Original article Design, synthesis and pharmacobiological evaluation of novel acrylic acid derivatives acting as lipoxygenase and cyclooxygenase-1 inhibitors with antioxidant and anti-inflammatory activities Eleni Pontiki a, * , Dimitra Hadjipavlou-Litina a, * , Konstantinos Litinas b , Orazio Nicolotti c , Angelo Carotti c a Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece b Laboratory of Organic Chemistry, Department of Chemistry, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece c Dipartimento Farmaco-chimico, University of Bari, Via E. Orabona 4, I-70125 Bari, Italy article info Article history: Received 6 May 2010 Received in revised form 14 October 2010 Accepted 29 October 2010 Available online 4 November 2010 Keywords: LOX COX-1 Antioxidant agents Anti-inflammatory agents Lipoxygenase inhibitors Cyclooxygenase inhibitors Substituted acrylic acids abstract A series of novel acrylic acid derivatives bearing at the 3 position thienyl, furfuryl and 3,5-ditert-butyl-4- hydroxyphenyl substituents have been designed, synthesized and tested as potential dual lipoxygenase/ cyclooxygenase-1 (LOX/COX-1) inhibitors and as antioxidant and anti-inflammatory agents. Some compounds have shown moderate antioxidant and COX-1 inhibitory activities, very good anti-inflammatory activity and an inhibition of soybean lipoxygenase (LOX) higher than caffeic acid. In particular, compound 4I disclosed a moderate in vitro LOX inhibition with an IC 50 ¼ 100 mM whereas compounds 1I and 2II exhibited the best, albeit poor, activity as COX-1 inhibition (75% inhibition at 100 mM). Good radical scavenging properties were shown by compounds 4I, 3I and 1II. Docking simulations performed on LOX inhibitor 4I and COX-1 inhibitor 1I indicated that hydrophobic key interactions may govern the enzyme- inhibitor binding. Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Arachidonic acid (AA) is metabolised to eicosanoids by the cyclooxygenase (COX), lipoxygenase (LOX) and epoxygenase path- ways [1]. In the COX pathway, the COX-1, COX-2, and COX-3 isoforms convert AA to the hydroxyendoperoxide PGH 2, which is further metabolized to prostaglandins (PGs), prostacyclin (PGI 2 ) and thromboxane A 2 (TXA 2 ). In contrast, AA is initially converted to hydroperoxyeicosatetraenoic acids (HPETE), subsequently to hydroxyeicosatetraenoic acids (HETE) and then to the leukotrienes (LTs) via the LOX pathway [2,3]. PGs and LTs produced in the COX and LOX pathways, respectively, have been recognized as pro- inflammatory mediators in numerous inflammatory diseases, allergic disorders [4e6] proliferation and neoangiogenesis [7,8]. Many non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit these enzymes. Acetylsalicylic acid, a classical NSAID, is a selective COX-1 inhibitor whereas naproxen and indo- methacin are non-selective COX inhibitors. In the late 1990s, selective COX-2 inhibitors (i.e, coxibes) have been introduced in clinical trials for the treatment of inflammatory conditions without causing gastric irritation. However, several coxibes (e.g., rofecoxib and valdecoxib) have been withdrawn because they have been associated with myocardial infraction and cardiovascular throm- botic events [9e11]. COX-2-specific inhibitors, such as celecoxib (Celebrex Ò ) and rofecoxib (Vioxx Ò ) lack antiplatelet activity because they do not inhibit the COX-1 isoform and therefore do not inhibit thromboxane synthesis [12]. These thrombotic side effects seem to be due to the decreased level of vasodilatory and anti- aggregatory prostacyclin (PGI 2 ) along with an increased level of the prothrombotic platelet aggregator TXA 2 [3,13e15]. In addition, it has been pointed out that inhibiting COX pathway could shunt the metabolism of AA toward the 5-LOX pathway [15], increasing the formation of leukotrienes leading to inflammation. Unfortunately, NSAIDs-induced important adverse effects e.g. asthma and gastrointestinal damages, that limit their use [16e18]. Compounds that combine COX and LOX inhibition may present multiple advantages because they synergistically block metabolic pathways of arachidonic acid cascade and thrombosis and possess * Corresponding author. Tel.: þ302310997627; fax: þ302310997679. E-mail addresses: epontiki@pharm.auth.gr (E. Pontiki), hadjipav@pharm.auth.gr (D. Hadjipavlou-Litina). 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.2010.10.035 European Journal of Medicinal Chemistry 46 (2011) 191e200 394