Design, Synthesis And Biological Evaluation Of HCV NS5A Inhibtors And NAChR Ligands As Well As Synthesis Of 3-Alkenyl Indoles

Hepatitis C Virus (HCV) infection has become one of the major problems threatening human health. HCV non-structured protease 5A (NS5A) is closely related to the replication of the virus and participates in virus assembly and release, interferes with the important signaling pathways in cells and affects the cell cycle and the immune system and ultimately promptes the occurrence and development of chronic liver disease. High toxicity, severe side effects, long endurance and drug resistance still exist in the existing anti-HCV drugs. Therefore, HCV NS5A has become an attractive target for the development of anti-HCV drugs. Based on the review of the development of HCV NS5A and HCV NS5A inhibitors, and structure-activity relationships of HCV NS5A inhibitors and the docking results between inhibitors and HCV NS5A,29 compounds have been designed and synthesized. All the compounds were examined for anti-HCV activity and cytotoxic activity against Huh-7 cells in vitro. The results showed that:(1) Most of them showed moderate to good anti-HCV activity and a few compounds showed equivalent anti-HCV activity with positive control of BMS-790052. (2) All the compounds showed very low cytotoxicity. (3) The activity of compounds containing piperazine is much lower than the compounds containing arylimidazole. Base on the biological data, the structure-activity relationships of the compounds are analyzed and discussed in order to offer basis for further design and optimation of new compounds.Nicotinic acetylcholine receptor (nAChR) is a complex of ligand gating ion channel and participates in the transmission of excitability of nervous system. The occurrence and development of many human diseases are closely associated with nAChR, such as nicotine addiction, Parkinson’s disease, Alzheimer’s disease, Schizophrenia, etc. Low specificity, severe toxicity and side effects still exist in existing neurological drugs. Therefore, nAChR has become one of the important targets to develop neurological drugs with high efficiency, low toxicity and high specificity. Based on the review of the development of nAChR and nAChR ligands, the analysis of structure-activity relationships of nAChR ligands, the binding mode of ligands and nAChR and docking results between the designed ligands and nAChR,75 guanidine compounds have been designed and synthesized. Binding assay of these compounds was tested against KXα3β4R2 and KXα4β2R2 cell lines in vitro. Results showed that: (1) Most of the monoguanidines showed moderate to good α4β2 nAChR binding activity and some of them showed good binding activity and subtype selectivity. In addition, several of them showed moderate α3β4 nAChR binding acitivity, but poor subtype selectivity. (2) Most of the bisguanidines showed moderate to good α4β2 nAChR binding activity and subtype selectivity. (3) Twelve compounds were chosen for function assay against Heck cell lines by measuring the change of membrane potential induced by nAChR. The results found that most of them showed moderate to good antagonist activity against α4β2 nAChR, very few of them showed very good antagonist activity against α4β2 nAChR and subtype selectivity. Further activity studies of the compounds in vivo and in vitro are underway. According to the biological data, structure-activity relationship are analyzed and discussed to provide the basis for further design and optimization of new compounds.Palladium-catalyzed synthesis of 3-alkenyl indoles at room temperature was developed. The reaction was realized using 2-azido-3-arylacrylates and terminal alkenes via a domino process involving sequential intramolecular cyclization and olefination with moderate to good yields. There were many advantages of the reaction, such as readily available starting material, mild condition, and good regioselectivity, etc.