Synthesis And Biological Activity Of6-aryl-1,3-thiazine Derivatives

Influenza is an acute respiratory infection disease caused by the influenza virus inhumans and other animals, resulting in a worldwide pandemic frequently. In recent years, thepopular H5N1and H1N1influenza become one of the most important global health problems.Neuraminidase plays an important role in the replication and infection cycle of influenza virus,thereby it becomes an effective target for antiviral drugs. the neuraminidase inhibitor is themost effective anti-influenza drugs, because of the relatively conservative of the influenzavirus neuraminidase. Based on the differece of the neuraminidase structure group-1andgroup-2, considering the newly found430-loop and150-loop of the group-1, a series ofcompounds is synthesised. Against for SA and430-loop,150-loop and430-loop dual-targetinhibitors of1,3thiazine was designed and synthesised. All compounds were evaluatedagainst the inhibitory activity of NA in vitro.Ten kinds of4-tert-butyl-6-aryl-2-acetylamino-1,3-thiazine was designed andsynthesized according to150-loop and430-loop(hydrophobic aryl and tert-butyl aim at the150-loop and430-loop). With aromatic aldehyde and3,3-dimethylbutan-2-one in the ethanol,sodium hydroxide as catalyst,4,4-dimethyl-1-aryl-1-alkenyl-3-pentanone was obtained. Andthen with thiourea in refluxing in the ethanol, concentrated hydrochloric acid as the catalystand water separator4-tert-butyl-6-aryl-2-amino-1,3-thiazine hydrochloride was synthesized.Finally, by acetylation to give4-tert-butyl-6-aryl-2-acetylamino-1,3-thiazine, The structuresconfirm by1HNMR.Eleven kinds of4-methyl-6-aryl-2-acetylamino-1,3-thiazine-5-acid ester was designedand synthesized based on SA and430-loop, hydrophobic arylphase combine with the430-loop, acetylamino and the ester connect with the SA cavity. through the Knoevengelreaction aromatic aldehydes and acetoacetateester obtain2-(substituted benzilidene) aceto-acetateester. with thiourea under the amount of catalyzing hydrochloric acid1,3thiazide wasobtained, then after acylation the target product has been obtained. All the target compoundsare confirmed by1HNMR.All the target compounds are carried out in vitro neuraminidase activity testing, the bestactivity of the compounds is4-methyl-6-(3-nitrophenyl)-2-acetamido-1,3-thiazine-5-acid(2-methoxyethyl)ester, Inhibition rate is59.81%, IC50is29.38μmol/mL. It is valuable for thesubsequent development of Neuraminidase inhibitors.