Synthesis,Crystal Structure And Urease Activity Of Metal Complexes Derived With Piperazine Hydroxamic Acid Derivatives

In recent years,hydroxamic acid derivatives have played an important role in the anti-tumor,anti-bacterial,anti-metalloenzyme,anti-tuberculosis,flotation minerals and other fields with their unique structure,especially studies of urease inhibitory activities.Urease,containing two metal nickel ions protease,was ubiquitous and had a large negative impact on plants and animals.Acetyloxynonanoic acid was recognized as a good urease inhibitor,as a traditional organic small molecule compound,it had obvious shortcomings such as short acting time and low efficiency.Therefore,it was very important to synthesize a novel urease inhibitor with good inhibitory effect.In this paper,this study utilized the chelation of hydroxamic acid and the multi-drug effect of piperazine ring,eight piperazine hydroxamic acids were designed and synthesized.Then,nine metal complexes were synthesized by using ligands reacted with transition metal salts.Structural determind by infrared spectroscopy,elemental analysis and X-single crystal diffraction.And,the complexes were tested for in vitro urease inhibitory activity,serum albumin binding capacity and cytotoxicity assay.The synthesized metal complexes 1-7 were copper metal complexes,the crystal system of these complexes was triclinic.And the central ion were five-core copper complexes with four-coordination,forming the 12 crown 4 metal crown ether structure.Complexes 8 and 9,were silver metal complexes,were monoclinic crystal systems.And the central ions were monocytes with three coordination.The results of urease inhibitory activity test in vitro showed that the IC50 of the nine complexes ranged from 0.168 to 0.327 μM and were superior to the positive control group AHA(7.93 μM).The data analysis of structure-activity relationship indicated that the halogenated group was superior to other substituents and the silver ion was superior to the copper ion.In order to explore further the inhibitory mechanism between compounds and urease,kinetic experiments were carried out.And the results showed that the all complexes were competitive inhibition by competing with urea for urease active sites.For finding potential clinical urease inhibitors,the serum albumin binding and cytotoxicity experiments were conducted.The quenching constants,binding constants and binding sites showed that complexes 1-9 were all static fluorescence quenching,not only binding to BSA and HAS,but also releasing into tissues and organs.And all complexes were less toxic to cells in vitro.Therfore,the nine metal complexes have the characteristics of low toxicity and high efficiency and can be used as new and potential urease inhibitors for further research.