Synthesis And Bioactivity Of 3-(2-Aryl-vinyl)-indole Derivatives

Stilbenes, in nature, is the product of the immune system of plant against the infraction (such as bacteria, viruses, optical radiation, chemical pollution, etc.), provided with antibacterial, anti-oxidation, lipid lowering, anti-thrombosis, pesticides and many other physiological activities.Using of nonclassical bio-isosteric replacement in drug design, we design a series of new aza-stilbene derivatives, of which one benzene ring is replaced with aromatic heterocycle such as indole, pyrrole and imidazole. The aromatic heterocycle is also substituted with secondary amino group, methoxy, benzoxy, hydroxyl, halogen and alkenely group. Based on computer-aided virtual screening,3-styrylindole derivatives are highly potential to inhibit HIV-1 protease.In this paper, Knoevenagel condensation reaction, Grignard reaction, Wittig-Horner reaction, Wittig reaction and Mannich reaction, are used to synthesize 3-(2-aryl)vinylindole derivatives. By comparing the advantages and disadvantages of different reactions, we disclose a convenient method for the synthesis of 3-vinylindoles through N-(p-methylphenyl sulfonyl)-indole-3-aldehyde with Ph3P=CHPh. The p-methylphenyl sulfonyl group, an electron-withdrawing group, can enhance aldehyde character so remarkable that the yield of Wittig reaction is not less than 81%. The p-methylphenyl sulfonyl group is removed in the same reaction system, so the method for the synthesis of 3-styryl indole derivatives is an effective way. We use Eschenmoser salt to prepare 1-[(dialkylamino)methylene]-3-[(2-aryl)vinyl]-indole derivatives in the yield of 95%. In this dissertation, ten 3-vinylindole derivatives are synthesized and unreported, including 1-[(dimethylamino)methylene]-3-[(2-aryl)vinyl]-indole, 1-[(1-pyrrolidinyl)methylene]-3-[(2-aryl)vinyl]-indole, 1-[(4-morpho linyl)methylene]-3-[(2-aryl)vinyl]-indole and 3-[(2-aryl)vinyl]-5-fluoro-indole. All these compounds are characterized by NMR and mass spectrometry.Three derivatives, (E)-3-(2,5-dimethoxystyryl)-1H-indole, (E)-3-(2,5-dimethoxystyryl)-1-(morpholinomethyl)-1H-indole and (E)-3-(3,5-dimethoxystyryl)-1-(morpholinomethyl)-1H-indole are evaluated for their integrating with HIV Vif protein on the Biacore. At the concentration of 20μg/ml, the binding rate with vif protein is 37.5%,47.8% and 41.5%, respectively. This result indicates that this kind of compounds may target HIV-1 Vif.