Synthesis And NA Inhibitory Activity Of Amide Derivatives Containing Thiazole Ring Or Piperazine Ring

Ferulic acid has extensive biological activities as a natural product.However,the study on influenza virus neuraminidase?NA?inhibitory activity was rarely reported.In this paper,the cinnamic acid amide derivatives 1 were designed according to active splicing principle and synthesized by the condensation of cinnamic acid derivatives and piperazine fragments with NA inhibitory activity.Keeping the active pharmacophores based on activity feedback of compound 1,target compound 2 was designed by introducing 2-aminothiazolamide fragment with NA inhibitory activity.In order to further optimize the target compounds 1 and 2 with better activity and explore the structure-activity relationship more comprehensively,carbon-carbon double bonds of the compounds 1 and 2 with good activity were removed to shorten the carbon chain between the benzene ring and the heterocycle ring;then the target compounds 3 and 4 were designed.Simultaneously,the thiourea fragment was introduced into the intermediate carbon chain of compound 2 to design and synthesize the acylthiourea thiazole compound 5.There are thirty-seven target compounds totally designed,synthesized and tested for NA inhibitory activity.Different substituted benzaldehydes and malonic acid were condensed according to Knoevenagel reation to obtain a series of cinnamic acid derivatives.The cinnamic acid derivatives or vanillic acid and the amine fragment were condensed using EDCI/HOBt as the condensing agent in different reaction solvents and temperatures to synthesize the target compounds 1⁴.The target compound 5 was synthesized by acetylation reaction,acid chloride reaction,nucleophilic substitution reaction,nucleophilic addition reaction and hydrolysis successively with ferulic acid as the starting material.All the target compounds 1⁵ were characterized by ¹H NMR and¹³C NMR;the representative compound 2c was further confirmed by X-Ray single crystal diffraction test.The NA inhibitory activity results showed that the most of the ferulic acid amide derivatives in the compounds 1 and 2 had better NA inhibitory activity than ferulic acid;amongst the compounds 1 and 2,the activity of ferulic acid thiazole amide compound 2g was better than others with IC₅₀ value of 39.66±0.17?M.The vanillic acid derivative 4a exhibited the most potent NA inhibitory activity with IC₅₀ value of38.56±3.99?M.The structure-activity relationship discussed the influence of the substituents on the benzene ring,amine fragments and the acrylamide carbon chain of the ferulic acid amide derivatives on the NA inhibitory activity.Molecular docking was performed to study the possible interactions between the ferulic acid amide derivatives and the active site of NA.