Original article Synthesis of novel 2-mercapto benzothiazole and 1,2,3-triazole based bis-heterocycles: Their anti-inflammatory and anti-nociceptive activities Syed Shafi a, * , Mohammad Mahboob Alam a , Naveen Mulakayala b , Chaitanya Mulakayala c , G. Vanaja d , Arunasree M. Kalle d , Reddanna Pallu d , M.S. Alam a, * a Department of Chemistry, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India b Institute of Life Science, University of Hyderabad Campus, Hyderabad 500046, India c Department of Biochemistry, Sri Krishnadevaraya University, Anantapur 515003, India d Department of Animal Sciences, University of Hyderabad, Hyderabad 500046, India article info Article history: Received 17 September 2011 Received in revised form 6 January 2012 Accepted 16 January 2012 Available online 24 January 2012 Keywords: Benzothiazole 1,2,3-Triazole Click chemistry bis-Heterocycles Anti-inflammatory activity COX abstract A focused library of novel bis-heterocycles encompassing 2-mercapto benzothiazole and 1,2,3-triazoles were synthesized using click chemistry approach. The synthesized compounds have been tested for their anti-inflammatory activity by using biochemical cyclooxygenase (COX) activity assays and carra- geenan-induced hind paw edema. Among the tested compounds, compound 4d demonstrated a potent selective COX-2 inhibition with COX-2/COX-1 ratio of 0.44. Results from carrageenan-induced hind paw edema showed that compounds 4a, 4d, 4e and 4f posses significant anti-inflammatory activity as compared to the standard drug Ibuprofen. The compounds showing significant activity were further subjected to anti-nociceptive activity by writhing test. These four compounds have shown comparable activity with the standard Ibuprofen. Further ulcerogenic studies shows that none of these compounds causing gastric ulceration. Ó 2012 Elsevier Masson SAS. All rights reserved. 1. Introduction Benzothiazoles are bicyclic ring system with multiple applica- tions. Benzothiazole ring is a part of several marine and terrestrial natural compounds that are having useful biological activities [1]. Heterocycles containing thiazole fraction are present in many natural products, such as bleomycin, epothilone B, lyngbyabellin and dolastatin 10 [2]. In the 1950s, a number of 2- aminobenzothiazoles were intensively studied as central muscle relaxants after the discovery of Riluzole [3]. Riluzole (6- trifluoromethoxy-2-benzothiazolamine, PK-26124, RP-25279, Rilutek) was found to interfere with glutamate neurotransmission in biochemical, electrophysiological and behavioral experiments. Since then benzothiazole derivatives have been studied extensively and found to have diverse chemical reactivity and broad spectrum of biological activity. A large number of therapeutic agents were synthesized with the help of Benzothiazole nucleus. These compounds have special significance due to their remarkable pharmacological potentialities. Although thiazoles have been known from long time [4e6], their varied biological features are still of great scientific interest. Benzothiazoles shows broad spectrum of biological activities including antitumor activity, especially phenyl-substituted benzo- thiazoles [7e9] while condensed pyrimidobenzothiazoles and benzothiazoloquinazolines exert antiviral activity [10]. Some of the bis-substituted amidinobenzothiazoles have been found to be potential anti-HIV agents [11] while some of the substituted 6- nitro-and 6-aminobenzothiazoles [12] are reported to exhibit potential antimicrobial activity. The studies of structureeactivity relationship of benzothiazoles interestingly reveal that change of the structure of substituent group at C-2 position commonly results the change of its bioactivity [13]. The new class of 2-substituted aminobenzothiazoles has shown a wide range of biological activities including antibacterial, antitumor, anti-tubercular, carbonic anhydrase inhibitory activities [14]. Significant anti-inflammatory activity is displayed by some new 2-(4 0 -butyl-3 0 -5 0 -dimethylpyrazol-1-yl)-6-substituted benzo- thiazoles and 4-butyl-1-(6 0 -substituted-2 0 -benzothiazolyl)-3- * Corresponding authors. Tel.: þ91 9717927759/9891171278; fax: þ91 011 26059663. E-mail addresses: shafirrl@gmail.com (S. Shafi), msalam@jamiahamdard.ac.in (M.S. Alam). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2012.01.032 European Journal of Medicinal Chemistry 49 (2012) 324e333