Original article Synthesis, analgesic and anti-inflammatory evaluation of some novel quinazoline derivatives Ahmed M. Alafeefy a, * , Adnan A. Kadi a , Omar A. Al-Deeb a , Kamal E.H. El-Tahir b , Nabila A. Al-jaber c a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, P.O. Box 2457, Saudi Arabia b Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, P.O. Box 2457, Saudi Arabia c Department of Chemistry, College of Science, King Saud University, Riyadh 11451, P.O. Box 2455, Saudi Arabia article info Article history: Received 11 February 2010 Received in revised form 24 July 2010 Accepted 29 July 2010 Available online 12 August 2010 Keywords: Quinazoline Analgesic Anti-inflammatory Synthesis abstract Two series of some new 2,4,6-trisubstituted-quinazoline derivatives were prepared and screened for their analgesic, anti-inflammatory activity and acute toxicity. Four compounds were more potent analgesic agents than the reference drug Indomethacin and thirteen compounds showed significant anti-inflam- matory activity. Seven compounds showed combined ability to inhibit both pain and inflammation. Compounds tested for acute toxicity showed no toxic symptoms or mortality rates 24 h post-administration implying their good safety margin. Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Autoimmune diseases and allergies, such as rheumatoid arthritis, septic shock, transplant rejection, asthma and psoriasis, are considered to be caused by abnormalities of T cell immune responses [1,2]. In particular, the activation of T cells initiates a network of events that results in the overproduction of certain transcription factors and proinflammtory cytokines [3,4]. Tran- scription factors are DNA-binding proteins that regulate the production of proinflammtory cytokines and a variety of other cellular regulators. Nuclear factor- k B (NF- K B) is a pivotal transcription factor that functions to enhance the transcription of proinflammtory cytokines which are thought to be important in the generation of acute inflammatory responses [5,6]. Activation and regulation of NF- K B are tightly controlled by members of a family of inhibitory proteins referred to as I- K B. In the resting cells, NF- K B is sequestered in the cytoplasm through its interaction with its inhibitor. However, a large variety of inflammatory conditions, such as inflammatory cytokines, bacterial and viral infections and certain chemical agents, induce NF- K B activity [7]. The inhibition of NF- K B activation would lead to suppression of proinflammtory cytokines levels and be beneficial for the treatment of the aforementioned diseases [8]. Tobe et al. [9,10] conducted a reporter gene-based screening, with the reporter DNA having the binding sequence for NF- K B and the luciferase gene, to find new structural class NF- K B activation inhibitors. This effort led to the identification of quinazoline I as a lead compound (IC 50 ¼ 2.381 mM), Fig. 1 . In the present work, two new series of quinazoline compounds of the general formula II and III were designed in such a way to accommodate phenyl, 4-chlorophenyl at position 2, so as to modify the electronic effects. 4-Methyl piperidine, 4-phenylpiperidine, 4-methylpiperazine, 4-phenylpiperazine, at position 4, to impart structural similarity to compound I. Hydrogen, bromine, iodine atom at position 6, to improve lipophylicity, aiming to identify new candidates that may be of value as potent, selective and less toxic analgesic and anti-inflammatory agents. 2. Results and discussion 2.1. Chemistry The synthesis of the quinazoline derivatives 6aem, 7ael and 8e13 was carried out following Schemes 1e3. Briefly, the appro- priate acid chloride was allowed to react with the selected anthranilic acid derivative in dichloromethane containing catalytic * Corresponding author. Tel.: þ966 1 4673765; fax: þ966 1 4676220. E-mail address: aalafeefy@yahoo.com (A.M. Alafeefy). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.07.067 European Journal of Medicinal Chemistry 45 (2010) 4947e4952