Full Paper Synthesis and Biological Evaluation of 4-Arylphthalazones Bearing Benzenesulfonamide as Anti-Inflammatory and Anti-Cancer Agents Shafiya Yaseen 1 , Syed Ovais 1 , Rafia Bashir 1 , Pooja Rathore 1 , Mohammed Samim 1 , Surender Singh 2 , Vinod Nair 2 , and Kalim Javed 1 1 Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, India 2 Department of Pharmacology, All India Institute of Medical Science, New Delhi, India Nine 4-arylphthalazones bearing benzenesulfonamide (2a–i) were synthesized by the condensation of the appropriate 2-aroylbenzoic acid (1a–i) and 4-hydrazinobenzenesulfonamide in ethanol. The structures of these compounds were elucidated by elemental analysis, IR, 1 H NMR, 13 C NMR, and MS spectroscopy. Two compounds, 2b and 2i, showed significant anti-inflammatory activity comparable to that of the standard drug celecoxib in the carrageenan-induced rat paw edema model. These compounds (2b and 2i) had selective inhibitory activity towards the COX-2 enzyme. Compound 2b had a better selectivity ratio (COX- 1/COX-2) compared to that of celecoxib and can be used as a novel template for the design of selective COX-2 inhibitors. Compounds 2d and 2i were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). The compounds 2d and 2i displayed mild activity toward the renal cancer cell line UO-31. Keywords: Anti-cancer / Anti-inflammatory / COX-2 inhibitor / Phthalazone / Sulfonamides Received: February 11, 2013; Revised: March 21, 2013; Accepted: March 28, 2013 DOI 10.1002/ardp.201300056 Introduction Inflammation is the first response of the body to infection, irritation or other injuries. It is an essential process to neutralize aggressor agents and to repair damaged tissues, assuring this way the survival of the host. Unfortunately, the available anti-inflammatory treatments are not always suffi- ciently effective and frequently present numerous and severe side effects especially in long-term use. Most of the current non-steroidal anti-inflammatory drugs (NSAIDs) show serious side effects including gastrointestinal disorders and kidney damage. NSAIDs exert their side effects by inhibition of the COX-1 enzyme. Since the COX-1 isoform is the constitutive one that is responsible for regulation of physiological processes and the COX-2 isoform is discovered to be the enzyme induced by inflammatory stimuli, selective inhibition of COX-2 provides a rationale for developing anti-inflammatory and analgesic agents that lack the GI liabilities. Unfortunately, some NSAIDS including selective COX-2 inhibitors have been shown to be associated with cardiovascular events, thus it has become a challenge to explore novel NSAIDs with reduced gastrointestinal tract and cardiovascular side effects. In the last few years, attention was oriented towards the synthesis and biological evaluation of phthalazine deriva- tives as they exhibit a broad spectrum of biological activities (Fig. 1). These derivatives have been reported to possess anti- hypertensive [1, 2], anticonvulsant [3, 4], antidiabetic [5, 6], antimicrobial [7], antitrypanosomal [8], anti-inflammatory [9–11], and PDE4 inhibitory activities [12]. The phthalazinone nucleus has been proven to be a versatile system in medicinal chemistry. Some of the phthalazinone derivatives like hydra- lazine [13], budralazine [14], azelastine [15], ponalrestat [16], and zopolrestat [17] have found application in clinical medicine. Recently, several groups have studied the structure-activity relationship of novel series of 4-arylsubsti- tuted phthalazinones and showed that the presence of 4-aryl substituted on the phthalazinone nucleus contributes to good anti-inflammatory and antinociceptive activities [18]. Correspondence: Kalim Javed, Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India E-mail: kjaved@jamiahamdard.ac.in Fax: þ91-11-26059666 Arch. Pharm. Chem. Life Sci. 2013, 346, 491–498 491 ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim