Toward orthopoxvirus countermeasures: A novel heteromorphic nucleoside of unusual structure

Two privileged drug scaffolds have been hybridized to create the novel heteromorphic nucleoside 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4(1H,3H)-dione (2). Compound 2 inhibited the replication of two orthopoxviruses, vaccinia virus (VV) (EC50 = 4.6 +/- 2.0 mu M), and cowpox virus (CV) (EC50 = 2.0 +/- 0.3 mu M). Compound 2 exhibited reduced activity against a thymidine kinase (TK) negative strain of CV, implying a requirement for 5 '-monophosphorylation for antior-thopoxvirus activity. Compound 2 was efficiently phosphorylated by VV TK, establishing that VV TK is more promiscuous than previously believed.