Design And Synthesis Of Cyclooxygenase-2 Inhibitors

Cyclooxygenase is the key enzyme in the biosynthesis of prostanoids, involved in pathological conditions such as inflammation. It is well known that this enzyme exists three isoforms: a constitutive (COX-1), an inducible form (COX-2) and a new found COX-3. Observations that COX-1, involved in several homeostatic processes, plays a housekeeping role while COX-2 expression was associated with inflammation condition have led to the development of COX-2 selective inhibitors in order to reduce the classical side-effects associated with the use of traditional NSAIDs. COX-3 is selectively inhibited by NSAIDs such as acetaminophen and antipyrine, and might represent a new therapeutic target.The following work-has been carried out in the thesis:1. Five series of compounds with different skeleton as below were designed and synthesized in order to search for new lead compounds with anti-inflammatory activity.2. Thirty-three target compounds were synthesized, all of which were identifiedby ~1HNMR and elemental analysis(or high revolution mass spectroscopy).3. An efficient and fast procedure for the preparation of 2-nitrophenylamines under microwave conditions was investigated in this research work, reaching a positive results.4. Thirty compounds were biologically evaluated in vitro and strcture and activity relationships were analyzed to provide valuable clues for further study. The compound 11-12 manifested an analgesic effect.5. By means of DOCK 4.0 a molecular simulation was performed for the typically synthesized compounds and the binding features were investigated and discussed.