Original article Synthesis and anti-inflammatory activity of novel (substituted)benzylidene acetone oxime ether derivatives: Molecular modeling study Mohammed I. El-Gamal a , Said M. Bayomi a , Saadia M. El-Ashry a , Shehta A. Said b , Alaa A.-M. Abdel-Aziz c , Naglaa I. Abdel-Aziz a, * a Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt b Department of Pharmacology, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt c Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia article info Article history: Received 4 July 2009 Received in revised form 5 December 2009 Accepted 18 December 2009 Available online 28 December 2009 Keywords: Benzylidene acetone oxime ether derivatives Anti-inflammatory activity Molecular modeling study abstract Herein, we report the design, synthesis, and pharmacological properties of a series of substituted ben- zylidene acetone oxime ether derivatives from the corresponding oxime derivatives. All the newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carra- geenin-induced rat paw oedema model. Among the compounds examined, compounds 5b and 7a showed the highest activity, nearly equivalent to that of the standard drug diclofenac sodium. Hence, they were screened for their analgesic activities using acetic acid-induced writhing model in mice and also, their ulcerogenic effects were studied. Compound 7a was found to possess significant anti- inflammatory and analgesic activities with negligible ulcerogenic effect. Docking study of the synthe- sized compound 7a into the active site of COX-1 and COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. Ó 2009 Elsevier Masson SAS. All rights reserved. 1. Introduction Inflammation is a normal response to any noxious stimulus that threatens the host and may vary from a localized response to a generalized one [1]. The inflammatory process protects our body from diseases by releasing cells and mediators that combat foreign substances and prevent infection [2]. In 1971 [3], the role of pros- taglandins (PGs) in the inflammatory process was observed. PGs are synthesized from arachidonic acid which is released by the action of phospholipase A 2 on damaged tissues. Arachidonic acid is con- verted by cyclooxygenase (COX) enzymes to cyclic PGG 2 and PGH 2 which cause vasoconstriction and pain. They, in turn, are converted to PGE 2 and PGF 2a which cause vasodilatation and pain [4]. Two isoenzymes of cyclooxygenase were postulated, cyclo- oxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is a constitutive enzyme and is responsible for the production of the basic level of PGs. Inhibition of this enzyme by all older, non-selective non-steroidal anti-inflammatory drugs is primarily responsible for a number of their side effects [5]. However, the existence of COX-2 enzyme was confirmed [5]. It is an inducible enzyme which is induced in response to the release of several proinflammatory mediators, leading to the inflammatory non-selective NSAID response and pain [6]. To our knowledge, several attempts to derive COX selective inhibitors from flurbiprofen (A) [7] and indomethacin (B) [8] have been published (Fig. 1). These strategies introduced the desired selectivity by systematic structural modification of the lead NSAIDs. Alternatively, selectivity may be introduced by using the available information on the tricyclic COX-2 selective inhibitors (Fig.1) structurally related to SC-558 (C) [9]. Thus, there was an active search for the development of specific inhibitors of COX-2 enzyme. In this context, the present work describes the synthesis and the investigation of the analgesic and anti-inflammatory properties of new substituted benzylidene acetone oxime ether derivative (D) (Fig. 1). Our strategy for the synthesis of such derivatives is based on the modification of the structure of the known potent non-selective NSAID inhibitor. The strategy is intended to obtain potent anti- inflammatory activity without ulcerogenic effects using traditional medicinal chemistry techniques motivated by the comparative modeling of COX-1 and -2 complexed with A and C together with the available pharmacophore. 2. Results and discussion 2.1. Chemistry 2.1.1. Synthesis of compounds 1–11(Scheme 1) Aldol condensation of benzaldehyde or its derivatives with acetone was performed in the presence of aqueous ethanolic * Corresponding author. Tel./fax: þ20 502247496. E-mail address: Naglaabdalaziz2005@yahoo.com (N.I. Abdel-Aziz). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2009.12.041 European Journal of Medicinal Chemistry 45 (2010) 1403–1414