| Since 1971,Cisplatin?cis dichloride diamine platinum?successfully applied in clinical cancer therapy,developing biologically active metal complexes as novel possible therapeutic agents have become a hotspot in bioinorganic chemistry.Urease,a nickel-containing metalloenzyme,had some negative impacts on plants and animals.Therefore,it was an important goal to control the activity of urease with the use of inhibitors.The traditional organic chemistry urease inhibitors have some certain defects such as side effects,unknown inhibitory mechanisms.To seek novel urease inhibitors with less side effects and specific inhibitory mechanisms were very significant.Piperazine derivatives have many kinds of biological activities such as antibacterial,antitumor,suppression of antipsychotic,prevention of cardiovascular and diabetes,treatment of Alzheimer's disease?AD?and so on.According to the previous work of our group,the transition metal complexes based on the ligands containing nitrogen heterocyclic ring have good urease inhibitory activity.In this paper,three carboxylic acids containing piperazine ring were synthesized and reacted with different transition metal salts.Nine mononuclear transition metal complexes based on these ligands above were synthesized,structurally determined by single-crystal X-ray diffraction and infrared spectrum analysis.At the same time,in vitro urease inhibitory activities,the urea enzyme inhibition mechanism,albumin binding properity and cell toxicity were carried out.The details of contents were as follow:Nine novel transition metal complexes,[Cu?L1?2·H2O]?1?,[Ni?L1?2·2H2O]?2?and[Cd?L1?2·2H2O]?3?which based on 2-[4-?3,4-dichlorophenyl?piperazin-1-yl]acetic acid;[Cu?L2?2·2H2O]?4?,[Ni?L2?2·2H2O]?5?and[Cd?L2?2·2H2O]?6?which based on2-[4-?2-methoxyphenyl?piperazin-1-yl]aceticacid;[Cu?L3?2?H2O?]?7?,[Zn?L3?2?H2O?2]·CH3OH·1.5H2O?8?,[Ni?L3?2?H2O?1.8]·CH3OH·1.2H2O?9?which based on 2-{4-[bis?4-fluorophenyl?methyl]piperazin-1-yl}acetic acid,were synthesized and characterized by elemental analysis,IR,and X-ray diffraction single crystal analysis.All acquired complexes were mononuclear.The crystal system of these complexes was monoclinic,triclinic and orthogonal,respectively.The center metal ions were mainly six coordinated.However,the copper ion could adopt distorted rectangular pyramid or pseudo-octahedral coordination environment due to different ligands.All acquired compounds were tested the urea enzyme inhibitory activity against jack bean urease in vitro.As a result,all ligands showed no inhibitory activity against urease,while coordinating with copper ion led to strong urease inhibitory activity,the IC50 value of complexes 1,4 and 7 was 8.17±0.91,2.25±0.35 and 11.23±3.31?M,respectively.In order to explain the inhibitory mechanism between compounds and urease,molecular docking simulation and kinetics studies were carried out.Complex 1 was a competitive inhibitor of urease,which could combine with the active center of urease?3LA4?through intermolecular hydrogen bonds,electrostatic interactions,and hydrophobic interactions.Complex 4 was an anticompetitive inhibitior of urease,which could combine with the essential amino acid residues of non-active site changing the three-dimensional structure caused inactivation.Complex 7 was a mixed competitive inhibitor of urease.Not onlt could it combine with the active site,but also could combine with the essential amino acid residues of non-active site.Noteworthily,when the size of organic ligands'side chain was same,electron-with drawing groups showed strong urea enzyme inhibition activity,while large side chain revealed weak urea enzyme inhibition activity.The result indicated that inhibitory activities of metal complexes were influenced by ligand substituents,electronic configurations,and by the nature of metal center.In addition,compared with other antaiurese research by coordinated Cu?II?ion,complexes 1?4?7 showed similar or even better activities against urease,which resulted in the improved inhibitory activity.In order to seek the potential clinical urease inhibitors,we also tested the serum protein binding ability and in vitro for complexes 1,4,and 7.The results showed that all had good bovine serum albumin?BSA?and human serum albumin?HSA?binding ability,and meanwhile the low cytotoxicity against human normal liver cell lines?HL-7702?.Above all,complexes 1,4 and 7 may be the potential of urease inhibitors in the future. |
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