Synthesis And NA Inhibitory Activity Of 1,2,4-triazole Thione (Ether) Imine Derivatives

The flu is a disease that is frequent and has a high mortality rate and is a serious threat to human health.The four neuraminidase inhibitors used to treat influenza have developed resistant strains,and the development of new anti-influenza drugs is imminent.In this study,a 1,2,4-triazole thione ring with wide range of biological activities and multiple substitution sites was selected as the core.(E)-4-((4-(dimethylamineo)benzylidene)amino)-5-(6-methylpyridin-3-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione(36f)is a lead compound,and its various substitution sites are gradually optimized,and 33 1,2,4-triazolethione(ether)imine derivatives are designed and synthesized and evaluated against influenza viruses(H1N1)neuraminidase(NA)in vitro.Moreover,structure activity relationships(SAR)were established and molecular docking studies were performed to understand the binding interaction between active compounds and NA.The key intermediates C1-C12 were obtained by one-step or three-step method in 53.4%~90.1% yield,and futher reacted with aromatic aldehydes to obtain A1-A28 in 55.2%~89.0% yield.Compounds B1-B5 were synthesized by thialkylation of compound A17 with brominated derivatives in 48.2%~78.7% yield.The reaction conditions of thioalkylation were optimized.The optimum conditions were selected as follows: the mole ratio of compound A17,C3H7 Br,K2CO3 and Et OH is 1:2:0.6:70,and the reaction mixture is refluxed for 13.5 h.The structures of all compounds were confirmed by 1H NMR and 13 C NMR,and some of them were further confirmed by IR and MS.The results of single crystal X-ray diffraction of compounds A17 and B2 showed that compounds A are sulfur ketone,compounds B are sulfur ether,and both of C=N of compounds A and B are E configuration.The results of NA(H1N1)inhibitory activity showed that Compounds A17 and A20 in series A showed good activity with IC50 values of 14.97±0.70 and 14.68±0.49 μg/m L,respectively,compounds B1 and B2 in series B exhibited excellent activity with IC50 values of 6.86±2.08 and 9.1±1.56 μg/m L,respectively.The SAR and molecular docking research exhibited that when the substituted group(R)on benzene ring was 4-hydroxy-3-methoxy,1,2,4-triazole ring-5-substituted group(Y)was ethyl or hydroxyethyl and 1,2,4-triazole ring-3-substituted group(R1)was ethyl,it showed the most potent NA inhibitory activity.The results showed that 1,2,4-triazole thione(ether)derivatives possess good NA inhibitory activity,and compound B1 has the value as a lead compound for further research.