Analgesic and Anti-Oxidant Activities of Certain (E)-3 Arylidene Flavanones Synthesized by One Pot Method
Lincy Joseph* and Mathew George
School of Pharmacy, Jaipur National University, Jaipur, Rajasthan, India
*Corresponding Author E-mail: mathewlincg@yahoo.com
ABSTRACT
Objective of the study was to synthesize (E)-3-arylidene flavanones by one pot method and to screen synthesized compounds for their analgesic and anti-oxidant activities.
A set of four (E)-3 arylidene flavanones were synthesized by simple base catalyzed condensation of appropriate aryl aldehydes and 2’-hydroxy acetophenone. Analgesic activity screened by hot plate method and anti-oxidant activity evaluated by spectrophotometrically using 2,2-diphenyl-1-picrylhydrazyl (DPPH) .
Results indicated that only compound I, II, and III were showed remarkable analgesic activity while compound IV didn’t exhibited analgesic activity at all, but compound IV exhibited maximum anti- oxidant activity. Due to structural similarity with those of natural flavanones, all the synthesized compounds were expected to exhibit analgesic activity, but only three were found to exhibit analgesic action. But all exhibited anti-oxidant activity.
Graphical Abstract of Synthesis:
KEYWORDS: 2’-hydroxy acetophenone, Aromatic aldehyde, Curcumin, Analgesic , anti-oxidant.
INTRODUCTION:
3-Arylidene flavanones are also known as flavindogenides. Basic structure of (E)-3 arylidene flavanones have four rings, Ring A, Ring B, Ring C and Ring D.
Flavonoids are a group of polyphenolic compounds, which are widely distributed through out the plant kingdom (Katschalowsky.A et al., 1904). Their synthesis was performed mainly by the acid-catalyzed condensation of chromonones and aromatic aldehydes (F.Arndt et al., 1974, P.Pfeifer et al., 1988, O. Dann et al,.1982). Flavonoids can be classified into flavonols, flavones, flavanones and dihydroflavonols (Fanteen, A. K et al., 1978). 3-arylidene flavanones are also known as flavindogenides
In addition to basic structure of flavanone, (E)-3 -arylidene flavanone has an extended conjugation at C-3 with carbonyl group. The special feature of long conjugation with the keto group of flavanone moiety is expected to impart very significant biological activity of this type of compounds. Krishna murthy (Krishnamurthy et al., 1989) suggests (E)-3 arylidene flavanones and their heterocyclic analogues have poor solubility in aqueous medium starting either from 2-hydroxy chalcone or from o-hydroxy acetophenone. The reactivity of condensing aldehyde is an important factor in the synthesis. Presence of alcohol enhances the formation of products, which have been utilized for alkali-catalyzed synthesis of many arylidene flavanones been reported by them. Seikel et al.( Seikel M.K et al,,1962) and sha et al.( Shah, P.R et al.,1964) reported the formation of 3-arylidene flavanone in alkaline medium. Chawla et al. (Chawla H.M et al., 1987) reported the synthesis of seven 3- arylidene flavanone by condensing 2-Hydroxy acetophenones with aromatic aldehydes in aqueous alkaline medium, along with corresponding chalcones. According to these authors arylidene flavanones were accessible only by a low-yielding circuitous route. Knishnamurthy et al. (Krishnamurthy et al., 1989) concluded that 3-arylidene flavanones are obtained by acid catalyzed condensation between flavanone and aryl halide.
Katshalowsky and Kostanecky synthesized the first representatives of flavanoids in 1904(Katschalowsky.A et al., 1904). For a long time, (E)-3 Arylidene flavanones were synthesized solely by the acid catalyzed condensation of flavanone and aromatic aldehydes (Ryan, H.et al., 1929, Algar. J., M, et al., 1930, Diesbach. H. et al.,1945, Szell, T. et al 1968, Reichel. L. et al .,1968, Reichel.L. et al ., 1966,). The reaction usually has been performed in alcoholic solution saturated with anhydrous hydrochloric acid at various temperatures and for different time. Albert levai( Levai,A.J. et al, 1998) introduced photoisomerization of corresponding (Z)-3 isomers for the synthesis of (E)-3-arylidene flavanones. Keane et al .( Keane D.D et .al.,1970) explained the stereochemistry of synthetic(E) and (Z)- 3- arylidene flavanones. A mixture of equimolar amounts of flavanones and aromatic aldehyde and a few drops of piperidine was allowed to react at 1500 C and E-3 arylidene flavanones were obtained in good yield without any purification (A.Levai et al., 1992).
So here is an attempt made to synthesize a few (E)-3 -arylidene flavanones in an alkaline condition by one pot method and to screen the synthesized compounds for the analgesic and anti-oxidant activities.
MATERIALS and METHODS:
Chemicals used:
For the synthesis of proposed compounds, 2’-hydroxyacetophenone, 1,1-diphenyl-2-picrylhydrazyl and curcumin have been purchased from Sigma Aldrich chemical company Inc. U.S.A, benzaldehyde, furfuraldehyde, p-chloro benzaldehyde, and anisaldehyde have been purchased from S.D fine chemicals, Mumbai, India. Gum acacia, potassium hydroxide and methanol purchased from Nice Chemicals, Kochi, India.
Instruments used:
U.V : Beckman 650 iu Spectrophotometer
I.R : Shimadzu – FTIR 8300
I H NMR: Varian Gemini-200 MHz
Synthetic Protocol:
The proposed compounds were synthesized separately as per the following procedure; ( Dhara MG et al 1996). To each mixture of 2’-hydroxy acetophenone (1 mM) and an aromatic aldehyde (2.5 mM), a warm (450C) aqueous methanolic solution of potassium hydroxide (15%) was added and stirred the solution to get a uniform solution, the solution was kept standing for four days in a stoppered condition. Methanol was added dropwise to remove turbidity formed on cooling. The separated material was washed with cold aqueous alcohol (50 % methanol). Then recrystallized from aqueous methanol.
Basic structure of (E)-3-arylidene flavanone
Biological Experimental Protocol for Analgesic activity:
To study the analgesic activities of the synthesized compounds, albino mice of either sex were used. All mice were screened by exposure to thermal stimulus. Mice weighing between 20-25 g selected and made into six groups having six animals in each group. Respective compounds administered orally. The first group served as control which received only 2% gum acacia suspension. Second group received diclofenac sodium orally at a dose of 20mg/Kg body weight of animal. Remaining four groups had been given test compounds. Suspension of test compounds (20mg/ml) was prepared in 2% gum acacia. Animals were placed on perspax cylinder on heated surface and the time to exhibit discomfort reaction (licking paws or jumping) was considered as reaction time with the cut off time being 60 seconds. The first reading was taken immediately after administration of compounds and afterwards at the intervals of 30 minutes. The results were recorded.
Experimental protocol for Anti-oxidant activity:
Equimixture of 1,1-diphenyl-2-picrylhydrazyl (3.9 mg in 10 ml ethanol) and test compounds (10 mg /10 ml ethanol) mixed and kept for 20 minutes at room temperature. Then absorbance measured at 517 n.m. Curcumin used as standard drug to compare the activity.
Assessment of Synthesized compounds:
Physical data of tested compounds are as follows. Ethanol was used as solvent to find out λ -max by U.V spectroscopy. KBr pellets were used to measure I.R spectrum and CDCl3 used for 1 HNMR spectrum.
Compond I: (Chemically: 2-phenyl, 3-benzylidene chromonone)
λ -max-244 n.m, Molecular weight-312, % yield-25%
I.R (KBr): 1650.77 c.m -1 (C=O), 1286.29 and 1195.65 c.m -1 (C-0-C), 3110.54 and 3305.39 c.m -1 (C-H), 836.95 and 782.958 c.m -1 (C-H def), 1596.77 and 1382.71 c.m -1 (C=C).
1HMR(CDCl3 ppm): 6.65-6.68(H-2), 6.9-7(H-6, H-8), 7.25(CHCl3), 7.9-8(H-3), 7.2-7.4(H).
Compound II: (Chemically: 2-furanyl, 3-furylidene chromonone)
λ -max – 232 n.m, Molecular weight – 292. % yield- 30%
Table:1 Analgesic activity of synthesized compounds.
|
Compound I.D |
Dose(orally) Mg/Kg |
Average reaction time in seconds a after administration |
|||
|
0 |
30 |
60 |
90 |
||
|
I |
200 |
3.25 |
3.55 |
3.59 |
3.59 |
|
II |
200 |
3.30 |
4.00 |
4.00 |
4.00 |
|
III |
200 |
3.00 |
4.25 |
4.50 |
4.40 |
|
IV |
200 |
2.50 |
2.58 |
2.59 |
2.55 |
|
Std. |
200 |
3.00 |
5.25 |
8.25 |
8.28 |
|
Control |
----- |
3.00 |
3.00 |
3.00 |
3.00 |
a=Average reaction time expressed as mean (±S.D) of a group.
Table2:Anti-oxidant activity.
|
Compound I.D |
Absorbance at 517 n.m |
Relative % activity considering that of standard as 100% |
|
Curcumin |
2.596 |
100% |
|
I |
0.662 |
25.5% |
|
II |
0.748 |
28.8% |
|
III |
1.826 |
70.31% |
|
IV |
2.142 |
77.5% |
I.R (KBr): 1658.41 c.m -1(C=O), 1272.79 and 1151.9 c.m -1 (C-O-C),2967 c.m -1 (C-H), 763.673 and 833.098 c.m -1 (C-H def), 1575.56 and 1533.49 and 1413.57 c.m -1 (C=C). 1HMR(CDCl3 ppm) 6.1-6.2(H-3’,H-4’), 6.5-6.55(H-4”), 6.92-6.953(H-.9-8(H-5)8),
7-7.07(H-6),7-7.1(H-2),7.25 CHCl3, 7.4-7.5 (H-7), 7.5-7.6(H-5”),7.9-8(H-5).
Compound III: (Chemically: 2-phenyl,3-benzylidene, chloro chromonone)
λ-max-240 n.m. , Molecular weight- 346, % yield – 27%.
I.R(KBr):1657.53 c.m -1(C=O), 1248.65 and1160.94 c.m -1(C-O-C), 2927.41 c.m -1(C-H),914.093 c.m -1(C-H def), 767.53 c.m -1(Cl), 1610.27 and 1419.35c.m -1(C=C).
1HMR (CDCl3ppm) 6.5-6.56(H-2), 6.9-7(H-6, H-8), 7.9-7.96(H-5), 8.02-8.05(H-β).
Compound IV: (Chemically: 2-phenyl,3-benzylidene methyl chromonone)
λ-max- 230 n.m, Molecular weight-372, % yield – 33%.
I.R(KBr):1664.12c.m-1 (C=O),1361.5 and 1249.65c.m-1 (C-O-C), 943.02 and 844.669 c.m-1 (C-H def), 1637.27, 1523.49 and 1454.06(C=C).
1HMR(CDCl3 ppm): 6.59-6.625(H-2),6.82-7.0(H-6, H-8, H-3’, H-5’),7.2-7.43(H-7, H-2’, H-6’, H-2”, H-6”), 3.7-3.9 (OCH3 proton),9.1-7.95 (H-5),3.99(OCH3),8.02-8.2(H- β).
RESULTS:
As per the synthetic protocol four E-3 Arylidene flavanones have been synthesized and screened for their analgesic activity by hot plate method. Anti-oxidant activity tested by spectrophotometric method. Although the yields were relatively low((25-33%)given in assessment of synthesized compounds ), crystals formed were pure. The structures of the compounds prepared (I-IV) were elucidated by IR and I H NMR spectroscopy. Characterestic C=O band is found between 1650-1664 c.m-1.Observations for analgesic activity are shown in table1, that of anti-oxidant activity in table 2.
DISCUSSIONS:
Four E-3 Arylidene flavanones have been synthesized by one pot method.
The results of the assessment of synthesized compounds have good agreement with the data given in the literature for this type of compounds.(Boykin DW et al.,1991).
Due to structural similarity with those of natural flavanones, all the synthesized compounds were expected to exhibit analgesic activity, as per the studies only three were found to exhibit analgesic action. The results shows less analgesic activity for all tested compounds than the standard drug namely Diclofenac sodium. Among the four compounds compound III shows maximum analgesic activity whereas compound IV showed the least analgesic activity. Among the three active compounds, compound III showed higher activity than others, probably due to the presence of a more electronegative atom like chlorine.
Considering anti-oxidant activity, in contrast to analgesic activity compound IV showed maximum activity and compound I showed least activity. More anti-oxidant activity of compound-IV may be due to the presence of methoxyl group.
CONCLUSION:
In summary, it can be concluded that we have synthesized four (E)-3 arylidene flavanones in a simple aqueous –alkaline medium at room temperature. According to difference in substitution, their extent of biological activity also varied. An inverse relationship between analgesic and antioxidant activity observed as compound IV didn’t showed analgesic activity, but had maximum anti-oxidant activity among the synthesized compounds.
ACKNOWLEDGEMENTS:
The authors are thankful for those who gave suggestions and comments during the research which made more progress. Also wish to thank Sigma Aldrich, S.D Fine chemicals and Nice Chemicals, Kochi.
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Received on 28.05.2009 Modified on 05.07.2009
Accepted on 08.08.2009 © AJRC All right reserved
Asian J. Research Chem. 2(3): July-Sept., 2009, page 318-321