Synthesis and Evaluation of Antiinflammatory and Analgesic Activities of a Novel Series of Substituted-N-(4-methyl-2-oxo-2H-chromen-7-yl) benzamides
19 December 2011 (online)
A novel series of coumarinyl amides (IVa-1) have been synthesized by reacting 7-amino-4-methylcoumarin (III) with various substituted aromatic acid chlorides. IR, 1H NMR, 13C NMR and HRMS spectral data characterized the structure of the synthesized compounds. The title compounds were screened for in vivo acute anti-inflammatory activity using the carrageenan-induced rat paw edema assay model. Among the compounds tested, 2-chloro-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (IVb) and 4-chloro-N-(4-methyl-2-oxo-2H-chromen-7-yl)benzamide (IVc) showed 60.5 and 62.3% edema protection, respectively, as compared to the standard drug diclofenac (CAS 15307–86–5) (63.5%) after third hour. Compounds N-(4-meth-yl-2-oxo-2H-chromen-7-yl)-4-nitrobenz-amide (IVf) and N-(4-methyl-2-oxo-2H-chromen-7-yl)cinnamamide (IVg) showed moderate activity. The new compounds have been also tested for in vivo analgesic activity. Quantitative structure-activity relationship studies indicated that the chloro substitution at the aromatic ring enhanced the anti-inflammatory activity (IVb and IVc). These compounds were also found to provide significant protection in acetic acid induced writhing animal model, showing remarkable analgesic activity. Compounds IVb and IVc showed 55.1% and 56.3% protection, respectively, as compared to acetylsalicylic acid (CAS 50–78–2) (57.7%).
- 1 Murakami A, Gao G, Omura M, Yano M, Ito C, Furukawa H et al. 1,1-Dimethylallylcoumarins potently supress both lipopolysaccharide- and interferon-γ-induced nitric oxide generation in mouse macrophage RAW 264.7 cells. Bioorg. Med. Chem. Lett. 2000; 10: 59-62
- 2 Kuznetsova NA, Kaliya OL. The photochemistry of coumarins. Russ. Chem. Rev. 1992; 61 (7) 683-696
- 3 Ryoichi N, Noriko K, Fukagawa T, Shigeru K, Kitoh S, Kun-imoto KK. Synthesis, absorption and fluorescence properties and crystal structures of 7-aminocoumarin derivatives. J Photochem Photobiol A Chem. 2007; 188: 378-386
- 4 Jung J, Lee J, Oh S, Lee J, Park O. Synthesis and antitumor activity of 4-hydroxycoumarin derivatives. Bioorg Med Chem Lett. 2004; 14: 5527-5531
- 5 Kirkiacharian S, Thuy DT, Sicsic S, Bakhchinian R, Kurkjian R, Tonnaire T. Structure-activity relationships of some 3-substituted-4-hydroxycoumarins as HIV-1 protease inhibitors. Farmaco. 2002; 57: 703-708
- 6 Manohar VK, Imthyaz AK, Chung MS. One pot synthesis of oxygenated tri-heterocycles as anti-microbial agents. Eur J Med Chem. 2005; 40: 1168-1172
- 7 Jolanta NM, Nawrot E, Julita G. In vivo antitumor in vitro antibacterial activity and alkylating properties of phospho-rohydrazine derivatives of coumarin and chromone. Eur J Med Chem. 2006; 41: 1301-1309
- 8 Roelens F, Huvaere K, Dhooge W, Van Cleemput M, Comhaire F, De Keukeleire D. Regioselective synthesis and estrogenicity of (±) 8-alkyl-5,7-dihydroxy-4-(4-hydroxy-phenyl)-3,4-dihydrocoumarins. Eur J Med Chem. 2005; 40: 1042-1051
- 9 Hoerr R, Noeldner M. Ensaculin: A Multitransmitter Approach to Dementia Treatment. CNS Drug Rev.. 2002; 8: 143-158
- 10 Kulkarni GM, Kalkhambkar RG, Shivkumar H, Nagendra RR. Synthesis of novel triheterocyclic thiazoles as antiinflammatory and analgesic agents. Eur J Med Chem. 2007; 42 (10) 1272-1276
- 11 Refouvelet B, Guyon C, Jacquot Y, Girard C, Fein H, Be Valot F et al. Synthesis of 4-hydroxycoumarin and 2,4-quinolin-ediol derivatives and evaluation of their effects on the viability of HepG2 cells and human hepatocytes culture. Eur J Med Chem. 2004; 39: 931-937
- 12 Maddi V, Kallur RS, Rao MNA. Synthesis and anti-inflammatory activity of 3-(benzylideneamino)coumarins in rodents. J Pharm Sci. 1992; 81: 964-966
- 13 Maddi V, Mamledesai SN, Satyanarayana D, Swamy S. Synthesis and anti-inflammatory activity of substituted (2-oxo-chromen-3yl)benzamides. Ind J Pharm Sci. 2007; 69: 847-849
- 14 Bolakatti GS, Maddi VS, Mamledesai SN, Ronad PM, Palkar MB, Swamy S. Synthesis and evaluation of anti-inflammatory and analgesic activities of a novel series of coumarin Mannich bases. Arzneimittel-Forschung (Drug Research). 2008; 58 (10) 515-520
- 15 Robinson D inventor; BioCarb AB, assignee. 7-Amino-4-methyl-coumarin-3-carboxyalkyl derivatives and fluorescent conjugates thereof. United States patent US 4956480. 1990 Sep 11.
- 16 Pretka JE inventor; American Cyanamid Company assignee. 4-Substituted-7-carboalkoxyaminocoumarin. United States patent US 3008969. 1961 Nov 14.
- 17 Vogel’s Textbook of Practical Organic Chemistry. 4th ed. London: ELBS Pub.; p. 792
- 18 OECD/OCDC, OECD. Guidelines for testing of chemicals. Revised draft guidelines 423. Acute oral toxicity class method. Revised document. October 2000
- 19 Winter CA, Risley EA. Nuss GW Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol. Med. 1962; 111: 544-547
- 20 Koster R, Anderson M, Debeer E. Acetic acid for analgesic screening. Fed Proc Fed Am Soc Exp Biol. 1959; 18: 412-413
- 21 Chunduri VR, Maheswara M, Siddaiah V, Lakishmi G, Vasantha D, Yerra KR. A solvent-free synthesis of coumarins via Pechmann condensation using heterogeneous catalyst. J Mol Catal A Chem. 2006; 255: 49-52