Studies On The Synthesis And Activities Of Pyrrole And Pyrazole Compounds

The ocean is abundant in biological resources; in which Marine pyrrole alkaloids are widely exist. Marine pyrrole alkaloids which exhibit a wide range of biological activities and application prospects possess the characteristics of wide varieties, particular structures. Enormous professionals and researchers have been attracted because of antibacterial activity, antitumor, enzyme inhibition and so on. However, the development and research of pyrrole alkaloids is restricted by many factors. For example, living marine resources are getting increasingly scarce; the ocean environment is complex and sampling is difficult, at the same time the extracting process of pyrrole alkaloids makes lots of waste and difficulties. Research shows that much of pyrazole compounds possess the anti-arteriosclerosis and anti-inflammation activities.On the other hand,some of those compound are also used as herbicides. The purpose of this project is connected pyrrolic compounds with pyrazole compounds, to get new ones which may have higher bioactivity, lower side effects and would be used as leading conmpounds for drug development. Based on the idea, a series of pyrrole-pyrazole compounds were designed and synthesized. The structures were identified by TLC, IR, and HNMR; Their activities were studied initially by virtual screening; The results of virtual screening were verified by the testing the inhibitory activities of urease, acetylcholinesterase and xanthine oxidase of the compound.. The thesis is divided into the following sections:1. Design and synthesis of compoundsThe analogues of marine pyrrole alkaloids were synthesized by using the common chemicals (ethyl acetoacetate, sodium nitrite) as the starting material, The starting material were oxidized into corresponding aldehydes using ceric ammonium nitrate (CAN), Then eleven chalcones were synthesized by the aldol condensation reaction using the aldehydes which have been obtained; Fifteen azole compound were synthesized with the eleven produces as the starting material, hydrazine hydrate, semicarbazide hydrochloride and aminothiourea as the cyclization reagents. The structures of the synthetic compounds have been confirmed by TLC, IR, and HNMR.2. Enzyme inhibitory activities of the synthesized compoundsDocking MOE database with urease(PDB ID:1E9Y), acetylcholinesterase(PDB ID:1ACJ) and xanthine oxidase(PDB ID:3NRZ), MOE database is composed of the synthetic compounds. Through this method, the inhibitory activities were detected preliminarily. The results indicate that compound2shows stronger binding activity towards acetylcholinesterase. The hydrophobic interaction between pyrrole ring in compound2and Phe330, Trp84in acetylcholinesterase are strong, meanwhile pyrrole ring, Ser81、Asp72and Ser122was driven by hydrogen bonding. compound3shows stronger binding activity towards xanthine oxidase. The benzene ring in compound3forms cationic force with LysB1228and ArgA426in xanthine oxidase. The electronic absorption effect is found between the carbonyl oxygen of molecule and ArgA426. The inhibitory activities of the compounds against urease, acetylcholinesterase and xanthine oxidase were tested by colorimetric method. The compounds which inhibition rate were more than60%were turther tested for the value of IC50. The results showed that compound la has better urease inhibitory activity with the inhibition rate of34.71%; Compound la and Compound2show better acetylcholinesterase inhibitory activities with the inhibition rate of69.98%and77.38%, IC50value of37.54μmol/L and18.48μmol/L respectively. Compound8and compound9showed potent xanthine oxidase inhibitory activity with the inhibition rate of81.38%and63.39%, IC50value of18.97μmol/L and23.07μmol/L respectively. Enzyme kinetic studies showed compound8is a noncompetive inhibitor of xanthine oxidase, with the Ki of12.83μmol/L.Eighteen pyrrole compounds and pyrazole compounds were synthesized in this thesis The study of the bio-activities showed that compound2possessed the best acetylcholinesterase inhibitory activity and compound8possessed the potent xanthine oxidase inhibitory activity. The two coumpounds maybe for the treatment of Alzheimer’s disease or goult with the further research and improvement.