Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides

A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. All novel compounds were evaluated for their Antiviral activities against a large number of DNA and RNA viruses including herpes simplex virus type 1 and 2, varicella zoster virus, feline herpes virus, human cytomegalovirus, hepatitis C virus (HCV), HIV-1 and HIV-2. Among these molecules, only compound 31 showed activity against human cytomegalovirus in HEL cell cultures with at EC50 of ∼10 μM. Compounds 8a, 13, 14, and 24 demonstrated pronounced anti-HCV activity without significant cytotoxicity at 100 μM.

Antiviral properties; CC(50); DNA; EC(50); HSV; MCC; MDCK; Madin–Darby canine kidney; Modified heterocycles; Nucleosides; Olefin cross metathesis; RNA; Synthesis; VSV; VV; VZV; compound concentration affording 50% inhibition of cell growth; compound concentration affording 50% inhibition of the viral cytopathicity; deoxyribonucleic acid; herpes simplex virus; minimum cytotoxic concentration required to afford a microscopically detectable alteration of cell morphology; ribonucleic acid; vaccinia virus; varicella zoster virus; vesicular stomatitis virus.