芳基取代噻唑和噻嗪衍生物合成 晶体结构及其生物活性-synthesis of crystal structure and biological activity of aryl substituted thiazole and thiazine derivatives.docx

AbstractInfluenza caused by virus H1N1，H5N1 of type A is a kind of disease with highly contagious acute viral infection of the respiratory. And it’s a big threaten to the health of person. Influenza virus neuraminidases (NA) inhibitors can inhibit influenza virus A and B selectively. And NA inhibitors are the most effective drugs to treat influenza H1N1, H1N5 virus. NA has a relatively conservative in influenza virus mutation process which makes it a good target. However, influenza viruses can develop resistance to the ‘Tamiflu’ via point mutations in NA. The recent emergence of Tamiflu-resistant strains has raised serious concerns about a global flu pandemic because of their potential lethality to humans. So it’s very necessary to research new NA inhibitor. The mapping analyses revealed the presence of novel druggable hot spots in the 150- and 430-loop regions, providing further support for the feasibility of developing high-affinity inhibitors capable of binding these areas. Such inhibitors may be applicable to the group-1 NA’s including N1, N4, N5, and N8, which have nearly identical active site regions, but not necessarily group-2 enzymes (N2, N3, N6, N7, and N9), which appear to lack such well defined cavities. The paper designed and synthesized a series of 3-thiazole-ethyl benzoate, 1,3-thiazine NA inhibitors against the double -binding-site of SA/150-Cavity, 150-Cavity/430-Cavity and SA/430-Cavity of the open conformation of N1 from influenza virus H1N1. All compounds were evaluated against the inhibitory activity of NA in vitro.NA inhibitor against SA /150-Cavity double-binding-site.The first chapter designed and synthesized a series of ethyl benzoate NA inhibitors against SA and 150-Cavity double-binding-site. Though the compound ethyl 4-(N-acetyl -amino)-3-aminobenzoate 1 as intermediate, using the thiazole, urea, amide connect the ethyl 4-(N-acetylamino)-benzoate against SA binding sites and substituted aryl against 150-Cavity binding sites, in o