Synthesis and anti-Hantaan virus activity of N(1)-3-fluorophenyl-inosine.
As part of an ongoing effort to develop new antiviral nucleoside analogs, our interest was drawn to N(1)-aryl purines as a novel structural class and potential scaffold for drug discovery. Herein, we describe the synthesis of N(1)-3-fluorophenyl-inosine (FPI) and N(1)-3-fluorophenyl-hypoxanthine (FP-Hx) and their antiviral activity against hantaviruses. The EC(50) for FPI and FP-Hx were 94 and 234microM, respectively, against Hantaan virus. FPI was not toxic to mammalian cells at concentrations that exhibited antiviral activity. Analysis of its metabolism revealed a low conversion of FPI in Vero E6 or human cells to a 5'-triphosphate, and it was a poor substrate for human purine nucleoside phosphorylase. Further, the compound did not alter GTP levels indicating FPI does not inhibit inosine monophosphate dehydrogenase. With respect to the virus, FPI did not decrease viral RNA levels or increase the mutation frequency of the viral RNA. This suggests that the antiviral activity of FPI might be solely due to the interaction of FPI or its metabolites with viral or host proteins involved in post-replication events that would affect the levels of infectious virus released. Synthesis of other compounds structurally similar to FPI is warranted to identify more potent agents that selectively abrogate production of infectious virus.
Chung
Dong-Hoon
DH
Department of Biochemistry and Molecular Biology, Southern Research Institute, Birmingham, AL 35205, USA.
Strouse
J Jacob
JJ
Sun
Yanjie
Y
Arterburn
Jeffrey B
JB
Parker
William B
WB
Jonsson
Colleen B
CB
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001711:Biotransformation; D002460:Cell Line; D002522:Chlorocebus aethiops; D018063:Hantaan virus / Q000187:drug effects*; D006801:Humans; D007042:Hypoxanthines / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D020128:Inhibitory Concentration 50; D007288:Inosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D008826:Microbial Sensitivity Tests
D000998:Antiviral Agents; D007042:Hypoxanthines; C541982:N1-3-fluorophenyl-hypoxanthine; C541981:N1-3-fluorophenyl-inosine; D007288:Inosine