Synthesis And Anti-HBV Activities Of Ethyl 5-Hydroxy-1H-Indole-3-Carboxylate And Ethyl Quinoline-3-Carboxylate Derivatives

Hepatitis B seriously threatens the healthy of human beings.In this paper we focused largely on the biological characteristics of hepatitis B virus（HBV）,and introduced the development of anti-HBV agents in detail.Previously,we have obtained a series of ethyl 5-hydroxy-1H-indole-3-carboxylate derivatives with the abilities to inhibit the replication of HBV in vitro.Based on the research of structure-activity relationship（SAR）between the modification of substituents on the indole cycle and anti-HBV activity,42 ethyl 5-hydroxy-6-bromo-1H-indole-3-carboxylate derivatives have been designed and synthesized.The main modifications were focused on 2-position of indole ring where cycloalkane,substituted thiazolyl etc.were introduced.The others modification and optimization were occurred on 1-position and 4-position on the indole ring.Quinoline derivatives have many bioactivities,such as antimalarial,anti-rheumatoid arthritis,antimicrobial,anticancer and antivims etc.Using ethyl 5-hydroxy-1H-indole-3-carboxylate derivatives as lead compounds,we designed and prepared 40 novel ethyl 6-hydroxyquinoline-3-carboxylate derivatives in which the indole ring was expanded to a quinoline ring based on the principles of bioisosterism.In these new compounds,the bromine was replaced by an electron-donating methoxy group,and other substitutents were reserved on the relative positions of quinoline ring.The other modifications and optimizations were focused on positions 2 and 5 of the quinoline ring.In order to further study the SAR of quinoline derivatives and their activities,the relative position of substitutents on quinoline ring,such as methoxy,hydroxy and Mannich base,were changed.The other modifications and optimizations were made on 2-position and 8-position, and 34 novel ethyl 7-hydroxyquinoline-3-carboxylate derivatives were designed and synthesized.All of the target compounds were not reported in literatures,and their structures were confirmed by MS,¹H-NMR and IR.The anti-HBV activities of all target compounds were evaluated with radioimmunoassay（RIA）and dot-blotting asssy in HepG2.2.15 cells stably transfected with HBV.This evaluation included the measurement of the compounds’ abilities to inhibit the secretion of both HBsAg and HBeAg and to inhibit HBV DNA replication.In addition,the cvtotoxicities of all target compounds to HepG2.2.15 cells were assessed.The results showed that 10 compounds which exhibited more potent inhibition of HBV DNA replication than the control drug lamivudine(IC₅₀=311.2μM)among the 42 indole derivatives.When thiazolyl and thiadiazolidinyl were introduced into 2-position of indole ring, these resulted compounds mainly exhibited the inhibitory potency against HBeAg secretion, and the IC₅₀values of 11 indole derivatives were less than 0.4μM.Ethyl quinoline-3-carboxlate derivatives showed the ability to inhibit the replication of HBV DNA in different degrees.Among 74 ethyl quinoline-3-carboxylates,the IC₅₀of 33 compounds were less than that of lamivudine,and the SI of 12 compounds were higher than or comparable to that of lamivudine（SI=7.1）.The SAR between these ethyl 5-hydroxy-6-bromo-1H-indole-3-carboxylates,ethyl 6-hydroxy-7-methoxyquinoline-3-carboxylates,ethyl 7-hydroxy-6-methoxy-quinoline-3-carboxylates and their antiviral activities against hepatitis B virus were discussed,respectively, which would provide preliminary theoretical and practical foundations for the further research and development of new efficient anti-HBV agents in the future.