.08; H,4.90; N,4.68; O,16.08
QP12: (2E)-3-(1-chlorophenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd:58%. Rf:0.69. Mp:68 °C. IR shows the peak at 3060 cm-1(NHStr); 1050 cm-1 (C-OStr.); 1667cm-1 (C=C Str.); 1573 cm-1 (C=C str.ring); 1725 cm-1 (C=O); 3648 cm-1(OH); 749 cm-1(Ortho); 799 cm-1(C-Cl). Anal. Calcd. for C18H12ClNO2: C,69.735; H,3.874; N,4.52; O,10.331; Cl,11.461; found: C,70.087; H,4.06; N,5.07; O,11.08; Cl,12.09
QP13: (2E)-3-(1-bromophenyl)-1-(8-hydroxyquinolin-7-yl) prop-2-en-1-one.
Yd:47%. Rf:0.72. Mp:76°C. IR shows the peak at 3160cm-1(NHStr); 1685cm-1 (C=C Str.); 1567 cm-1 (C=C str.ring); 1795 cm-1 (C=O); 3610 cm-1(OH); 747 cm-1(Ortho); 598 cm-1(C-Br). Anal. Calcd. for C18H12BrNO2: C,60.983; H,3.388; N,3.953; O,9.035; Br,22.559 found: C,61; H,3.876; N,3.977; O,10.01; Br,23.09
Amongst all the synthesized compounds, compounds QP1 and QP 11 have shown the poor inhibition against all the selected bacterial strains. Compounds QP2, QP5, QP8 and QP9 showed moderate inhibition. Compounds QP3, QP4 QP6, QP7, QP 10, QP12, QP13 showed maximum inhibitory activity against all the Gram positive and Gram negative bacteria. The variation in activity could be due to electronegative atom present in the substituted compounds. Minimum Inhibitory Concentration (MIC) values for the compounds having maximum zone of inhibition was found to be 100 μg/ml.
Table 2: Zone of Inhibition of the compounds
|
Sr. No. |
Code of Compound |
Zone of inhibition (mm) |
||||
|
B. subtilus |
S. aureus |
P. aeurigenosa |
E. coli |
S. typhi |
||
|
1) |
QP1 |
10 |
12 |
14 |
13 |
11 |
|
2) |
QP2 |
18 |
16 |
19 |
18 |
20 |
|
3) |
QP3 |
20 |
21 |
22 |
24 |
21 |
|
4) |
QP4 |
21 |
22 |
24 |
21 |
21 |
|
5) |
QP5 |
16 |
18 |
18 |
17 |
20 |
|
6) |
QP6 |
21 |
24 |
23 |
22 |
21 |
|
7) |
QP7 |
22 |
23 |
21 |
22 |
23 |
|
8) |
QP8 |
16 |
17 |
19 |
18 |
17 |
|
9) |
QP9 |
18 |
17 |
16 |
17 |
19 |
|
10) |
QP10 |
21 |
24 |
21 |
25 |
23 |
|
11) |
QP11 |
10 |
12 |
11 |
14 |
10 |
|
12) |
QP12 |
22 |
24 |
23 |
24 |
25 |
|
13) |
QP13 |
21 |
23 |
21 |
23 |
24 |
|
14) |
Ciprofloxacin |
26 |
28 |
28 |
29 |
25 |
Maximum inhibition: > 20 mm, Moderate inhibition: 16-20 mm, Poor inhibition: 10-15 mm. NA: No activity
SUMMARY AND CONCLUSION:
Synthesis of quinoline derivatives of chalcone using inexpensive starting material 8-hydroxy quinoline and various derivatives of benzaldehyde have been attempted successfully. The method is novel, low cost, and environmental friendly. The data reveals that, the compounds substituted with Chlorine, bromine, nitro derivatives have proven to be effective antibacterial agents against Gram positive and Gram negative organisms. These compounds can be explored further for their potential activity against resistant bacterial strains.
ACKNOWLEDGMENT:
The authors are thankful to the Management of Maharashtra Academy of Engineering and Educational Research, Pune 411 038 for providing necessary facilities to carry out this research work.
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Received on 21.09.2012 Modified on 09.10.2012 Accepted on 24.10.2012 © RJPT All right reserved
Research J. Pharm. and Tech. 5(11):November, 2012; Page 1452-1456