Synthesis,molecular Docking And Biological Evaluation Of Coumarin Derivatives Containing Piperazine Skeleton As Potential Antibacterial Agents

The emergence of bacterial resistance is becoming a serious global health problem Such as the spread of multiresistant Gram-positive bacteria:methicillin-resistant Staphylococcus aureus(MRSA)and vancomycin-resistant Staphylococcus aureus(VRSA),pose a major threat to human health.So it’s necessary to find a new target to develop efficient antimicrobial agents.Since fatty acid synthesis(FAS)pathways are divided into two distinct forms:FAS-I in humans and FAS-Ⅱ in bacterias,for most bacterias,FabI is responsible for the concluding reduction step of each elongation cycle,it represents a key physiological regulator of fatty acid biosynthesis,and it has been carried out to be an important drug target for the development of novel antibacterials.Therefore,FabI is an attractive target.Coumarins are a class of compounds found widely in nature,they show a broad spectrum of activities including antibacterial,antitumor,anti-HIV and so on,and they are frequently associated with low toxicity,they can be considered as a privileged scaffold and an ideal framework for the design of compounds that can interact with different targets as their inherent affinity for several biological targets.Piperazine is a kind of nitrogen-containing heterocyclic basic group which is often used in medicinal chemistry,it can form hydrogen bonds or ionic bonds with the protein easily,regulate the acid-base equilibrium constant and lipid water partition coefficient of drugs effectively,and it has good antibacterial activity.By introducing piperazine into molecules,it can increase the water solubility and alkaline of the molecules;And by adjusting the physical and chemical properties of drugs,improving the pharmacokinetic properties of then,it can enhance the biological activity of molecules.On these basis,according to the split of drug design and activity superposition principle,the Ligand Fit Dock protocol of Discovery Studio was used as the in silico screening tool,two series of 28 coumarins derivatives(4a-4n,5a-5n)owning piperazine skeleton were synthesized,and 24 of them were new(compounds 5a,5i,51 and 5m were reported before).The chemical structure of them had been determined by such methods as elemental analysis and magnetic resonance(HNMR).Their antibacterial activities against(B.subtilis)and Staphylococcus aureus(S.aureus),Escherichia coli(E.coli),Pseudomonas aeruginosa(P.aeruginosa),and Enoyl-ACP-reductase(FabI)inhibitory activities were tested.Compound 4g represented the most potent antibacterial activity against B.subtilis and S.aureus with MIC of 0.236,0.355 μg/mL,respectively,being better than the positive control penicillin.What’s more,it showed the most potent activity against FabI with IC50 of 0.57 μM.Docking simulation was performed using the X-ray crystallographic structure of FabI in complex with the most potent inhibitor to explore the binding mode of the compound at the active site.The results indicated that compound 4g has demonstrated significant FabI inhibitory activity as a potential antibacterial agent and provides valuable information for the design of FabI inhibitors.Additionally,we also used the results of molecular orbital calculations(3D-QSAR model)to study the structure-activity relationship and guide the further study.