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SUBSTITUTED ANTHRANILIC ACID DERIVATIVES International Journal International Journal of Drug Development & Research | April-June 2011 | Vol. 3 | Issue 2 | ISSN 0975-9344 | µÀÑ Available online http://www.ijddr.in Covered in Official Product of Elsevier, The Netherlands ©2010 IJDDR SYNTHESIS AND PHARMACOLOGICAL SCREENING OF N- SUBSTITUTED ANTHRANILIC ACID DERIVATIVES Dileep Tiwari 1,2 , Shafiul Haque 4, Shweta Misra 3, Ramesh Chandra 1,2 1. Ambedkar Center for Biomedical Education and Research, New Delhi, India. Covered in Official Product of Elsevier, The2. Nether Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi-110007, India. 3. Department of Biotechnology, Integral University, Kursi Road, Lucknow-226026, India 4. Gene Expression Laboratory, Department of Biotechnology, Jamia Millia Islamia (A Central University), New Delhi-110025, India Abstract How to Cite this Paper : In the present work eight newly synthesized structurally Dileep Tiwari, Shafiul Haque, Shweta Misra diverse anthranilic acid derivatives were evaluated for their and Ramesh Chandra “Synthesis and anti-inflammatory activity against carrageenan induced Full Length Research Paper pharmacological screening of N- substituted oedema in albino rats. All the anthranilic acid derivatives were compared for their percentage inhibition of the anthranilic acid derivatives”, Int J. Drug Dev. & Res., oedema using control drug phenylbutazone. The desired April-June 2011, 3(2): 265-271. anthranilic acid derivatives 5-bromo-2-{[5-{[(2 E)-3-(2- substitutedphenyl)prop-2-enoyl]amino}-1,3,4,-oxadiazol-2- Copyright © 2010 IJDDR, Dileep Tiwari et al . yl) methyl]amino}benzoic acid (compounds 1-4) were This is an open access paper distributed under the synthesized by condensation of 5-bromo-N - (2'-amino acetyl -1',3',4'-oxadiazol-5'-ylmethyl) anthranilic acid and copyright agreement with Serials Publication, which substituted aromatic aldehydes, respectively, and the permits unrestricted use, distribution, and compounds 5-bromo-N – [2'-amino [1"-acetyl-5''- reproduction in any medium, provided the original (substitutedaryl-2'-pyrazolin-3"-yl]-1'3'4'-oxadiazol-5'- work is properly cited. ylmethyl) anthranilic acid ( compounds 5-8) were synthesized by the condensation of compounds (1-4) with Article History: -- ---------------------- the hydrazine hydrate in the presence of few drops of glacial acetic acid. Compound 5 was found to be a potent Date of Submission: 16-05-2011 member of this series which showed 51.05% anti- Date of Acceptance: 31-05-2011 inflammatory activity with ED 50 of 51.05 mg/kg while Conflict of Interest: NIL phenylbutazone exhibited 47.23% anti-inflammatory Source of Support : NONE activity at the same dose. The structures of the newly synthesized compounds have been established on the basis l a n d s 1 of spectral (FTIR and H-NMR ) data and elemental analysis. *Corresponding author, Mailing address: INTRODUCTION Dr. Dileep Tiwari Anthranilic acid is a constituent of many of the Ambedkar Center for Biomedical Education and Research, New Delhi, India bioactive compounds that exhibits a range of E -mail:[email protected], biological activities. Specifically, the nucleus of [email protected] words : Key words : Anthranilic acid derivatives, anti- anthranilic acid is the biochemical precursor to the inflammatory, pyrazolin-3"-yl amino acid and its derivatives as well as constituents Int. J. Drug Dev. & Res., April-June 2011, 3 (2): 265-271 Covered in Scopus & Embase, Elsevier 265 Dile ep Tiwari et al: Synthesis and p harmacological screening of N- substituted anthranilic acid derivatives of several alkaloids. The biological activities of this H2SO 4, afforded compound 5-Bromo-N-(2’-amino- basic moiety have been well reported. Some of them 1’,3’,4’-oxadiazol-5,’ylmethyl) anthranilic acid was like mefenamic acid and meclofenamates, both N- made. ( IV) phenyl anthranilic acid derivatives, have been used as Compound made at step (IV) when reacted with anti-inflammatory agents. Looking at the importance acetyl chloride, gives compound 5-Bromo-N-(2’- Covered in Official Productof ofanthranilic Elsevier, The Nether acid in biological system it was thought amino acetyl-1’,3’,4’-oxadiazol-5,’ylmethyl) worthwhile to design and synthesize derivatives of anthranilic acid, ( V) which, on condensation with anthranilic acid and screen them for their potential proper aromatic aldehyde yields into compound (1- biological activities. Derivatives of anthranilic acid (1- 4) . Compounds (5-8) were synthesized by the 9) were synthesized successfully with good yield and condensation of compounds (1-4) with the hydrazine their molecular structures were confirmed by the hydrate in the presence of few drops of glacial acetic FTIR, 1H-NMR and elemental analysis data. The acid. Full Length ResearchFTIR Pape spectra of newly synthesized compounds Synthesis of anthranilic acid derivatives (1-8) showed the presence of characteristic absorption General procedure for synthesis bands in the region 3250-3350, 3000-3100,1670- 1) Solution containing 5-bromo-N-(2 '-aminoacetyl- 1730,1430-1600 and 1100-1200 cm -1 which can be N- 1',3 ', 4'-oxadiazol-5'-ylmethyl) H Stretching, Ar-H stretching, C=O stretching, C=N Anthranilic acid (3.55 gm, 0.01mol) in 60.0 ml of stretching and C-N stretching, respectively. ethanol with different aldehydes (0.01 mol) in the presence of 2.0% sodium hydroxide were refluxed for EXPERIMENTAL 10 h, while progress and completion of reaction was The melting points of newly synthesized anthranilic monitored by TLC. The reaction mixture was distilled acid derivatives were checked in capillary tubes were off, cooled and poured in to ice-water and filtered. uncorrected. The reactions were monitored by TLC The product formed was filtered, dried in vacuum using chloroform: methanol (8:2) solvent system. and recrystallized from ethanol-water to give desired r The purity of compounds was checked by TLC using compounds (1-4) . iodine vapour as detecting agent. The IR spectra were 2) Solution of the compound, 5-bromo-2-{[5-{[(2 E)- recorded in KBr on a FTIR Paragon 500 (Perkin 3-(2-substituted phenyl) prop-2-enoyl]amino}-1,3,4,- -1 1 Elmer) ( ν max in cm ) and H NMR spectra were oxadiazol-2-yl)methyl]amino} benzoic acid (0.991 recorded in DMSO-d6 on Bruker-300 FT instrument gm, 0.002 mol) in absolute alcohol, 99% hydrazine l a n d s (chemical shift [ δ] in ppm). Tetra-methyl silane hydrate (0.004 mol) was added drop by drop with (TMS) was used as internal standard. N- substituted constant stirring in the presence of few drops of anthranilic acid derivatives were synthesized by glacial acetic acid. The reaction mixture was refluxed reacting anthranilic acid with bromine, after for 12 h, distilled off and cooled. The separated solid bromination it had given 5-bromoanthranilic acid (i) was filtered, washed with petroleum ether and re- 5-bromoanthranilic acid with ethylchloroacetate had crystallized from ethanol-water to give compounds given compound 5-bromo-N-(ethylanthranilic (5-8) . anthranilic acids} (ii) which was further reacted with semicarbazide hydrochloride to yield the compound 5-Bromo-N-(semicarbazido carbonyl methyl) anthranilic acid, (iii) which on dehydration with Int. J. Drug Dev. & Res., April-June 2011, 3 (2): 265-271 266 Covered in Scopus & Embase, Elsevier Dileep Tiwari et al: Synthesis and p harmacological screening of N- substituted anthranilic acid derivatives Compound 1: stretching), 1215.8 (C −N stretching), 1144.5.(C-O-C 5-Bromo-2-{[5-{[(2 E)-3-(2-nitrophenyl) prop- stretching), 928.7 (N-N stretching), 521.1cm -1 (C −Br 2-enoyl]amino}-1,3,4,-oxadiazol-2-yl) stretching). methyl]amino}benzoic acid (1) 1 H NMR (DMSO) δ: 1.23 (s,2H, CH 2), 3.34 (s, 1H, ν IR (KBr) : 3516.4 (O-H stretching), 3216.5 (N-H NH), 5.65 (d, 1H, COCH), 5.81 (d, 1H, CH-Ar), 7.42- stretching), 3020.1 (aromatic C −H stretching), 7.99 (m, 4H, aromatic), 8.28-8.64 (m, 3H, aromatic), Covered in Official Product of Elsevier, The Nether 2926.5 (C −H sym stretching), 1710 (C=O stretching ), 10.23 ppm (s, 1H, O-H). 1603 (ring C C stretching), 1652.9 (C=N SCHEME-1 Synthesis of N-substituted anthranilic acid COOH Br COOH Br 2 Full Length Research Paper glacial acetic acid NH2 NH2 Anthranilic acid 5-bromoanthranilic acid ClCH 2COOC 2H5 anhydrous K 2CO 3 Br COOH Br COOH NH 2NHCONH 2.HCl CO NH NH NH 2 NH CH COOC H NH (ii) 2 2 5 (iii) O H2SO 4\NH 3 COOH COOH NHCOCH NH Br NH O 3 Br NH O 2 ClCOCH 3 N N N N OHC (v) (iv) l a n d s NaOH R Compound 1 R =o-nitro Br COOH O O Compound 2 R = m-nitro NH NH Compound 3 R =o- chloro NN R NH 2.NH 2.H 2O Compound (1-4) Compound 4 R =m - chloro Br COOH O N NH NH N COCH 3 NN Compound 5 R=o-nitro R Compound 6 R=m-nitro Compound 7 R= o Compound 8 R=m-chloro Int. J. Drug Dev. & Res., April-June 2011, 3 (2): 265-271 Covered in Scopus & Embase, Elsevier 267 Dileep Tiwari et al: Synthesis and p harmacological screening of N- substituted anthranilic acid derivatives Table 1. Characterization data of compounds Compound Molecular MP (°C) Mol. (%) Rf Elemental analysis (%) [Calculated (found)] Code Formula weight Yield value C (%) H (%) N (%) 1 C19 H14 BrN 5O6 189-190 252.32 72.33 0.85 76.16 (76.13) 6.39 (6.37) 11.10 (11.08) 2 C19 H14 BrN 5O6 138-141 282.35 67.48 0.81 72.32 (72.30) 6.34(6.29) 9.92 (9.89) 3 C19H14BrClN4 135-138 282.35 71.23 0.82 72.32 (72.31) 6.34(6.30) 9.92 (9.90) O4 Covered in Official Product of Elsevier, The Nether 4 C19 H14 BrClN 4 146-148 321.21 81.21 0.82 59.83 (59.81) 4.39 (4.37) 8.72 (8.70) O 5 C22 H18 N2ONO 2 160-163 297.32 63.45 0.83 66.64 (66.62) 5.09 (5.08) 14.13 (14.11) 6 C16 H15 N2ONO 2 165-167 297.32 74.27 0.86 66.64 (66.63) 5.09 (5.07) 14.13 (14.12) 7 C16 H15 N2OBr 145-147 331.22 61.35 0.83 58.02 (57.99) 4.56 (4.53) 8.46 (8.45) 8 C28 H24 N2O 185-187 404.52 81.23 0.84 83.14 (83.12) 5.98 (5.94) 6.93 (6.92) Full Length Research Paper Compound 2: CH 2), 3.24 (s, 1H, NH), 4.81 (d, 1H, COCH), 6.60 (d, 5-Bromo-2-{[5-{[(2 E)-3-(3-nitrophenyl) prop- 1H, CH-Ar), 7.60-7.99 (m, 4H, aromatic), 8.16-8.52 2-enoyl] amino}-1,3,4,-oxadiazol-2- yl) (m, 3H, aromatic), 10.18 ppm (s, 1H, O-H).
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