Synthesis And Bioactivity Evaluation Of Novel Spiro Amide And Its Derivatives

Chitin is an essential component in the growth and development of fungi.The biosynthesis of chitin is catalysized by the chitin synthase,thus chitin synthase has become a special target for designing antifungal drugs.The purpose of this thesis is to design and synthesis of new chitin synthase inhibitor.Acording to the structural characteristics of the reported chitin synthase inhibitor,series of spiro amide derivatives has designed and synthesized,and their affinity to chitin synthase and antibacterial activity are evaluated as well.The main work is summarized as follows:1.Compound 5 is synthesized from ethyl pyruvate and methylhydrazine sulfate by condensation,Vilsmeier reaction,aldehyde group reduction and bromine substitution reaction.Compound 9 is synthesized from isonipecotic acid.Then compound 9 couple with compound 5 under alkali to afford compound 10,which can afford key intermediate spiro amide 15 through four steps of reaction.2.Compound 21a-r is synthesized by through six steps of reaction with D-tartaric acid as raw material,and then compound 21a-r condensed with compound15 to produce the target products 23a-r.3.The synthesis conditions of the intermediates and target compounds are optimized.Eighty-five compounds are synthesized,and their structures are confirmed by¹H NMR and¹³C NMR,among these compounds forty-seven are new compounds.4.The inhibitory activity of the target compound on chitin synthase was determined.The test results showed that some compounds have good inhibitory activity on chitin synthase,especially compounds 23n and 23r showed excellent inhibitory activity,and their IC₅₀0 values is 0.1 mM and 0.11 mM,respectively.5.The antifungal and antibacterial activities of the target compounds are tested in vitro.The antifungal test results showed that the antifungal activity of the target compound 23a-r are much weaker than these of the control drugs fluconazole and polyoxin B.The anti-bacterial test results showed that some compounds have weak inhibitory effect on bacteria,and the inhibitory activity of all compounds is weaker than that of the control drug levofloxacin.6.FIC values of some compounds combining with fluconazole are determined.The results showed that most of the tested compounds showed no significant effect on the combination of fluconazole,and only compound 23p showed synergistic effect with fluconazole in Crytococcus neofonmans?ATCC 32719??FIC=0.375,FIC<0.5?.