Synthesis of novel pyrazolyl tetrazoles as selective COX-2 inhibitors
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Med Chem Res (2013) 22:4886–4892 DOI 10.1007/s00044-013-0500-0
ORIGINAL RESEARCH
Synthesis of novel pyrazolyl tetrazoles as selective COX-2 inhibitors Kolli Sri Swetha • Ravula Parameshwar • B. Madhava Reddy • V. Harinadha babu
Received: 13 October 2012 / Accepted: 16 January 2013 / Published online: 31 January 2013 Ó Springer Science+Business Media New York 2013
Abstract A series of novel pyrazolyl tetrazoles were synthesized by introducing tetrazole moiety at the fourth position of 1,3-substituted pyrazole nucleus. Synthesis was carried out by cyclization of different pyrazolonitriles using sodium azide in the presence of triethylammonium chloride as phase transfer catalyst. The structures of the synthesized compounds were confirmed on the basis of physical and spectral data. Among the synthesized compounds, 4b and 4e displayed significant anti-inflammatory activity with no observable ulcerogenic effect when compared with diclofenac sodium. Furthermore, compounds 4b and 4e were found to have COX-2 selectivity with a ratio of 0.44 and 0.48, respectively. Keywords Pyrazoles Tetrazoles Anti-inflammatory activity Acute ulcerogenicity In vitro COX inhibitor study
Introduction Currently marketed non steroidal anti-inflammatory drugs (NSAIDs) have been associated with several side effects like gastrointestinal mucosal damage, bleeding, intolerance, renal toxicity, and hepatotoxicity. The pharmacological effects of NSAIDs occur due to inhibition of the membrane enzyme called cyclooxygenase (COX-1 and COX-2), which is involved in prostaglandin biosynthesis. Electronic supplementary material The online version of this article (doi:10.1007/s00044-013-0500-0) contains supplementary material, which is available to authorized users. K. S. Swetha R. Parameshwar B. M. Reddy V. H. babu (&) Medicinal Chemistry Division, G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad 500028, India e-mail: [email protected]
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COX-1 is predominantly expressed ubiquitously and constitutively, and it serves a housekeeping role in stomach and kidneys. By contrast, COX-2 is involved in the production of prostaglandin, mediating pain and supporting the inflammatory process. Gastric side effects associated with classical NSAIDs are attributed to the nonselective inhibition of the isoenzymes. Even the selective COX-2 inhibitors have been associated with the unexpected cardiovascular adverse effects. Thus, development of a reliable and selective anti-inflammatory agent with a fewer side effects is a major challenge to medicinal chemists. Pyrazole template is considered as an important chemical entity of various physiological significances and pharmaceutical utility. Pyrazoles have drawn a greater attention due to their wide range of therapeutic activities including anticonvulsant (Abdel et al., 2009), antidepressant (Abdel et al., 2009), antitumor (Peng-cheng et al., 2010), (Christodoulou et al., 2010), (Lin et al., 2007), antimicrobial (Bondock et al., 2010), (Radi et al., 2010), ACE inhibitor (Menichini et al., 2010)
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