A study on the anti-inflammatory effects of new derivatives of 3-hydroxy pyridine-4-one


1 Department of Pharmacology and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Derivatives of pyridine-4-one act as iron chelators and possess various pharmacological effects such as antifungal, antimalarial, antiviral, anti-inflammatory, and analgesic effects. The aim of our study was to evaluate the anti-inflammatory effects of the three new derivatives of pyridine-4-one.
Materials and Methods: Carrageenan-induced paw edema in rats and croton oil-induced ear edema in mice were used to evaluate the anti-inflammatry effects of three 3-hydroxy-pyridine-4-one derivatives (compounds A, B, and C). Compound A (10, 20 mg/kg), compound B (200, 400 mg/kg), and compound C (100, 200 mg/kg), vehicle (1 mL/kg), and indomethacin as standard drug (10 mg/kg) were injected intraperitoneally 30 min prior to carrageenan injection and 4 h later, the paw volume was measured using a mercury plethysmograph. The maximum dose of each test compound was used in the croton oil-induced ear edema test.
Results: All compounds showed significant anti-inflammatory activity in both tests. On a molar basis, compound A had the greatest potency, which may be due to the presence of a benzyl group substitution on the pyridine ring.
Conclusions: Because cyclooxygenase and lipoxygenase as key enzymes of the inflammation pathway are heme-dependent, it seems that the anti-inflammatory effect of derivatives of pyridine-4-one may be related to their iron chelating properties. However, more investigations are needed to find out their exact mechanism of actions.


1. Muirden KD. Ferritin in synovial cells in patients with rheumatoid arthritis. Ann Rheum Dis 1966;25:387-401.  Back to cited text no. 1
2. Senator GB, Muirden KD. Concentration of iron in synovial membrane, synovial fluid and serum in rheumatoid arthritis and other joint diseases. Ann Rheum Dis 1968;27:49-53.  Back to cited text no. 2
3. Halliwell B. Superoxide dependent formation of hydroxyl radicals in the presence of iron salts. Its role in degradation of hyaluronic acid by a superoxide generating system. FEBS Lett 1978;96:238-44.  Back to cited text no. 3
4. Brunton LL, Lazo JS, Parker KL. Goodman and Gilman′s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 2006.  Back to cited text no. 4
5. Kulmacz RJ, Lands WE. Prostaglandin H synthase. Stoichiometry of heme cofactor. J Biol Chem 1984;259:6358-63.  Back to cited text no. 5
6. Sedgwick AD, Blake DR, Winwood P, Moore AR, Al-Duaij A, Willoughby DA. Studies into the effects of the iron chelator desferrioxamine on the inflammatory process. Eur J Rheumatol Inflamm 1984;7:87-94.  Back to cited text no. 6
7. Hewitt SD, Hider RC, Sarpong P, Morris C, Blake DR. Investigation of the anti-inflammatory properties of hydroxypyridinones. Ann Rheum Dis 1989;48:382-8.  Back to cited text no. 7
8. Ozturk G, Erol DD, Uzbay T, Aytemir MD. Synthesis of 4 (1H)-pyridinone derivatives and investigation of analgesic and anti-inflammatory activities. Farmaco 2001;56:251-6.  Back to cited text no. 8
9. Ozturk G, Erol DD, Aytemir MD, Uzbay T. New analgesic and antiinflammatory agents 4(H)-pyridinone derivatives. Eur J Med Chem 2002;37:829-34.  Back to cited text no. 9
10. Aytemir MD, Uzbay T, Erol DD. New 4 (1H)-pyridinone derivatives as analgesic agents. Arzneimittelforschung 1999;49:250-4.  Back to cited text no. 10
11. Hajhashemi V, Saghaei L, Fassihi A, Mojiri-Froshani H. A study on the analgesic effects of four new derivatives of 3-hydroxy pyridine-4-one. Res Pharm Sci 2012;7:37-42.  Back to cited text no. 11
12. Nikazma A. Synthesis of 1-aryl-2-methyl-3-hydroxypyridine-4-one derivatives as iron chelators. School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, A PharmD Thesis, 2001. p. 33-6.  Back to cited text no. 12
13. Winter CA, Risely EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med 1962;111:544-7.  Back to cited text no. 13
14. Koshihara Y, Fujimoto Y, Inoue H. A new 5-lipoxygenase selective inhibitor derived from Artocarpus communis strongly inhibits arachidonic acid-induced ear edema. Biochem Pharmacol 1988;37:2161-5.  Back to cited text no. 14
15. Tubaro A, Dri P, Delbello G, Zilli C, Logia RD. The croton oil ear test revisited. Agents Actions 1985;17:347-9.  Back to cited text no. 15
16. Sawadago WR, Boly R, Lompo M, Some N. Anti inflammatory, analgesic and antipyretic activities of Dicliptera verticallata. J Pharmacol 2006;2:435-8.  Back to cited text no. 16
17. Jedinak A, Dudhgaonkar S, Wu QL, Simon J, Sliva D. Anti-inflammatory activity of edible oyster mushroom is mediated through the inhibition of NF-kB and AP-1 signaling. Nutr J 2011;10:52-62.  Back to cited text no. 17
18. Okusada K, Nakamoto K, Nishida M, Fujita-Hamabe W, Kamiya K, Mizushina Y, et al. The antinociceptive and anti-inflammatory action of the CHCl3-soluble phase and its main active component, damnacanthal, isolated from the root of Morinda citrifolia. Biol Pharm Bull 2011;1:103-7.  Back to cited text no. 18
19. Santos EN, Lima JC, Noldin VF, Cechinel-Filho V, Rao VS, Lima EF, et al. Anti-inflammatory, antinociceptive, and antipyric effects of methanol extract of Cariniana rubra stem bark in animal models. An Acad Bras Ciênc 2011;2:557-66.  Back to cited text no. 19
20. Besra SE, Sharma RM, Gomes A. Anti-inflammatory effect of petroleum ether extract of leaves of Litchi chinensis Gaertn (Sapindaceae). J Ethnopharmacol 1996;54:1-6.  Back to cited text no. 20
21. Botting RM. Vane's discovery of the mechanism of action of aspirin changed our understanding of its clinical pharmacology. Pharmacol Rep 2010;62:518-25.  Back to cited text no. 21
22. Capone ML, Tacconelli S, Rodriguez LG, Patrignani P. NSAIDs and cardiovascular disease: Transducing human pharmacology results into clinical read-outs in the general population. Pharmacol Rep 2010;62:518-25.  Back to cited text no. 22
23. Harris SG, Padilla J, Koumas L, Ray D, Phipps RP. Prostaglandins as modulators of immunity. Trends Immunol 2002;3:144-50.  Back to cited text no. 23
24. Charles AW, Edwin AR, George WN. Carrageenin induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Biol Med 1962;1:544-7.  Back to cited text no. 24
25. Matsuda R, Tanihata S. Suppressive effect of sialic acid on the prostaglandin E2-mediated oedema in carrageenininduced inflammation of rat hind paws (Japanese). Nippon Yakurigaku Zasshi 1992;99:363-72.  Back to cited text no. 25
26. Gabor M. Models of acute inflammation in the ear. Methods Mol Biol 2003;225:129-37.  Back to cited text no. 26
27. Saraiva RA, Araruna MK, Oliveira RC, Menezes KD, Leite GO, Kerntopf MR, et al. Topical anti-inflammatory effect of Caryocar coriaceum Wittm. (Caryocaraceae) fruit pulp fixed oil on mice ear edema induced by different irritant agents. J Ethnopharmacol 2011;136:504-10.  Back to cited text no. 27
28. Rao TS, Currie JL, Shaffer AF, Isakson PC. Comparative evaluation of arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation. Inflammation 1993;17:723-41.  Back to cited text no. 28
29. Furstenberger G, Csuk-Glanzer BI, Marks F, Keppler D. Phorbol ester-induced leukotriene biosynthesis and tumor promotion in mouse epidermis. Carcinogenesis 1994;15:2823-7.  Back to cited text no. 29
30. Abeysinghe RD, Roberts PJ, Cooper CE, MacLean KH, Hider RC, Porter JB. The environment of the lipoxygenase iron binding site explored with novel hydroxypyridinone iron chelators. J Biol Chem 1996;271:7965-72.  Back to cited text no. 30
31. Aruoma OI, Grootveld M, Bahorun T. Free radicals in biology and medicine: From inflammation to biotechnology. Biofactors 2006;27:1-3.  Back to cited text no. 31