Synthesis, anticonvulsant, and anti-inflammatory evaluation of some new benzotriazole and benzofuran-based heterocycles Kamal M. Dawood, a, * Hassan Abdel-Gawad, b Eman A. Rageb, a Mohey Ellithey c and Hanan A. Mohamed b a Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt b Applied Organic Chemistry Department, National Research Centre, Cairo, Egypt c Pharmacology Department, National Research Centre, Dokki, Cairo, Egypt Received 29 September 2005; revised 10 January 2006; accepted 12 January 2006 Available online 7 February 2006 Abstract—Treatment of 2-bromoacetylbenzofuran with 1H-benzotriazole afforded 1-(benzofuran-2-yl)-2-(benzotriazol-1-yl)etha- none which reacted with phenylisothiocyanate to give the corresponding thioacetanilide derivatives. Treatment of the latter etha- none and thioacetanilide derivatives with hydrazonoyl chlorides afforded the corresponding pyrazole and 1,3,4-thiadiazole derivatives. The thioacetanilide derivative reacted with a-haloketones and a-halodiketones to afford thiophene and thiazole deriv- atives, respectively. The newly synthesized compounds were found to possess anticonvulsant and anti-inflammatory activities with the same mechanism of action of selective COX-2 inhibitors. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Synthetic approaches based on nonsteroidal anti-inflam- matory drugs (NSAID) chemical modification have been taken with the aim of improving their profile 1 where the action of NSAID is in lowering the prosta- glandin production through inhibition of cyclooxygen- ase (COX). Very limited work however has been focused on the development of NSAID. 2,3 Benzofuran derivatives were among the COX-2 inhibitors. 4,5 In addition, diverse pharmacological properties have been associated with benzofuran derivatives. 6–10 These in- clude pesticidal and insecticidal, 11 anti-inflammatory, 12 antihistaminic, 13 antiallergic, 14 and antitumor 15 agents. On the other hand, benzotriazole derivatives have shown potential antimycobacterial, 16 antitubercular, 17 antitumor, 18 antiproliferative, 19 anesthetic, 20 and anti- inflammatory 21 activities. Furthermore, pyrazole deriva- tives were found to possess anti-inflammatory, 22 and antimicrobial 23 activities. In addition, 1,3,4-thiadiazoles were reported as highly anti-inflammatory, 24 antimicro- bial, 25 and anticonvulsant 26 agents. In continuation of our research work on the synthesis of benzofuran deriv- atives, 27–30 we report here some new heteroaromatic derivatives having benzofuran and benzotriazole moie- ties. The biological activity and structure–activity rela- tionship (SAR) of the newly synthesized compounds were evaluated using Wistar albino mice and some of the obtained products were found to possess anticonvul- sant, antinociceptive, and anti-inflammatory activities. 2. Results and discussion 2.1. Chemistry When 2-bromoacetylbenzofuran (1) was treated with 1(H)-benzotriazole in refluxing tetrahydrofuran in the presence of triethylamine, it afforded the novel 1-(benzo- furan-2-yl)-2-(benzotriazol-1-yl)ethanone (2). The struc- ture of compound 2 was established on the basis of its elemental analysis and spectral data. For example, its IR spectrum showed the presence of a strong absorption peak at 1698 cm À1 due to a carbonyl group and its 1 H NMR spectrum revealed a singlet signal at d 5.3 charac- teristic of active methylene proton. Reaction of 1-(benzofuran-2-yl)-2-(benzotriazol-1-yl)- ethanone (2) with hydrazonoyl chlorides 3a,b in Bioorganic & Medicinal Chemistry 14 (2006) 3672–3680 0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2006.01.033 Keywords: Benzotriazoles; Benzofurans; 1,3,4-thiadiazoles; Thioph- enes; Anticonvulsant and anti-inflammatory activities. * Corresponding author. Fax: +20 25727556; e-mail: dr_dawood@yahoo.com