Design,Synthesis,and Biological Evaluation Of Oxime Derivatives As Potential Anti-HBV Agents

Hepatitis B virus(HBV)infection is a serious worldwide health problem,which can cause acute and chronic hepatitis B,cirrhosis,hepatocellular carcinoma,and other hepatic diseases.Drugs used in treatment of anti-HBV including interferons and nucleosides currently.Resistance,side effects and high recurrence occurred in long-term treatment with nucleoside analogs,and expensive and low effect of interferons treatment,limited anti-HBV treatment effects.Finding and invention of new and more effective drugs for treatment of HBV promote many researchers to focus on anti-HBV treatment methods.A large number of studies have shown that compounds with the oxime group have biological activities.Currently a series of phenylpropanoid oxime ester derivatives with the structure of C6-C3 fragment which displayed anti-HBV activity were studied in our works.The docking studies shown that O in the oxime group(-O-N=C)of these compounds interacted with amino acid residue by hydrogen bond in active site of human leukocyte antigen A(HLA-A)protein(HLA-A*02:03,PDB ID:30X8),which conjectured role of oxime group in anti-HBV activities.In this thesis,a series of ethyl ester-oxime,2-methyl furan-oxime,amide-oxime derivatives were designed and docked with HLA-A protein.Docking results revealed that there was strong interaction between designed compounds and HLA-A protein,which predicted that the designed compounds have potential anti-HBV activity.Oxime-ether compounds with an acylamino group,in particular,might have the strongest anti-HBV activity.Series of oxime derivatives were synthesized by Friedel-Crafts reaction,esterification(amidation),and oximation from p-Benzene(Methylbenzene,Methoxybenzene,Chlorobenzene).The structures were characterized by 1H NMR,13C NMR and GC-MS methods.Anti-HBV activity of synthesized compounds was evaluated with HepG2 2.2.15 cell line in vitro.Results showed that most compounds displayed low cytotoxicity to HepG2 2.2.15 cell lines and some demonstrated potent inhibitory effects on the secretion of HBsAg and HBeAg.Among them,compounds 5c-2 and 5a-2 showed the most potent activity on inhibiting the secretion of HBsAg(IC50=1.32?M and 62.23 ?M,SI=31.93 and 12.54,respectively).Compound 3c-3 displayed the potent activity on inhibiting the secretion of HBsAg(IC50=2.93?M,SI=1.74)and HBeAg(IC50=79.10?M,SI=1.61).It indicated that compounds 5c-2,5a-2,and 3c-3 have strong anti-HBV activity.Investigation of structure-activity relationships on oxime derivatives indicated that the introduction of acylamino group to 2-C and methyl to O in oxime group could enhance the inhibitory effect on the secretion of HBsAg and HBeAg.