Synthesis And Neuraminidase Inhibitory Activity Of Triazolethione Derivatives

Influenza is an acute respiratory infectious disease caused by influenza viruses which can infect human with high mortality.Currently,the drug resistance problem becomes serious on account of the high mutability of the virus.Neuraminidase is a hydrolytic enzyme which acts as an essential role in the infection,and its structure is relatively conserved,so it is regarded as an attractive target for structure-based drug design.Triazolethione is a heterocycle which is easy to synthesis and has a wide range of pharmacological activities.Based on the structure of neraminidase,three series of triazolethione derivatives were designed and synthesized.The aminotriazolethione E was synthesized by the condensation of methyl 6-methylnicotinate D,hydrazine hydrate and carbon disulfide.Then,compound E was treated with aromatic aldehyde to obtain schiffbase A1-A9,and compounds B1-B13 were synthesized by the condensation of A and 2-bromo-1-phenylethanone derivatives.For the synthesis of compounds C1-C3,6-methylnicotinate D was treated with trichloroisocyanuric acid to get compound I,then I was treated with morpholine and hydrazine hydrate successively to get compound J,and J was treated with hydrazine hydrate and carbon disulfide to get compound G.Lastly,the compounds C1-C3 were synthesized by the condensation of G and 2-bromo-l-phenylethanone derivatives.The structures of compounds A1-A9,B1-B13 and C1-C3 were characterized by1H NMR and 13C NMR.In addition,the process for the synthesis of aminotriazolethione E was optimized.Ethanol is a suitable solvent for the preparation of M1.The molar ratio of M1 to N2H4 H2O is 1:4,and the overall yield of the two-step procedure is 83.4%.All of the target compounds were evaluated for the neuraminidase inhibitory activity against the influenza viral neuraminidase(H1N1)in vitro,and the results showed that the compounds bearing N(CH3)2 exhibited good inhibitory activities.Among them,compound A9 showed the most potent inhibitory activities with IC50 value of 19.82± 0.53)ig/mL.Furthermore,molecular docking was performed on the most active compound A9 in order to provide more insight into the mechanism of interaction.Our work contributes to the furthur optimization to get new neuraminidase inhibitors with better activity and easy to synthesize.