Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                            ISSN 0974 – 9446 SYNTHESIS AND P...
Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                                       ISSN 0974 – 9446promi...
Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                               ISSN 0974 – 9446             ...
Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                             ISSN 0974 – 9446water, dried an...
Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                             ISSN 0974 – 9446N`[(4-acetamido...
Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                             ISSN 0974 – 9446One group has b...
Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                           ISSN 0974 – 9446TABLES AND FIGURE...
Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                               ISSN 0974 – 9446             ...
Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024                             ISSN 0974 – 9446               ...
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Synthesis and pharmacological screening of some benzoxazole derivatives as an anti inflammatory agents

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Synthesis and pharmacological screening of some benzoxazole derivatives as an anti inflammatory agents

  1. 1. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446 SYNTHESIS AND PHARMACOLOGICAL SCREENING OF SOME BENZOXAZOLE DERIVATIVES AS AN ANTI-INFLAMMATORY AGENTS Sunila T. Patil1* , Dr.Parloop A. Bhatt2 1 Research Scholar Jodhpur National University, Jodhpur-342003, Rajasthan, India. 2 L. M. College of Pharmacy, Ahmedabad-380009, Gujrat, India. Sunila Patil Email:Devanshu31@gmail.comABSTRACT The main objective of the medicinal chemistry is to synthesize the compounds that show promisingactivity as therapeutic agents with lower toxicity. Benzoxazole derivatives are very useful compoundwith well known biological activity. Notable among these are antibacterial, antiviral ,antifungal,analgesic, anti-inflammatory and antitubercular. In the current research work, the title compoundsN`[substituted sulfonyl]-1,3-benzoxazole-5-carbohydrazide, were synthesized by electrophilic aromaticsubstitution on p-hydroxy methyl benzoate (I) with concentrated nitric acid and concentrated sulfuricacid under reflux condition. Compound (II) on reduction with sodium dithionate with alcohol gives 3-amino-4-hydroxy-benzoic acid methyl ester (III). Reaction of compound (III) with two appropriatealiphatic acids (formic acid and acetic acid) produced corresponding 2-subtituted benzoxazole-5-carboxylic acid methyl esters. The reaction of compounds (IV) with hydrazine hydrate in ethanol onrefluxing yielded the corresponding 2-substituted benzoxazole-5-carboxylic acid hydrazides. On furtherreaction of compounds (V) with the different sulfonyl chloride derivatives afforded the correspondingeight N`[substituted sulfonyl]-1,3-benzoxazole-5-carbohydrazide. The identification and characterizationof the synthesized compounds were carried out by Elemental analysis, melting point,Thin LayerChromatography, FT-IR, NMR and Mass data to ascertain that all synthesized compounds were ofdifferent chemical nature than the respective parent compound. The compounds were screened foranti-inflammatory activity. The antiinflammatory activity of compounds was done by using carrageenaninduced rat paw edema method. The test compounds VIa, VId and VIe showed significantantiinflammatory activity compared with the standard drug Ibuprofen.Key Words: Anti-inflammatory activity. Benzoxazole, Carrageenan, Ibuprofen..INTRODUCTION The main objective of the medicinal chemistry is to synthesize the compounds that show International Journal of Pharma Research and Development – Online www.ijprd.com 165
  2. 2. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446promising activity as therapeutic agents with compounds were also subjected to C, H, N andlower toxicity. Benzoxazoles have been S analysis(ThermoFinnigan) at IIT Mumbai.reported to show a broad spectrum of biological scheme of synthesisactivities. Notable among these areantihistaminic [1], antifungal[2], Cyclooxygenase COOCH3Inhibiting[3], antitumor[4], antiulcer[5],anticonvulsant[6], hypoglycemic[7], anti-inflammatory[8,9] and antitubercular activity[10].The pharmacological properties of HOBenzoxazoles encouraged our interest in (I)synthesizing several new compounds. In the Methyl p-hydroxy benzoate (I)present study we synthesized a series of somenovel eight derivatives of N`[substitutedsulfonyl]-1,3-benzoxazole-5-carbohydrazide. H2SO4,HNO3The compounds were screened for Anti- (0-15o)inflammatory Activity. CONHNHSO2R2 O2N COOCH3 NR1 O HO N`[substituted sulfonyl]-1,3-benzoxazole-5- (II) carbohydrazide 4-Hydroxy-3-nitro-benzoic acid methyl ester (II)MATERIALS AND METHODS Na2S2O4,H2O Reflux,1.5hAll the reagents and solvents used were oflaboratory grade. The melting points of H2N COOCH3synthesized compounds were determined byopen capillary method and were uncorrected.The purity and homogeneity of compoundswere checked using TLC technique. IR HOspectra[11] of compounds were recorded using (III)KBr pellets on Perkin Elmer 337 3-Amino-4-hydroxy-benzoic acid methyl esterspectrophotometer. 1H-NMR spectra[12] were (III)recorded on Bruker Avance-300 MHz R1COOHSpectrophotometer using dimethyl sulfoxamideas solvent at Indian Institute of Technology(IIT), Reflux, 2hMumbai. Mass Spectra of the synthesizedcompounds were recorded on LiquidChromatography Mass Spectrometer at IndianInstitute of Technology(IIT), Mumbai. The International Journal of Pharma Research and Development – Online www.ijprd.com 166
  3. 3. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446 COOCH3 N`[substituted sulfonyl]-1,3-benzoxazole-5- N carbohydrazide R1 • Synthesis and Characterization of Compounds: O (IV) 1) 4-Hydroxy-3-nitro-benzoic acid methyl 2-subtituted benzoxazole-5-carboxylic acid ester (II) methyl ester (IV) In a 1 lit. three necked round bottom NH2NH2, H2O Ethanol flask equipped with water condenser, Reflux, 4h mechanical stirrer and thermometer, of p- hydroxy methyl benzoate (10 g, 0.74 mol) was CONHNH2 placed. A mixture of concentrated suphuric acid N (6.2 ml) and concentrated nitric acid (6.2 ml) in R1 a dropping funnel, cool the flask in an ice bath to 0-10ْ° and then run in the nitrating mixture in O p-hydroxy methyl benzoate with stirring, while (V) maintaining the temperature of the reaction 2-substituted benzoxazole-5-carboxylic acid between 5 to 15° the addition continued upto 1 ; hydrazide (V) h. Poured the reaction mixture in to of crushed R2SO2Cl ice (70 g). Filtered off the crude m-nitro, p- Dry Pyridine hydroxy methyl benzoate at the pump and wash 0-10o, 2h with cold water. Transfer the solids into 500 ml CONHNHSO2R2 flask and stirred it with ice cold methanol in N order to remove a small amount of ortho isomer R1 and other impurities. The mixture was filtered with suction and washed with little methanol and O dried in the air. Then the product was (VI) recrystallised using methanol as solvent. Percentage Yield- 84%, M.P. 65-67° Rf-0.76 , N`[substituted sulfonyl]-1,3-benzoxazole-5- (Ethyl acetate: methanol, 1:1), carbohydrazide ۫2) 3-Amino-4-hydroxy-benzoic acid methylLead Nucleus with Different substituents (R1 ester (III)and R2) were summarized in Table No.1: In a 500 ml three necked flat bottom flask equipped with reflux condenser with guard tube, compound II (10 g) was dissolved in boiling alcohol (50%, 100 ml) and sodium dithionate was added to this boiling alcohol solution until it CONHNHSO2R2 becomes almost colorless. Then the alcohol N was reduced to one third of its volume by R1 distillation and the residual liquid was triturated with ice cold water. The resulting colorless, O shiny product was filtered, washed with cold International Journal of Pharma Research and Development – Online www.ijprd.com 167
  4. 4. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446water, dried and recrystalise using methanol as b) 2-methyl-benzoxazole-5-carboxylic acidsolvent. hydrazide (Vb)Percentage Yield- 70%, M.P. 110-112° Rf- , Percentage Yield- 80%, M.P. 144-146°C, R-0.67 (Saturated methanol), f -0.7 (Methanol)3) 2-subtituted benzoxazole-5-carboxylic 5) N`[substituted sulfonyl]-1,3-benzoxazole-acid methyl ester (IV) 5-carbohydrazide (VIa-h) Compound III (0.01mol) was heated with an To a cooled and stirred solution of compoundappropriate aliphatic acid (formic acid and VIa and VIb (4 g) in pyridine (25 ml) tolueneacetic acid) in excess under reflux for 2h. The sulfonyl chloride was slowly added (3.8 ml).reaction mixture was cooled and poured in After two hours the solution was poured intocrushed ice (100 gm) with stirring. The product mixture of ice and concentrated hydrochloridethus separated was filtered under suction and acid and water; the pale yellow coloredwashed with cold water. The products were precipitate was recovered. Washed with diluterecrystallised by using methanol as a solvent. hydrochloric acid and water, and wasThe following two compounds were prepared by recrystallised using ethanol as a solvent.the above mentioned procedure,a) Benzoxazole-5-carboxylic acid methyl Compound (VIa)ester (IVa) N`[(4-methyl phenyl)sulfonyl]-1,3- Percentage Yield- 80%, M.P.74-76°C, Rf- benzoxazole-5-carbohydrazide.0.7 (Saturated methanol), Percentage Yield- 38%, M.P. 72-74° , Rf-0.63 Cb) 2-methyl-benzoxazole-5-carboxylic acid (Ethanol:Ethyl acetate)methyl ester (IVb) IR (KBr) cm-1: 3390 (-NH- str.), 1315 and 1398 Percentage Yield- 60%, M.P. 70-72°C, Rf- (-S-O str.), 1730 (-CO- str.), 1625 (C=N str.),0.7 (Saturated methanol), 3085 (Ar–H str.), 835 (C=C bending), 11654) 2-substituted benzoxazole-5-carboxylic (ether group in ring);acid hydrazide (V) 1 H NMR: (CDCl3) δ 7.34-7.95 (m, 8H), δ 8.0 (s,A mixture of an appropriate 2-subtituted 2H), δ 2.35 (d, 3H).benzoxazole-5-carboxylic acid methyl ester IV FAB-MS: (m/z, 100%): 331 (M+).(0.001 mol) in alcohol (25 ml) and hydrazinehydrate (99%, 0.015 mol) was heated under Compound (VIb)reflux on water bath for 4 hours. The alcohol N`[(4-methyl phenyl)sulfonyl]-1,3-was reduced to half of its volume and cooled. benzoxazole- 2-methyl-5-carbohydrazide.The product separated was filtered and washed Percentage Yield- 57%, M.P. 78-80° , Rf-0.60 Cwith small portions of cold alcohol and then with (Ethanol:Ethyl acetate)cold water, repeatedly and dried. The resultant IR (KBr) cm-1: 3319 (-NH- str.), 1315 (-S-Oproduct was recrystallised using methanol as str.), 1730 (-CO- str.), 1625 (C=N str.), 3010solvent. Using above mentioned procedure (Ar–H str.), 2230 (C-C str. );following two compounds were synthesized. 1 H NMR: (CDCl3) δ 7.34-7.95 (m, 7H), δ 8.0 (s,a) Benzoxazole-5-carboxylic acid hydrazide 2H), δ 2.35 (d, 6H).(Va) Percentage Yield- 90%, M.P. 108-110°C , R- Compound (VIc)f -0.6 (Methanol) International Journal of Pharma Research and Development – Online www.ijprd.com 168
  5. 5. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446N`[(4-acetamido phenyl) sulfonyl]-1,3- N`[benzene sulfonyl]-1,3-benzoxazole-5-benzoxazole-5-carbohydrazide. carbohydrazide.Percentage Yield- 74%, M.P. 92-94° , Rf-0.57 C Percentage Yield- 30%, M.P. 68-70° , Rf-0.62 C(Ethanol:Ethyl acetate) (Ethanol:Ethyl acetate)IR (KBr) cm-1: 3327 (-NH- str.), 1352 (-S-O IR (KBr) cm-1: 3350 (-NH- str.), 1329 (-S-Ostr.), 1730 (-CO- str.), 1116 and1172 (CONH str.), 1730 (-CO- str.), 3174 (CONH str.), 3097str.), 3010 (Ar–H str.); (Ar–H str.), 674 (C-C bending).1 H NMR: (CDCl3) δ 7.44-7.95(m, 8H), δ 8.0 (s, 1 H NMR: (CDCl3) δ 7.03-7.95 (m, Ar-H, 9H), δ3H), δ 2.02 (d, 3H). 8.0 (s, 2H).Compound (VId) Compound (VIh)N`[(4-actamido phenyl) sulfonyl]-1,3- N`[benzene sulfonyl]-1,3-benzoxazole- 2-benzoxazole-2-methyl-5-carbohydrazide. methyl-5-carbohydrazide.Percentage Yield- 40%, M.P. 89-90° , Rf-0.54 C Percentage Yield- 40%, M.P. 66-68° , Rf-0.72 C(Ethanol:Ethyl acetate) (Ethanol:Ethyl acetate)IR (KBr) cm-1: 3324 (-NH- str.), 1322 (-S-O IR (KBr) cm-1: 3204 (-NH- str.), 1346 (-S-Ostr.), 1730 (-CO- str.), 1629 (C=N str.), 3110 str.), 1730 (-CO- str.), 1625 (C=N str.), 3085(Ar–H str.), 3180 (CONH str.), 1165 (ether in (Ar–H str.), 2990 (C-C str.), 1165 (ether group inring); ring);1 H NMR: (CDCl3) δ 7.44-7.95 (m, 7H), δ 8.0 (s, 1 H NMR: (CDCl3) δ 7.03-7.95 (m, 8H), δ 8.0 (s,3H), δ 2.02 and 2.35 (d, 6H). 2H), δ 2.35 (d, 3H).Compound (VIe) • Physical data of compound. No. IIa-IIf wereN`[(4-chloro phenyl) sulfonyl]-1,3- summarized in Table No.2:benzoxazole-5-carbohydrazide.Percentage Yield- 75%, M.P. 110-112° , Rf- C • Elemental analysis of compound. No. IIa-IIl0.53 (Ethanol:Ethyl acetate) were summarized in Table No.3:IR (KBr): 3216 cm-1 (-NH- str.), 1339 cm-1 (-S-Ostr.), 3090 cm-1 (Ar–H str.), 772 cm-1 (C-Cl str.) Anti-inflammatory Activity:1 H NMR: (CDCl3) δ 7.44-7.95 (m, Ar-H, 8H), δ Carrageenan Induced Rat Paw Edema8.0 (s, 2H). Method[13]:Compound (VIf) Rats were divided into ten groups, each groupN`[(4-chloro phenyl) sulfonyl]-1,3- contained six animals. They were starvedbenzoxazole-2-methyl -5-carbohydrazide. overnight with water prior to the day ofPercentage Yield- 72%, M.P. 102-104° , Rf- C experiment.0.62 (Ethanol:Ethyl acetate) The injection of 0.1ml of freshly preparedIR (KBr) cm-1: 3204 (-NH- str.), 1354 and 1329 solution of carrageenan (1%) in physiological(-S-O str.), 1730 (-CO- str.), 3180 (CONH str.), saline (154 mmol/ml) NaCl was injected into3097 (Ar–H str.), 767 (C-Cl str.), subplantar region of the left hind paw of each1 H NMR: (CDCl3) δ 7.44-7.95 (m, 7H), δ 8.0 (s, rat. Then, Selected compounds were2H), δ 2.35 (d, 3H) suspended in 0.5% CMC and administered orally (200 mg/kg) after 1h of carrageenanCompound (VIg) dose. International Journal of Pharma Research and Development – Online www.ijprd.com 169
  6. 6. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446One group has been treated with Ibuprofen asstandard (50 mg/kg). The paw edema volume REFERENCES:was measured with the help of plethysmographby mercury displacement method, at zero h 1] Kastura Y, Tnoue Y, Nishino S, Chem.(Immediately after injecting carrageenan). Pharm.Bull., 40(6), 1992, 1424.The same procedure was repeated at1h, 2 h 2] ismail Y, lkay O, Özlem T, Acta Biochimicaand 3 h. which was summarized in Table No.4. Polonica, 47, 2000, 481-486.The difference between 1 h and subsequent 3] Shrinivasa R, Rao P, Kumar P, Bioorganichour readings was taken as actual edema and Medicinal Chemistry Letter, 13, 2003, 657-volume. The percentage (%) inhibition of paw 660.edema in the various treated groups was then 4] Aiello S, Wells G, Ston E, Kadri H, J. Med.calculated by using the formula; Chem.,51, 2008, 5135-5139.Percentage inhibition(%) = (1 – Vt/Vc ) X 100 5] Kastura Y, Inoue Y, Nishino S., Chem..... equation (1) Pharm. Bull., 40(6), 1992, 1424-1438.Where, Vt = mean relative change in a paw 6] Siddiqui N, Sarafaroz M, Alam M, Ahsan W,volume in test group. Polish Pharmaceiutical Vc = mean relative change in paw Society, Acta Poloniae Pharmaceiutica-Drugvolume in control group Research, 65(4), 2008, 449-455. 7] Arakova K, Inamasu M, Masumoto M, Chem.RESULTS AND DISCUSSION Pharm. Bull., 45(12), 1997, 1984. 8] Sondhi S, Singh N, Kumar A, Lozach O,Antiinflammatory activity data were Bioorganic and Medicinalsummarized in Table No.5. Chemistry, 14(11), 2006, 3758-3765. 9] Unlu S, Baytas S, Kupeli E, Archives derInhibition of carrageenin-induced inflammation Pharmazie, 336(6-7), 2003, 310.in rats is one of the most suitable test 10] Klimensova V, Koci J, Waisser K, Kaustovaprocedures to screen anti-inflammatory agents. J, Dahse M, Bioorganic andThe development of carrageenin-induced Medicinal Chemistry Letters, 12, 2002,oedema is bi-phasic, the first phase is attributed 3275-3278.to the release of histamine, 5-HT and kinins, 11] Silverstein R.M, Morrill T.C,while, the second phase is related to the Spectrophotometric Identification of Organicrelease of prostaglandins. The test compounds Compounds, John Wiley and Sons, NewVIa, VId and VIe showed significant work, Edn.4th,1981,312.antiinflammatory activity compared with the 12] Silverstein R.M, Morrill T.C,standard drug Ibuprofen. Spectrophotometric Identification of Organic Compounds, John Wiley and Sons, NewACKNOWLEDGEMENT work, Edn.4th,1981,192. 13] Vogel H, Gehard H, Drug Discovery andAuthors are thankful to Jodhpur National Evaluation, PharmacologicalUniversity, Jodhpur, Rajasthan, India for Assays, Springer-Verlag, Berlin Heidelberg,providing necessary support for research New York, 2, 2002, 759.purposed. International Journal of Pharma Research and Development – Online www.ijprd.com 170
  7. 7. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446TABLES AND FIGURES: ILLUSTRATIONS Table.No.1 COMPOUND R1 R2 VIa H Tosyl VIb CH3 Tosyl VIc H 4-aceta amido VId CH3 4-aceta amido VIe H 4-chloro VIf CH3 4-chloro VIg H Benzene VIh CH3 Benzene Table.No.2 Comp. Rf value No. R2 Molecular mp(0C) Yield(%) VIa 4-methyl phenyl C15H13N3O4S 72-74 48% 0.63 VIb 4-methyl phenyl C16H15N3O4S 78-80 57% 0.60 VIc 4-aceta amido C16H14N4O5S 92-94 72% 0.57 VId 4-aceta amido C17H16N4O5S 88-90 40% 0.54 VIe 4-chloro C14H10ClN3O4S 110-112 75% 0.53 VIf 4-chloro C15H12ClN3O4S 102-104 72% 0.64 VIg Benzene C14H11N3O4S 69-70 38% 0.62 VIh Benzene C15H13N3O4S 66-68 40% 0.72 International Journal of Pharma Research and Development – Online www.ijprd.com 166
  8. 8. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446 Table.No.3 Elemental Analysis (%)Compd R2 Molecular formula Calculated Found No. C H N C H N VIa 4-methyl phenyl C15H13N3O4S 52.9 4.04 13.08 52.5 4.04 13.12 VIb 4-methyl phenyl C16H15N3O4S 55.6 4.34 12.07 55.2 4.38 12.11 VIc 4-aceta amido C16H14N4O5S 53.63 3.91 15.64 53.67 3.87 15.68 VId 4-aceta amido C17H16N4O5S 52.57 4.12 14.43 52.61 4.16 14.47 VIe 4-chloro C14H10ClN3O4S 45.94 2.94 12.37 45.90 2.98 12.41 VIf 4-chloro C15H12ClN3O4S 47.81 3.37 11.81 47.85 3,41 11.85 VIg Benzene C14H11N3O4S 51.31 3.28 13.81 51.35 3.32 13.85 VIh Benzene C15H13N3O4S 53.12 3.75 13.12 53.16 3.79 13.08 Table.No.4 No. of groups Treatment Group- I Control Group- II Ibuprofen 50 mg/kg Group- III 1st derivative (200 mg/kg) Group- IV 2nd derivative (200 mg/kg) Group- V 3rd derivative (200 mg/kg) Group- VI 4th derivative (200 mg/kg) Group- VII 5th derivative (200 mg/kg) Group- VIII 6th derivative (200 mg/kg) Group- IX 7th derivative (200 mg/kg) Group- X 8th derivative (200 mg/kg) 167 International Journal of Pharma Research and Development – Online www.ijprd.com
  9. 9. Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-9/NOV/024 ISSN 0974 – 9446 Table.No.5 Group Test Material (dose) Mean increase in paw volume and % inhibition 1h 2h 3h 1. Control 0.44 + 0.00678 0.68 + 0.0091 0.76 + 0.0086 2. Standard 0.24 + 0.012 0.30 + 0.0085 0.38 + 0.0163 (Ibuprofen 50mg/kg) (43.1 %) (55.8 %) (49.3 %) 3. VIa 0.29 + 0.014 0.33 + 0.019 0.42 + 0.091 (200 mg/kg) (34.4 %) (51.5 %) (44.43 %) 4. VIb 0.27 + 0.0212 0.34 + 0.012 0.39 + 0.0192 (200 mg/kg) (36.3 %) (50.2 %) (48.2 %) 5. VIc 0.36 + 0.034 0.39 + 0.016 0.43 + 0.045 (200 mg/kg) (26%) (42.45%) (42.6%) 6. VId 0.26 + 0.0093 0,32 + 0.117 0.44 + 0.014 (200 mg/kg) (40.4 %) (52.4 %) (41.06%) 7. VIe 0.31 + 0.00961 0.31 + 0.0065 0.37 + 0.028 (200 mg/kg) (31.8 %) (54.4 %) (48.72%) 8. VIf 0.32 + 0.014 0.35 + 0.017 0.40 + 0.025 (200 mg/kg) (38.6 %) (48.5 %) (46.6 %) 9. VIg 0.30 + 0.012 0.42 + 0.096 0.41 + 0.059 (200 mg/kg) (29.34%) (29.67%) (45.3%) 10. VIh 0.28 + 0.012 0.45 + 0.072 0.51 + 0.063 (200 mg/kg) (36.3%) (26.45%) (33.45%) 168 International Journal of Pharma Research and Development – Online www.ijprd.com

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