Studies On Design, Synthesis And Biological Activity Of Territrem B Analogues And Preliminary Studies On Design, Synthesis And Biological Activity Of Diaryl Ethers Substituted Piperazine Derivatives

The first part of this thesis is that the studies were carried out on the lead compounds of territrem B,a potent acetylcholinesterase(AChE) inhibitors with IC₅₀ value of 7.8 nmol/L,based on our previous work.An important approach in drug discovery is the synthesis and structure modifications of active natural products.In our previous exploration,the ring D/E analogues of territrem B were synthesized using the strategy of simplification on the A/B/C ring system with multiple stereocenters and some good results were obtained.Seven series of pyridone analogs of territrem B(89 new compounds including 78 of the target molecules) were designed and synthesized in this thesis.In vitro anti-acetylcholinesterase evaluation indicated that only a few synthetic compounds existed weak inhibitory activity against AChE.Beyond our expectation,In vitro biological evaluation against cancer-cell lines indicated that some of the synthetic compounds existed certain cytotoxicities.Compounds 2.92,2.112,2.113 and 2.73 have the similar values on P388D1 tumor cell lines at 10^-6 mol/L scale as that of cisplatin.The second part of this thesis is the preliminary studies of diaryl ethers substituted piperazine derivatives.In order to extend the scope to screen the antitumor drug,two series of diaryl ethers substituted piperazine derivatives were designed and twenty-one new compounds were synthesized on the base of combination principle.The preliminary biological activity tests showed that some of the title compounds had good activities. Compounds 3.39 exhibited a potent cytotoxicity against the Eca109 and CNE cell lines with an IC₅₀ value of 7.1μmol/L and 4.5μmol/L respectively,which showed the similar activities to the positive control,cisplatin.Compound 3.50 also possesses an efficient cytotoxicity on CNE cell line with an IC₅₀ value of 8.5μmol/L.