Molecular Design,Synthesis And Bioactivity Research Of Novel Indole-imidazole Derivatives As Aromatase Inhibitors

Aromatase is a cytochrome P450?CYP19?enzyme that catalyzes the conversion of androgens androstenedione to the aromatic estrogenic steroids estrone.Aromatase inhibitors?AIs?can theoretically markedly reduce estrogen production.The enzyme is an important pharmacological target in the anti-cancer therapy.Aromatase inhibitors,on the basis of their chemical structures,are classified into two categories: steroidal and nonsteroidal.Compared with steroidal AIs,nonsteroidal AIs become the hotspot of anti-cancer drug researches for its high oral bioavailability and pharmacokinetic.The indole-imidazole derivatives were employed in the construction of three-dimensional quantitative structure-activity relationship?3D-QSAR?models obtained CoMFA and CoMSIA(CoMFA model: r²_cv=0.641,r²ncv=0.991,SEE=0.079,F=571.491,r²_pred=0.615;CoMSIA model: r²_cv=0.621,r²_ncv=0.961,SEE=0.160,F=134.519,r²_pred=0.603)by docking and pharmacophore strategy.With 2-phenyl indole-imidazole derivatives as led compound,we designed three novel classes of indole-imidazole derivatives and predicted by the CoMFA and CoMSIA models,which will further help in the design and synthesis of additional potent AIs.The indole-imidazole derivatives were prepared in three steps from 1H-indolecarboxylate.Starting material 1H-indolecarboxylate was converted to the 1-substitutedphenyl-1H-indolecarboxylate by N-alkylation with several1-bromosubstitutedbenzene.The reduction of the ester was achieved using lithium aluminum hydride?Li Al H4?in tetrahydrofuran.So obtained,1-substitutedphenyl-1Hindol-methanol was treated with 1,1'-carbonyldiimidazole?CDI?in dry acetonitrile to afford 1-substitutedphenyl-1H-indole-imidazol.There are 72 structures contained 50 new compounds and 24 target compounds that we synthesized and all the structures were confirmed mainly by proton and carbon-13 NMR spectroscopy.The anti-aromatase activity of those compounds was measured by enzyme-linked immunosorbent assay?ELISA?.The majority of those compounds exhibited aromatase inhibition.The most effective compounds were wjy-01,wjy-04,wjy-10,wjy-12 and wjy-16.