| In the early stage of this research group,MTS with anti-HBV activity was isolated from ethnic herbal medicine Dichondra repens Forst.a series of derivatives were designed and synthesized by using MTS as an anti-HBV lead compound.One of the derivatives Y101 has been finished its preclinical studies and phase 1 clinical trial..Because one of the amide bound in derivatives of MTS was easily hydrolyzed in vivo,and the activity of the major metabolite of Y101 was much lower than itself.In order to overcome the shortcoming of MTS derivatives which were easily hydrolyzed in vivo and improve the metabolic stability,the amide bond in MTS was replaced with a trifluoromethyl substituted methylamine unit to design and synthesize the fluorodipeptidomimetics of MTS,and their inhibitory activity against Hepatitis B virus(HBV)in vitro were evaluated using HepG2 2.2.15 cell model.Using L-phenylalaninol and methyl L-tyrosinate hydrochloride as starting materials,31 target compounds were synthesized by addition,reduction,oxidation,coupling,ring-opening,etc.Their structures were comformed by 1H-NMR,13C-NMR,19F-NMR,1H-1HCOSY and HSQC.The anti-HBV activities of 29 target compounds were evaluated in HepG2 2.2.15 cell for their activity to inhibit the replication of HBV DNA.Among them,compounds XSY-014,XSY-016,XSY-017,XSY-021 and XSY-026 showed inhibition rates anti-HBV activities of 92.95%,92.16%,91.38%,92.99%,and 94.94%at 20 μmol·L-1 lrespectively.Secondly,the compounds XSY-014,XSY-017,XSY-020,XSY-021,XSY-023,XSY-024,XSY-025,XSY-026,XSY-028,XSY-030 showed a certain dose-effect relationship.In this study,bioelectronic isosteric trifluoromethyl substituted methylamine units were used to replace one of the amide bond in the structure of MTS,and a series of derivatives were designed and synthesized to provide a scientific basis for the in-depth research and development of compounds with amide structures.. |
