Study On The Design, Synthesis And Bioactivity Of Hexapyrido - Indole - Imidazolium Salts

The hexahydropyrrolo[2,3-b]indole system, an excellent pharmacophore, is presented widely in natural products, such as physostigmine. Physostigmine’s derivatives are a kind of efficient acetyl cholinesterase inhibitors, which can be used to treat many different diseases. Recently, our group has synthesized a seris of imidazole salts with excellent antitumor activity. Base on the intrseting research, we focus on synthesis of novel compounds with hexahydropyrrolo[2,3-b] indole and imidazole structural units, and evaluation in vitro against a panel of human tumor cell lines to find some high selectivity and efficiency hexahydropyrrolo[2,3-b]indole-imidazolium salts compounds.This thesis includes two parts. In the first part, the synthesis and bioactivity of natural products with hexahydropyrrolo[2,3-b]indole and imidazole derivatives was simply reviewed.In the second part, a series of novel hexahydropyrrolo[2,3-b]indole-imidazolium salts were synthesized and evaluated in vitro against a panel of human tumor cell lines. The research results suggest that the 5,6-dimethyl-benzimidazole ring, and substitution of the imidazolyl-3-position with a 2-bromobenzyl or 2-naphthylmethyl group were important for the cytotoxic activity. Notably, Compound b43, bearing a 2-bromobenzyl substituent at position-3 of 5,6-dimethyl- benzimidazole, was found to possess the most potent derivative against five human tumor cell lines with IC50 values below 2.68μM and more selective towards SMMC-7721, A549 and SW480 cell lines.In this thesis,60 novel hexahydropyrrolo[2,3-b]indole-imidazolium salts were synthesized. Most of them showed strong anti-tumor bioactivity, and some of them have the potential to be the lead compounds with high efficient activity. On the basis of this work, we will continue to analysis the further structure-activity relationship reserach and find the new lead compounds with potent antitumor activity.