Synthesis And Biological Activity Of Semi-Calycanthaceous Alkaloids

Indole analogs exist widely in nature,and most of these alkaloids possess potent biological activities including anti-tumor,antibacterial,anti-viral,therapeutic hypertension,et al.Indole analogs have been widely used as the drugs for the treatment of diseases.Calycanthaceous is an important part of indole alkaloids isolated from the roots,leaves,flowers and fruits of chimonanthus praecox.semi-calycanthaceous alkaloids posess a variety of biological activities including inhibition of phytopathogenic fungi and bacteria.Calycanthaceous has a special hexahydropyrroloindole skeleton which can be used as the lead for the development of plant-derived pesticides,and a series of semi-calycanthaceous alkaloids have been synthesized by acylation and alkylation at the 3-N position of the skeleton in this thesis.Starting from indole-3-acetonitrile,the synthesis of two series of ssemi-calycanthaceous alkaloids was successfully carried out by oxidation,alkylation,reduction and acylation.25 compounds were obtained including two series:6 YDD-1 series of semi-clycanthine derivatives with the same substituents at the N-position or the C-3position and 19 YDD-2 series of semi-calycanthaceous alkaloids with the same substituents at the N-position or the C-3 position,with the following results:Compound Y was obtained by the oxidation reaction using indole-3-acetontrile as starting material,DMSO as the solvent and 37%HCl as a catalyst.The products Y₁ and Y₂were prepared by the compound Y and the excess 1-bromomethylnaphthalene and2-bromomethylnaphthalene using THF as the solvent and NaH as the base.The yields of compounds Y₁ and Y₂ are 64%and 60%.The products Y₁ and Y₂ possess the same substituent between the N position and C-3 position.Then the YD₁ and YD₂ were obtained by the cyclization with THF as the solvent,LiAlH₄ as the reducing agent.The yields of compounds YD₁ and YD₂ are 64%and 60%.25 derivatives were synthesized via acylation using compounds YD₁ and YD₂ as substrates The twenty five derivatives were characterized by ¹H-NMR,¹³C-NMR spectroscopy and ESI-MS.The 96-well plate microdilution method.was utilized to evaluate the biological activities of 25 semi-Calycanthaceous alkaloids analogues against Crytococcus Neofonmans,Escherichia coli,E.coli,Shinella sp,Candada albicans,Salmonella and Staphylococcus aureus.The results showed that 19 compounds exhibited high degrees of activity against Crytococcus Neofonmans and Escherichia coli.YDD-1-2,YDD-1-3,YDD-1-4,YDD-2-1,YDD-2-2,YDD-2-5,YDD-2-8,YDD-2-16,YDD-2-17 and YDD-2-19 exhibited high degrees of activity against Shinella sp.YDD-1-1,YDD-1-2,YDD-1-3,YDD-1-4 and YDD-2-8 exhibited significant inhibitory activity against Candada albicans.YDD-1-4showed significant inhibitory activity against Salmonella.YDD-1-2,YDD-1-3,YDD-2-10,YDD-2-12and YDD-2-13demonstratedsignificantinhibitoryactivityagainst Staphylococcus aureus.The MIC of the tested compounds were 1.95?g/mL.Most of the synthesied compounds exhibited a certain activity towards 6 kinds of bacteries.