Synthesis Of Mefenamic Acid Metal Complexes And Their Biological Activity Study

Non-steroidal anti-inflammatory drugs (NSAIDs) exert their pharmaceutical effect of anti-inflammatory, antipyretic, and analgesia by blocking the synthesis of prostaglandings (PGs) and leukotrienes (LTs) that catalyzed by cyclooxygenase (COX) and lipoxygenase (LOX) and clinically used to relieve the osteoarthritis, fever and pain. However long-term use of NSAIDs would induce severe gastrointestinal and tenal side effects. The coordination of NSAIDs to metal ions could decrease these side effects without impairing the pharmaceutical efficacy of NSAIDs, thus is to be an effective way to develop new anti-inflammatory drugs.In this thesis, a seris of mefenamic metal complexes (M-mef, M=Mn(Ⅱ)、 Co(Ⅱ)\Ni(Ⅱ)、Cu(Ⅱ)、 Zn(Ⅱ)) were synthesized and structurally well characterized. Their pharmaceutical effect was investigated. We found that Mn-mef complex exhibits the highest LOX inhibitory activity comparing to the modified Mn-mef derivatives. Mn-mef, Co-mef and Ni-mef show similar LOX inhibitory activity for they have similar three dimensional structure. However, the binuclear Cu-mef and the trinuclear Zn-mef almost exhibit no inhibitory effect to LOX. The docking between M-mef complexes and LOX confirmed the experimental results that Mn-mef complex compatitively inhibits LOX and the bulkier Mn-mef derivatives uncompatitively bind with LOX. Therefore, the high inhibitory activity of the Mn-mef complexes is closely related to their three dimensional structures, which determine their interaction with LOX. These complexes show different anti-oxidant abilities because of bearing different metal ions. Additionally, M-mef complexes show certain COX inhibitory activity, similar to the ligand mefenamic acid, but is slightly more potent towards COX-2than COX-1. This maybe caused by the different stabilities of the conjugates that M-mef formed with COX-1or COX-2. The high LOX and COX inhibitory activities, and strong anti-oxidant activity of M-mef complexes indicate that they are potential anti-inflammatory drug.