Design, Synthesis And Bioactivity Screening Of Novel Antituberculosis Compounds And Synthesis And The In Vivo And In Vitro Anti-hepatitis B Virusactivities Of The Novel Nucleosides Derivative Octadecyloxyethyl-tenofovir

The paper comprises two parts:PART1:Design, synthesis and bioactivity screening of novel antituberculosis compounds.Firstly, this part provides a discussion of synthesis and the in vivo and in vitro anti-tuberculosis activity of a natural product ternatolide and its analogues.Ternatolide isolated from Radix Ranuncoli Ternati is considered as the possibly active ingredient against Mycobacterium tuberculosis. It was reported that ternatolide killed the Mycobacterium tuberculosis possibly by enhancing the expression of GLS in PBLs indirectly. If the mechanism which acts via regulating the cellular proteins is believable, will differ from the present ones in the clinic and possess advantages against dormant TB and Drug-resistence TB. In consideration of the probably activities against Mycobacterium tuberculosis, ternatolide and its analogoues were synthesized in our present work.The structures of the compounds were confirmed by1HNMR and HR-MS. And the in vivo anti-TB activity of the ternatolide and some analogues was investigated in vitro by using a rapid direct susceptibility assay. At the same time, the vitro anti-mycobacterial ability of the ternatolide was evaluated by ways of establishing and applying murine acute tuberculosis model by aerosol infection.Our result indicated that the compounds were weakly active against MTB H37Rv ATCC27294directly, and there was no obvious activity in the murine acute tuberculosis model by aerosol infection.Secondly, this part also involves in design, synthesis and bioactivity screening of novel anti-TB small molecular compounds based on phenothiazines. Phenothiazine drugs were used in the treatment of psychiatric disorders in the clinic and its activity against TB was also observed. The possible mechanism of its anti TB activity was concerned a lot in the field. Due to this property, Cholorpromazine was used as modulate compound to generate3D pharmacophore hypotheses in Discovery studio3.0, and our in house compounds library was screened. The candidate compounds were cherry-picked manually for synthesis and evaluation for their anti-TB activity in vitro (MTB H37Rv ATCC27294). Fifteen compounds were screened by this way and13target compounds were synthesized.The structures of these compounds were confirmed by1H-NMR and HR-MS. The bioassay results showed that compound51(dopamine), which presented moderate potent inhibitory activity against MTB in vitro with a MIC value of8.0μg/ml, is more like lead compound by comparison with the phenothiazines, and shows potential for optimization to improve its anti-TB activity.PART2:Synthesis and the in vivo and in vitro anti-hepatitis B virus activity of the novel nucleosides derivative octadecyloxyethyl-tenofovir (ODE-TFV)The ODE-TFV, which is a predrug of TFV as same as the clinical drug TFV DF, seems as a potential and novel nucleosides derivative showing activity of anti-HBV. In this section, the anti-hepatitis B virus activities of ODE-TFV were estimated in both the cultured HBV-transfected human hepatoma2.2.15cells and One-day old DHBV infected Pekin-duckling model on the basis of synthesis of this target compound.The changes of hepatic pathology was viewed simultaneously. The results suggested that the IC50of ODE-TFV was0.38±0.18μmol·L-1and the inhibitory activity of ODE-TFV was about18times and13times stronger than that of TFV DV and3TC respectively in vivo; On the7th and14th day of medication the serum DHBV-DNA level in both of the high-and middle-dosage (100mg·g-1and200mg·kg-1seperately) ODE-TFV groups was obviously lower than that before medication; the high-and middle-dosage ODE-TFV is able to improve hepatocellular necrosis and inflammatory cell infiltration clearly caused by DHBV. This compound deserves further development and application.Fivity-four compounds were synthesized in this paper, seven of which are totally new structures.Twenty targets compouds were obtained, and three of them have never been reported. The structures of the most compounds were confirmed by1H-NMR, and the target ones also were anylyzed by HR-MS.In this paper, synthesis and initial bioactivity of compounds based on Tern skeleton and phenothiazines have been considered. Under the experimental condition as this thesis mentioned, Ternatolide and its analogoues rarely showed obvious activity, and the reason need being researched. When it comes to the in vivo anti-TB bioactivity screening of phenothiazines compounds, compound51(dopamine), which presented moderate potent inhibitory activity against MTB in vitro with a MIC value of8.0μg/ml, provides a new lead compound for the further discussion. The outcome that the novel nucleosides derivative ODE-TFV provides the apparent in vivo and in vitro anti-hepatitis B virus activity points out that this compound has a promising future.