General Issue ARKIVOC 2011 (ii) 69-82 N-Substituted [phenyl-pyrazolo]-oxazin-2-thiones as COX-LOX inhibitors: influence of the replacement of the oxo -group with thioxo- group on the COX inhibition activity of N-substituted pyrazolo-oxazin-2-ones Nora Bennamane, a Bellara Nedjar-Kolli, a Athina A. Geronikaki, b* Phaedra Th. Eleftheriou, c Rachedine Kaoua, a Kamal Boubekeur, d Pascal Hoffman, e Shailendra S. Chaudhary, f and Anil K. Saxena f a Laboratory of applied organic chemistry, University of Sciences and Technology “Houari Boumédiène”, Algiers, Algeria b School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece c Department of Medical Laboratory Studies, Alexander Technological Educational Institute of Thessaloniki, Greece d Pierre and Marie Curie University, Paris, France e Paul Sabatier University, Toulouse, France f Medicinal Chemistry Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow-226 001, India E-mail: geronik@pharm.auth.gr Abstract Targeting to the synthesis of potent dual acting COX/LOX inhibitors as future anti-inflammatory drugs, we attempted a modification of the compounds based on docking analysis results. A substitution of the oxygen of the oxo-group of the oxazin-2-one ring by sulphur resulted in a four to over ten fold improvement of COX and LOX inhibitory action. N-phenyl derivatives exhibited the best biological properties with the 4-methoxy-phenyl derivative showing the best COX-1 and LOX inhibitory action and the 4-Br-phenyl derivative exhibiting the best COX-2 inhibitory action combined with good COX-1 and LOX inhibitory capacity. Keywords: COX, LOX, inflammation, phenyl-pyrazolo-oxazin-2-ones, oxazin-2-thiones Introduction Inflammation is a multifactorial process. It reflects the response of organism to various stimuli and is related to many disorders such as arthritis, asthma, and psoriasis, which require prolonged or repeated treatment. Release of arachidonic acid via the action of phospholipase A2 on membrane phospholipids is one of the first events of inflammation. Cyclooxygenase (COX) and Page 69 © ARKAT-USA, Inc.