Synthesis,Characterization And Activity Study Of Non-steroidal Anti-inflammatory Drug Naproxen Metal Complex And Palladium Fluorescent Probe

Metal ions widely exist in nature.Some transition metals,such as Cu???,are essential trace elements for human body.They play an irreplaceable role in life activities,participate in and regulate various physiological processes,and play a role of structure and/or mediating cofactors in many proteins.In addition,copper-based drugs have also attracted attention for their excellent pharmacological activity.Other heavy metals,such as palladium ions,have been widely used in various fields.However,excessive accumulation of these metals can cause serious environmental problems and is extremely detrimental to human health.Therefore,there is an urgent need to design and develop new simple and effective analytical methods with high substrate selectivity to quickly detect such harmful metal ions.In recent years,the rapid development of metal complex drugs and small molecule fluorescent probes has attracted great attention of researchers.By complexing drug molecules with metal ions to form metal complex drugs or designing and synthesizing fluorescent probes that can be used to detect harmful heavy metal ions is an important means to improve drug molecular activity,reduce toxicity and achieve detection purposes.Therefore,in this paper,naproxen and N-?2-aminoethyl?morpholine are complexed with copper ions to form metal complexes to reduce the side effects of naproxen molecules and enhance or enrich their biological activities.In addition,we also designed and synthesized two small molecule fluorescent probes for detecting Pd²⁺.Specifically,the following two parts of the research work are carried out:1.Synthesis,Characterization and Activity Study of Copper Complex of Non-steroidal Anti-inflammatory Drug NaproxenNaproxen is a non-selective COX inhibitor with anti-inflammatory,antipyretic,and analgesic properties.As one of the most commonly used non-steroidal anti-inflammatory drugs?NSAIDs?,the use of such drugs can cause serious gastrointestinal and other adverse reactions.Therefore,certain structural modification of these drugs is an important means for developing new high-efficiency anti-inflammatory drugs with little toxic and side effects.It has been found that after the NSAIDs and metal ions coordinate to form metal complexes,the activity was better than its parent drug,and the side effects were greatly reduced.In this study,two metal complexes were synthesized with naproxen as the main ligand,N-?2-aminoethyl?morpholine as the auxiliary ligand and Cu???as the center ion.Their structures were characterized by IR,UV-vis,fluorescence,elemental analysis and X-ray single crystal diffraction.The complex 1[Cu?nap?₂?H₂O?₃]·H₂O?nap=naproxen?does not contain any auxiliary ligand and has a mononuclear structure.The X-ray single crystal diffraction analysis of the complex 2[Cu₂?nap?₄?morph?₂]?morph=N-?2-aminoethyl?morpholine?shows that it has a binuclear structure and the two central copper ions are bridged by two naproxen molecules.In addition,we discussed the anti-inflammatory,anti-ulcer and analgesic activities of naproxen and its complexes at the animal level,the anti-proliferative activity at the cellular level and other in vitro biological activities.The results showed that,compared with naproxen,the anti-inflammatory and analgesic activities of complexes 1 and 2 were significantly improved and the side effects of gastric mucosal injury were greatly reduced.The inhibition rate of complex 1 on toe swelling was as high as 93.6%after 3 hours of inflammation,which almost completely eliminated the inflammation.In the study of the side effects of gastric mucosal injury,the safety of complex 2 was higher,and its ulcer index?12.6±3.2?was only half that of naproxen?26.3±5.2?.In the study of analgesic activity,the analgesic effect of complex 2 was better,the pain inhibition rate was 76.3%,about 2 times that of naproxen and 1.4times that of complex 1.The antibacterial activity results showed that naproxen had no antibacterial activity.Complexes 1 and 2 had inhibitory activities against Gram-positive and Gram-negative bacteria with different inhibitory capacities.In addition,complex 2 also showed antifungal activity?MIC=56.25?g/m L?.The results of anti-proliferative activity showed that complex 1 only had a certain inhibitory effect on He La cells,while complex 2 showed varying degrees of anti-proliferative activity on He La,Hep G2 and MCF-7 cells,and the inhibition to MCF-7 cells was the strongest,IC₅₀value was 23.5±0.18?M similar to cisplatin?20.3±0.13?M?,and complex 2 could also induce apoptosis of MCF-7 cells.The complex also showed excellent urease inhibition and antioxidant activity.Complex 1(IC₅₀=2.80?M)and 2(IC₅₀=1.43?M)had much higher urease inhibitory activity than that of the positive control acetohydroxamic acid(IC₅₀=6.26?M).In the study of antioxidant activity,the activity of complex 2 was higher,especially the strongest scavenging activity to hydroxyl radicals,which can be as high as 91.4%,which is equivalent to antioxidant VC.In summary,we have obtained complexes with good anti-inflammatory and analgesic effects and small gastric side effects,which improve the effectiveness and safety of naproxen.In addition,the complexes also exhibit a wide range of biological activities and expand the scope of application.2.Design,synthesis and in vitro activity of palladium ion fluorescent probePalladium ion is one of the most important precious metals.Because of its excellent physical and chemical properties?such as high melting point,corrosion resistance and excellent catalytic performance?,it is widely used in medical,electronics,automotive,jewelry and catalyst industries.With the extensive use of palladium,the problem of its residue has attracted great attention.As we all know,palladium can combine with biological molecules in the body,such as DNA,proteins and thiol-containing amino acids,thereby interfering with various cellular processes and adversely affecting the human body.Based on this,it is of great significance to develop a method that can quickly and efficiently detect Pd²⁺.In this study,we used benzothiazole derivatives and pyrazole derivatives as fluorophores and propargyl as the recognition group to design and synthesize two fluorescent probes BP-Pd and PP1 for detecting Pd²⁺.After the probes BP-Pd and PP1 react with Pd²⁺,fluorescence quenching occurs,and the fluorescence intensity decreases linearly in the range of 0-0.1 eq.?BP-Pd?and 0-0.12 eq.?PP1?,the detection limits are 2.72 n M?BP-Pd?and 3.39 n M?PP1?,respectively.Compared with other common metal ions,BP-Pd and PP1 exhibit high selectivity and sensitivity to Pd²⁺.In addition,the two probes can also detect Pd²⁺in a wide p H range?3-12?BP-Pd?;7-12?PP1??,in particular,the fluorescence intensity of BP-Pd in the p H range of 3-12 can remain stable and the detection effect of Pd²⁺is not affected by p H,which shows the application potential of the probe in acid and alkaline environment.