ORIGINAL RESEARCH Design and synthesis of 3-[3-(substituted phenyl)-4- piperidin-1-ylmethyl/-4-morpholin-4-ylmethyl-4,5- dihydro-isoxazol-5-yl]-1H-indoles as potent anti-inflammatory agents Mohammad Amir Æ Sadique Akhtar Javed Æ Harish Kumar Received: 14 November 2008 / Accepted: 17 March 2009 / Published online: 23 April 2009 Ó Birkha ¨user Boston 2009 Abstract The synthesis of new indole derivatives bearing isoxazoline moiety (3a– d and 4a–d) has been described. IR, 1 H NMR, and mass spectral data supported the structures of synthesized compounds. The compounds were tested in vivo for their anti-inflammatory activity by carrageenin-induced rat paw edema method. The compounds that showed good anti-inflammatory activity were screened for their ulcerogenic and lipid peroxidation activities. The most active compound of this series is 3-[3-(4-methoxyphenyl)- 4-morpholin-4-ylmethyl)-4,5-dihydro-isoxazol- 5yl]-1H-indole 4d. Keywords Indole  Isoxazoline  Anti-inflammatory  Ulcerogenicity  Lipid peroxidation Introduction Almost all nonsteroidal anti-inflammatory drugs (NSAIDs) under current clinical usage have aryl acetic acid pharmacophore and are highly acidic in nature. Therefore, long-term use of these drugs is associated with gastrointestinal ulceration, bleeding, and nephrotoxicity (Langman et al., 1994), thus indicating a clear need to develop nonacidic nonsteroidal anti-inflammatory agents. Two NSAIDs, indomethacin and tenidap, which are derivatives of heterocyclic indole nucleus (Fig. 1), are used clinically for the treatment of different anti-inflammatory disorders and are known to induce erosions and ulcers in the gastrointestinal tract (Hardman and Limbird, 2001; Moore et al., 1996; Yoshikawa et al., 1993). Indole derivatives have been reported to possess a wide variety of biological properties M. Amir (&)  S. A. Javed  H. Kumar Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi 110 062, India e-mail: mamir_s2003@yahoo.co.in Med Chem Res (2010) 19:299–310 DOI 10.1007/s00044-009-9194-8 MEDICINAL CHEMISTR Y RESEARCH