Synthesis And Activity Study Of Indeno [1,2,3-ij] Isoquinolines

Indeno[1,2,3-ij]isoquinoline is the basic skeleton structure of azafluoranthene alkaloids.Azafluoranthene is a relatively small class of compounds in the isoquinoline alkaloids,which has good biological and pharmacological activities,especially antibacterial and antiviral activities.Therefore,azafluoranthene alkaloids can be used as a variety of drugs lead compounds.In this thesis,a series of compounds containing indeno[1,2,3ij]isoquinoline structures were synthesized and their structures were identified and their antibacterial and anticancer activities were studied.In this thesis,13 biphenylsulfonamide intermediates(5a-5m)were synthesized by nucleophilic addition,Hinsberg sulfonylation,and Suzuki crosscoupling reactions using benzaldehyde as raw material.Nine tetrahydroisoquinoline intermediates 6a-6i were successfully synthesized by cyclization of compounds 5a-5i with organic acids.Indeno[1,2,3-ij]isoquinolines 7a-7i were obtained by deprotection and oxidation with organic base DBU.After cyclization of compounds 5j-5m using protonic acid,compounds 7j-71 were synthesized under the action of organic base DBU.Compounds 7a-71 were synthesized for the first time.All the compounds were characterized by 1HNMR,13CNMR,HRMS and IR.At the same time,compound 71 was also analyzed by X-ray diffraction.The antibacterial activity of 12 synthetic target compounds was tested by the minimum inhibitory concentration(MIC)test method.Strains tested included Staphylococcus aureus,Bacilus subtilis,Pseudomonas aeruginosa and Escherichia coli.The results showed that the 12 target products had certain biological activities against the tested bacteria,and the minimum inhibitory concentrations of compounds 7d,7k,and 71 against Staphylococcus aureus could reach 16 μg/mL.The molecular docking calculation of compounds 7k and 71 showed that these two compounds could bind to filamentation temperaturesensitive protein Z(FtsZ)very well,and the binding free energies were-4.5 kcal/mol and-6.02 kcal/mol,respectively.The anticancer activities of 14 sulfonamide intermediates as well as 12 target compounds were tested by MTT assay in prostate cancer cells(PC-3)and triple-negative breast cancer cells(MDA-MB-231).The preliminary test results showed that the target products 7a and 7k had certain anticancer activities against PC-3 and MDA-MB-231 with IC50 values of 44-84μM.At the same time,it was found that the biphenylsulfonamide intermediates 5a-5m have excellent anticancer activity,with the lowest IC50 value of 7 μM.It provides a certain reference for the drug screening of these two types of compounds.