Synthesis and Evaluation of Anti-inflammatory and Analgesic Activities of a Novel Series of Coumarin Mannich Bases

Abstract

A novel series of coumarinyl Mannich bases (3a-l) have been synthesized by reacting 3-acetyl coumarin (1) with various substituted secondary amines (2a-l) in presence of paraformaldehyde. The structures of the newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR and HRMS (high resolution mass spectral) data. Title compounds were screened for in vivo acute anti-inflammatory activity using the carrageenan-induced rat paw edema assay model. Among the compounds tested, 3-[3-(diethylamino) propanoyl]-2H-chromen-2-one (3a) and 3-[3-(piperidine-1-yl) propanoyl]-2H-chromen-2-one (3c) showed 63.1 and 66.7% inhibition, respectively, as compared to the standard drug diclofenac (CAS 15307–86–5, 68.8%). These potent compounds showed encouraging analgesic and antipyretic activities.

Key words

Anti-inflammatories, non-steroidal - Coumarin Mannich bases, anti-inflammatory activity, synthesis

• References

• 1 Vane JR. Botting RM. Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol. 1996; 102: 9-21
• 2 Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RIG. Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs. N Engl J Med. 1992; 327: 749-754
• 3 Mohan H. Textbook of Pathology. 4^th ed. New Delhi (India): Jaypee Brothers Medical Publishers (Pvt); 2000. p. 525-527
• 4 Pairet M, Engekelhardt G. Distinct isoforms (COX-1 and COX-2) of cyclooxygenase: possible physiological and therapeutic implications. Fund Clin Pharmacol. 1996; 10: 1-15
• 5 Bijlsma JWJ. Treatment of endoscopy-negative NSAID-induced upper gastrointestinal symptoms with Cimetidine: an international multicentre collaborative study. Aliment Pharmacol Ther. 1988; 2: 75-83
• 6 Egan D, O’Kennedy E, Moran E, Cox D, Prosser E, Thornes RD. The Pharmacology, metabolism, analysis and applications of coumarin and coumarin related compounds. Drug Metab Rev. 1990; 22: 503-529
• 7 Kontogiorgis CA, Hadjipavlou-Litina DJ. Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage. BioorgMed Chem Lett. 2004; 14: 611-614
• 8 Dimmock JR, Amitabh J, Praveen K, Zello GA, Wilson Q, Eliud O et al. Cytotoxic 1,4-bis(2-oxo-l-cycloalkylmethyl-ene)benzenes and related compounds. Eur J Med Chem. 2002; 37: 35-44
• 9 Kontogiorgis CA, Hadjipavlou-Litina DJ. Synthesis and anti-inflammatory activity of coumarin derivatives. J Med Chem. 2005; 48: 6400-6408
• 10 Maddi VS, Kallur RS, Rao MNA. Synthesis and Anti-sinflammatory activity of 3-(Benzylideneamino)coumarins in rodents. J Pharm Sci. 1992; 81: 964-966
• 11 Gursoy A, Karali N. Synthesis, Characterization and primary antituberculosis activity evaluation of 4-(3-coumarinyl)-3-benzyl-4-thiazolin-2-one benzylidenehydrazones. Turk J Chem. 2003; 27: 545-551
• 12 Dimmock JR, Shyam J, Hamon N, Logan B, Raghavan S, Smith P. Evaluation of some Mannich bases derived from substituted acetophenones against P-388 lymphocytic leukemia and on respiration in isolated rat liver mitochondria. J Pharm SCi. 1983; 72: 887894-
• 13 OECD/OCDC.OECD Guidelines for testing of chemicals. Revised draft guidelines 423;Acute oral toxicity class method, Revised document. October 2000.
• 14 Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med. 1962; 111: 544-547
• 15 Koster R, Anderson M, Debeer E. Acetic acid for analgesic screening. Fed Proc Fed Am Soc Exp Biol. 1959; 18: 412-413
• 16 Loux JJ, DePalma P, Palma PD, Yanksell SL. Antipyretic testing of aspirin in rats. Toxicol Appl Pharmacol. 1972; 22: 672-676
• 17 Vogel HG. Drug Discovery and Evaluation: Pharmacological Assays. 3rd ed. Berlin, Heidelberg: Springer-Verlag; 2002
• 18 Awasthi AK, Tewari RS. A Novel and Convenient Synthesis of Substituted Coumarins. Synthesis. 1986; 12: 1061-1062
• 19 Bonsignore L, Cottiglia F, Lavagna SM, Loy G Secci D. Synthesis Of Coumarin-3-O-Acylisoureas By Different Carbodiimides. Heterocycles. 1999; 50: 469-478
• 20 Knoevenagel E. Condensation between malonester and aldehyde under the influence of ammonia and organic amine. Chem. Ber. 1898; 31: 2585-2596
• 21 Kuroda T, Suzuki F, Tamura T, Ohmori K, Hosoe H. A novel synthesis and potent antiinflammatory activity of 4-hydroxy-2-(1H)-oxo-1-phenyl-1,8-naph tharidine-3-carboxamides. J Med Chem. 1992; 1130-1136