Abstract
In the present study, a series of pyrazolo[3,4-d]pyrimidin-4(5H)-ones linked at 5-position to thiazoline or thiazolidinone ring systems through imino linkage (5–8) was designed and synthesized. The compounds were assessed for their anti-inflammatory activity and analgesic in vivo. Also, their ability to inhibit ovine COX-1/COX-2 isozymes was evaluated using in vitro cyclooxygenase (COX) inhibition assay. The newly synthesized compounds 7, 8d, and 8e showed potent anti-inflammatory and analgesic activity. Moreover, compound 7 displayed preferential COX-2 inhibitory potency (IC50 = 0.53 µM and COX-2 selectivity index = 10.07) which is more potent than the standard drug meloxicam. Interestingly, the tested compounds showed excellent gastrointestinal safety profile and were well tolerated by experimental animals with high safety margins than the reference drug meloxicam.
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References
Apostolidis I, Liaras K, Geronikaki A, Hadjipavlou-Litina D, Gavalas A, Sokovic M, Glamoclij J, Ciric´ A (2013) Synthesis and biological evaluation of some 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones as dual anti-inflammatory/antimicrobial agents. Bioorg Med Chem 21:532–539
Beretta C, Garavaglia G, Cavalli M (2005) COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: an in vitro analysis. Pharm Res 52:302–306
Beubler E (2003) Pharmacology of cyclooxygenase 2 inhibition. Wien Med Wochenschr 153:95–99
Cheng CC, Robins RK (1958) Potential purine antagonists VII. Synthesis of 6-alkylpyrazolo-[3,4-d]pyrimidines. J Org Chem 23:191–200
Devesa I, Alcaraz MJ, Riguera R, Ferrándiz ML (2004) A new pyrazolo pyrimidine derivative inhibitor of cyclooxygenase-2 with anti-angiogenic activity. Eur J Pharmacol 488:225–230
El-Enany MM, Kamel MM, Khalil OM, El-Nassan HB (2010) Synthesis and antitumor activity of novel 6-aryl and 6-alkylpyrazolo[3,4-d]pyrimidin-4-one derivatives. Eur J Med Chem 45:5286–5291
El-Kerdawy MM, El-Ashmawy MB, Shehata IA, Barghash AEM, El-Bendary ER, El-Kashef HA (1997) Fused pyrimidines synthesis and anti-inflammatory testing of certain novel imidazo[1,2-c]quinazoline, pyrazolo[3,4-d]triazolo[3,4-b]pyrimidine and pyrimido[2,1-a]phthalazine derivatives. Saudi Pharm J 5:46–51
El-Tombary AA (2013) Synthesis, anti-inflammatory, and ulcerogenicity studies of novel substituted and fused pyrazolo[3,4-d]pyrimidin-4-ones. Sci Pharm 81:393–422
Engelhardt G, Homma D, Schlegel K, Ultzmann R, Schnitzler C (1995) Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance. Inflamm Res 44:423–433
Blower AL, Brooks A, Fenn CG, HILL A, Pearce MY, morant S, Bardhan KD (1997) Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 11:283–291
Geronikaki AA, Lagunin AA, Hadjipavlou-Litina DI, Eleftheriou PT, Filimonov DA, Poroikov VV, Alam I, Saxena AK (2008) Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase inhibition. J Med Chem 51:1601–1609
Goel B, Ram T, Tyagi R, Bansal E, Kumar A, Mukerjee D, Shina JN (1999) 2-Substituted-3-(4-bromo-2-carboxyphenyl)-5-methyl-4-thiazolidinones as potential anti-inflammatory agents. Eur J Med Chem 34:265–269
Holla BS, Malini KV, Rao BS, Sarojini BK, Kumari NS (2003) Synthesis of some new 2,4-disubstituted thiazoles as possible antibacterial and anti-inflammatory agents. Eur J Med Chem 38:313–318
Kulmacz RJ, Lands WEM (1983) Requirements for hydroperoxide by the cyclooxygenase and peroxidase activities of prostaglandin H synthase. Prostaglandins 25:531–540
Laviola G, Alleva E (1990) Ontogeny of muscimol effects on locomotor activity, habituation and pain reactivity in mice. Psychopharmacology 102:41–48
Meshali M, El-Sabbagh E, Foda A (1983) Effect of encapsulation of flufenamic acid with acrylic resins on its bioavailability and gastric ulcerogenic activity in rats. Acta Pharm Technol 29:217–230
Mozsik G, Moron F, Javor T (1982) Cellular mechanisms of the development of gastric mucosal damage and of gastrocytoprotection induced by prostacyclin in rats. A pharmacological study. Prostaglandins Leukot Med 9:71–84
Omar AMME, AboulWafa OM (1984) Novel estradiol-17α-1,2,4-triazoline derivatives. Synthesis and in vitro anabolic-catabolic properties and binding affinity to steroid receptors. J Heterocycl Chem 21:1419–1423
Pairet M, Ryn Jv, Schierok H, Mauz A, Trummlitz G, Engelhardt E (1998) Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4′-isomer. Inflamm Res 47:270–276
Peet NP, Lentz NL, Sunder S, Dudley MW, Ogden AL (1992) Conformationally restrained, chiral (phenylisopropyl)amino-substituted pyrazolo[3,4-d]pyrimidines and purines with selectivity for adenosine A1 and A2 receptors. J Med Chem 35:3263–3269
Russo F, Guccione S, Romeo G, Barretta GU, Pucci S, Caruso A, Amico-Roxas M, Cutuli V (1993) Pyrazolothiazolopyrimidine derivatives as a novel class of anti-inflammatory or antinociceptive agents: synthesis, structural characterization and pharmacological evaluation. Eur J Med Chem 28:363–376
Schmidt P, Druey J (1958) Heilmittelchemische Studien in der heterocyclischen Reihe. 20. Mitteilung. Über die Herstellung von 2-Phenyl-3-amino-pyrazol als Aminokomponente eines langwirkenden Sulfonamids. Helv Chim Acta 41:306–309
Smith WL, Marnett LJ (1991) Prostaglandin endoperoxide synthase: structure and catalysis. Biochim Biophys Acta 1083:1–17
Srivastava SK, Yadav R, Srivastava SD (2004) Synthesis and biological activity of 4-oxothiazolidines and their 5-arylidenes. Indian J Chem 43B:399–405
Taher AT, Georgey HH, El-Subbagh HI (2012) Novel 1,3,4-heterodiazole analogues: synthesis and in vitro antitumor activity. Eur J Med Chem 47:445–451
Tollefson MB, Acker BA, Jacobsen EJ, Hughes RO, Walker JK, Fox DNA, Palmer MJ, Freeman SK, Bond YY (2010) 1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) inhibitors. Bioorg Med Chem Lett 20:3120–3124
Winter CA, Risely EA, Huss GM (1962) Carrageenaninduced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med 111:544–547
Acknowledgments
The author would like to thank Dr. Walid Mohammad, Biochemistry Department, Cairo General Hospital, Egypt for carrying out the in vitro screening. Thanks is also extended to Dr. Sally El-Awdan, Department of Pharmacology, National Research Centre, Dokki, Cairo, Egypt for facilities, help, and support during the anti-inflammatory, analgesic screening and the ulcerogenicity study.
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Kadry, H.H. Synthesis, biological evaluation of certain pyrazolo[3,4-d]pyrimidines as novel anti-inflammatory and analgesic agents. Med Chem Res 23, 5269–5281 (2014). https://doi.org/10.1007/s00044-014-1079-9
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DOI: https://doi.org/10.1007/s00044-014-1079-9