Synthesis of Novel Purine-Based Coxsackievirus Inhibitors Bearing Polycylic Substituents at the N-9 Position

The synthesis of a novel library of purine derivatives bearing various bicyclic and polycylic substituents at the N‐9 position is described. The series includes norbornanes, bicyclo[2.2.2]octanes, and bicyclo[3.2.1]octanes attached at the bridgehead position as well as bicyclo[3.1.1]heptanes, tetrahydro‐1‐naphthalenes, and adamantanes bonded either directly or via a linear chain to the 6‐chloropurine nucleobase. A number of prepared derivatives exerted significant activity against the enterovirus. Despite attempts to correlate the activity against picornaviruses with their phosphatidylinositol 4‐kinase KIIIβ inhibitory activity, it is clear that the inhibition of this host factor cannot explain the observed antiviral potency. The synthesis of a large series of 9‐substituted purine derivatives and the evaluation of their antiviral activities against coxsackievirus B3 are described. Although several derivatives reported in the series exert some activity against phosphatidylinositol 4‐kinase IIIβ, the antiviral activity does not entirely correlate with this inhibitory effect.