Highly convergent synthesis and antiviral activity of (E)-but-2-enyl nucleoside phosphonoamidates

Several hitherto unknown (E)-but-2-enyl nucleoside phosphonoamidate analogs (ANPs) were prepared directed with nitrogen reagents by cross-metathesis in water-under ultrasound irradiation. Two diastereoisomers were formally identified by X-ray diffraction. These compounds were evaluated against a large spectrum of DNA and RNA viruses. Among them, the phosphonoamidate thymine analogue 19 emerged as the best prodrug against varicella-zoster virus (VZV) with EC50 values of 0.33 and 0.39 mu M for wild-type and thymidine kinase deficient strains, respectively, and a selectivity index >= 200 mu M. This breakthrough approach paves the way for new purine and pyrimidine (E)-but-2-enyl phosphonoamidate analogs. (C) 2018 Elsevier Masson SAS. All rights reserved.