Synthesis and the biological evaluation of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles as potential anti-hepatitis B virus agents.
Current treatments for chronic hepatitis B virus (HBV) infection include the use of interferon-alpha and of nucleoside analogs lamivudine, adefovir and entecavir. However, the use of interferon-alpha has many side effects while that of nucleosidic inhibitors can lead to the emergence of resistant viruses. Hence, new drugs for the treatment of HBV infection are still highly desired. Oxadiazoles have been observed to exhibit antiviral activities against RNA viruses. In this study, a facile synthesis of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles is reported. The compounds were then evaluated for their anti-HBV activity. 1-[2-[5-(1-Benzenesulfonyl-propyl)-[1,3,4]oxadiazol-2-yl-sulfanyl]-ethyl]-4-(2-methoxy-phenyl)-piperazine (1i) was able to inhibit the expression of the viral antigens, HBsAg and HBeAg in a concentration-dependent manner with no cytotoxic effects and without any effects on the expression of viral transcripts. Concentration- and time-dependent reductions in virion production were also observed. The inhibition of virion production was comparable to that of lamivudine and EC(50) values of 1.63 and 2.96 microM were obtained for compound 1i and lamivudine, respectively. Thus, in addition to the antiviral effects on RNA viruses, oxadiazoles also have anti-HBV activities.
Tan
Theresa May Chin
TM
Department of Biochemistry, National University of Singapore, Medical Drive, Singapore. bchtant@nus.edu.sg
Chen
Yu
Y
Kong
Kah Hoe
KH
Bai
Jing
J
Li
Yang
Y
Lim
Seng Gee
SG
Ang
Thiam Hong
TH
Lam
Yulin
Y
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000096:biosynthesis; D006513:Hepatitis B e Antigens / Q000096:biosynthesis; D006515:Hepatitis B virus / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D022781:Hepatocytes; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared
D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D010069:Oxadiazoles