ORIGINAL RESEARCH Transformations of naproxen into pyrazolecarboxamides: search for potent anti-inflammatory, analgesic and ulcerogenic agents Abdullah G. El-Sehemi • Samir Bondock • Yousry A. Ammar Received: 29 January 2013 / Accepted: 25 May 2013 / Published online: 31 July 2013 Ó Springer Science+Business Media New York 2013 Abstract Many derivatives of naproxen containing a variety of pyrazolecarboxamides were synthesized through the reaction of naproxenoyl hydrazide with formylpyraz- ole, acetylacetone, enaminone, Mannich base, and arylhy- drazonomalononitrile derivatives. Also, many derivatives of naproxen were synthesized through the reaction of naprexenoyl chloride with amine derivatives containing pyrazole moiety. The synthesized compounds were screened for anti-inflammatory, analgesic, and ulcerogenic activities. Screening of anti-inflammatory revealed that compound 5 having a 1,3-diphenyl-pyrazol-4-yl moiety had the most promising activity. Compounds 8, 9, and 12, possessing 3,5-dimethyl-pyrazol-1-yl, 3-phenyl-pyrazol-1- yl, and 3,5-diamino-4-(4-methoxyphenylazo)-pyrazol-1-yl groups, respectively, showed moderate activity. Moreover, compounds 8 and 12 showed higher analgesic activity than the reference drug. In ulcerogenic effect, compound 22 which has methoxphenyl pyrazoline moiety devoid of ulcerogenic effect. Keywords Naproxen Á Pyrazoles Á Hydrazides Á Chalcones Á Anti-inflammatory activity Introduction Currently available non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, naproxen, diclofenac, indometh- acin, and flurbiprofen exhibit gastric toxicity. Long-term use of these drugs has been associated with gastrointestinal (GI) ulceration, bleeding, and nephrotoxicity (Kimmey, 1992). The GI damage from NSAIDs is generally attributed to two factors, local irritation by the carboxylic acid moiety, common to most NSAIDs (topical effect) and decreased tissue prostaglandin production, which undermines the physiological role of cytoprotective prostaglandins in maintaining the GI health and homeostasis (Smith et al., 1998; Hawkey et al., 2000). The pharmacological activity of NSAIDs is related to the suppression of prostaglandin bio- synthesis from arachidonic acid by inhibiting cyclooxy- genases (COXs) (Smith et al., 1998; Warner et al., 1999). Chronic use of NSAIDs, including ibuprofen, may elicit appreciable GI toxicity (Lanza, 1998). Naproxen was one of the leading NSAIDs used for relieving arthritic pain, but its long-term use invites GI complications ranging from stom- ach irritation to life threatening GI ulceration and bleeding (Cash and Klippel, 1994; Davies and Wallace, 1997; Wal- lace, 1997). These clinical shortcomings comprise a major challenge confronting medicinal chemists to develop safer agents that spare COX-1 and subsequently its gastric cyto- protective role. It was discovered that COXs exist in two isoforms, COX-1 and COX-2, which are regulated differ- ently (Marnett and Kalgutkar, 1999; Marnett and Kalgutkar, 1998). COX-1 provides cytoprotection in the gastrointesti- nal tract whereas inducible COX-2 mediates inflammation (Almansa et al., 2003). Therefore, synthetic approaches based upon NSAIDs chemical modification have been undertaken with the aim of improving the NSAID safety profile (Farag et al., 2013). Pyrazole derivatives have been A. G. El-Sehemi Á S. Bondock Á Y. A. Ammar Chemistry Department, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia S. Bondock Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt Y. A. Ammar (&) Chemistry Department, Faculty of Science, Al-Azahr University, Nasr City, Cairo, Egypt e-mail: yossry@yahoo.com 123 Med Chem Res (2014) 23:827–838 DOI 10.1007/s00044-013-0650-0 MEDICINAL CHEMISTR Y RESEARCH