Chemical Constituents And Biological Activities Of Piperis Longi Fructus

Piperis longi fructus was known as“bi ba”,“bi ba li”,“shu wei”in traditional Chinese medicine.It is pungent in taste and hot in nature.It belongs to the stomach and large intestine meridians.It has the effect of warming middle-jiao to decrease the coldness,lowering Qi to relieve the pain.It is often used to treat abdominal pain,vomiting,chest pain,heartache,headache,toothache,inflammation of the digestive tract and reproductive system etc.In order to provide a scientific basis for the further development and application of Piperis longi fructus,we have investigated the chemical constituents and biological activities of this plant.In this paper,the chloroform fraction of Piperis longi fructus were separated and purified by positive and reverse silica gel column chromatography,Sephadex LH-20 and semi high performance liquid chromatography.The structures were identified by HRMS,¹H NMR,¹³C NMR,HSQC,HMBC,DEPT,NOESY,CD and other spectral techniques.28 compounds were identified,including 21 amide alkaloids（9 piperidine amide alkaloids,4 dimeric amides alkaloids,4 isobutylamide alkaloids and4 pyrrole ring alkaloids）,3 lignans,2 sesquiterpenes and 2 other compounds.They were identified as dipiperamide H（1）,piprelonguminine（2）,piperine（3）,1-[1-Oxo-9（3,4-methylenedioxyphenyl）-2E,4E,8E-nonatrienyl]-pyrrolidine（4）,piperninaline（5）,piperolein B（6）,dipiperamide G（7）,1-[1-Oxo-5（3,4-methylenedioxyphenyl）-2E,4E-penta-dienyl]-pyrrolidine（8）,1-[1-Oxo-5（3,4methylenedioxyphenyl）-2Z,4E-pentadienyl]-pyrrolidine（9）,retrofractamide C（10）,retrofractamide B（11）,1-[1-Oxo-11（3,4-methylenedioxyphenyl）-2E,4E,10E-undecatrienyl]-pyrrolidine（12）,piperundecalidine（13）,piperchabamide B（14）,piperchabamide C（15）,（2E,4Z,8E）-N-[9-（3,4-methylenedioxyphenyl）-2,4,8-nonatrienyl]-piperidine（16）,Isopiperine（17）,dipiperamide A（18）,dipiperamide B（19）,coumaperine（20）,dihydropiperlonguminine（21）,sesamin（22）,fargesin（23）,phillygenin（24）,guaiol（25）,4-epi-isodauc-6-ene-10β,14-diol（26）,benzoic acid（27）,Isochavicinic acid（28）.Among of them,compound 1 was a new compound,dimeric amides alkaloids were isolated from Piperis longi fructus for the first time,including compounds1,7,18 and19;compounds 4,9,12 and 24-28 were isolated from this plant for the first time.Anti-inflammatory and anti-diabetic active constituents were screened from the constructed Piperis longi fructus chemical constituents database using SYBYL molecular docking technology.The results showed that some chemical constituents had good binding ability to the anti-inflammatory and anti-diabetic targets.Furthermore,compounds mainly generated hydrogen bond and hydrophobic interaction with targets,such as MIF,p38 andα-glucosidas.According to the results of molecular docking,the compounds with good binding ability were selected for MIF,p38 andα-glucosidase enzyme activity test in vitro.The results showed that pipernonaline,retrofractamide C and piperchabamide B had good inhibitory activity on MIF;dipiperamide H,1-[1-Oxo-11（3,4-methylenedioxyphenyl）-2E,4E,10E-undecatrienyl]-pyrrolidine and piperchabamide B had good inhibitory activity on p38;pipernonaline had good inhibitory activity onα-glucosidase.Based on the results of enzyme activity in vitro,it is suggested that piperis longi fructus and its chemical constituents have great potential in the treatment of inflammation and diabetes,which can provide reference for the development of anti-inflammatory and anti-diabetic drugs in the future.According to the results of enzyme activity in vitro,the compounds with good activities were selected for ADMET prediction.The results showed that all active constituents had good ADMET properties.