Synthesis and anti-inflammatory/antioxidant activities of some new ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives and of their 4,5-dihydro-(1H)-pyrazole analogues Asuncio ´ n Burguete, a Eleni Pontiki, b Dimitra Hadjipavlou-Litina, b, * Raquel Villar, a Esther Vicente, a Beatriz Solano, a Saioa Ancizu, a Silvia Pe ´rez-Silanes, a Ignacio Aldana a and Antonio Monge a a Unidad de Investigacio ´ n y Desarrollo de Medicamentos, Centro de Investigacio ´ n en Farmacobiologı ´ a Aplicada (CIFA), Universidad de Navarra, c/Irunlarrea s/n, 31080 Pamplona, Spain b Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece Received 7 September 2007; revised 1 October 2007; accepted 1 October 2007 Available online 5 October 2007 Abstract—We report the synthesis, anti-inflammatory and antioxidant activities of novel ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives and of their 4,5-dihydro-(1H)-pyrazole analogues. The tested compounds inhibit the carrageenin-induced rat paw edema (4.5–56.1%) and present important scavenging activities. Compound 2a is the most potent (56.1%) in the in vivo experiment and exhibits promising in vitro inhibition of soybean lipoxygenase (IC 50 <1 lM). Ó 2007 Elsevier Ltd. All rights reserved. Quinoxalines, including their fused-ring derivatives, dis- play diverse pharmacological activities (antiviral, anti- cancer, and antibacterial). 1,2 Scientists in Belgium and the United Kingdom have found that quinoxaline is a potential treatment for HIV infection, and works well with lamivudine, abacavir, and efavirenz. 3 Oxidation of both nitrogens of the quinoxaline ring dramatically increased the diversity of certain biological properties, such as antibacterial activity 4a,b,5,6 and hypoxia-selective anticancer activity. 7 Monge et al. 8–12 are involved in the synthesis and biological evaluation of new agents de- rived from quinoxaline 1,4-di-N-oxide and related com- pounds that have proved to be efficient cytotoxic agents for hypoxic cells in solid tumors. The poor tumor vascu- lar structure, the inefficient blood supply along with a high interstitial pressure generate a variable proportion of viable hypoxic cells in solid tumors which is one of the causes of cell resistance to anticancer treatments. Systemic hypoxia increases reactive oxygen species gen- eration and promotes leukocyte-endothelial adherence via reactive oxidant generation. Thus, antioxidants pre- vent the increase in leukocyte-endothelial adhesive inter- actions observed in hypoxia. 13 Bioreductive drugs have been designed to take advantage of the particular meta- bolic characteristics of hypoxic cells. The formation of reactive oxygen species (ROS) is char- acteristic of aerobic organisms that normally defend themselves against these highly reactive species using en- zymes, like superoxide dismutase and glutathione perox- idase and naturally occurring antioxidants. 14 ROS, like superoxide radical anion, hydrogen peroxide, and hy- droxyl radical, are produced during the inflammation process by phagocytic leukocytes (e.g., neutrophils, monocytes, macrophages, eosinophils) that invade the tissue. Moreover, these reactive species are involved in the biosynthesis of prostaglandins and in the cycloxy- genase- and lipoxygenase-mediated conversion of ara- chidonic acid into proinflammatory intermediates. 15,16 Persistently high levels of ROS may involve pathological conditions, as the active species can modify essentially 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.10.002 Keywords: Quinoxaline 1,4-di-N-oxide; a,b-Unsaturated ketone; 4,5- Dihydro-(1H)-pyrazole; Anti-inflammatory agents; Antioxidant agents. * Corresponding author. Tel.: +30 2310997627; fax: +30 2310997679; e-mail: hadjipav@pharm.auth.gr Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 17 (2007) 6439–6443