Synthesis and antiviral evaluation of C5-substituted-(1,3-diyne)-2′-deoxyuridines

Starting from acetylated 5-ethynyl-2′-deoxyuridine (3), 14 hitherto unknown C5-substituted-(1,3-diyne)-2′-deoxyuridines (with cyclopropyl, hydroxymethyl, methylcyclopentane, p-(substituted)phenyl and disubstituted-phenyl substituents) have been synthesized via a nickel-copper catalyzed C–H activation between two terminal alkynes, in yields ranging from 19% to 67%. Their antiviral activities were measured against a large number of DNA and RNA viruses including herpes simplex virus type 1 and type 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. The 5-[4-(4-trifluoromethoxyphenyl)buta-1,3-diynyl]-2′-deoxyuridine (26) is the most potent inhibitor of this series against VZV with an EC50 of ∼1 μM and a CC50 of 55 μM. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including influenza virus A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and vesicular stomatitis, coxsackie B4 and respiratory syncytial virus in HeLa cell cultures and against human immunodeficiency virus type 1 and 2 in CEM cell cultures, with no specific antiviral effect. This class of compounds could be of further interest for lead optimization as anti-infectious (i.e. herpetic) agents.

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► 14 Novel C5-substituted uridine analogues bearing diyne scaffolds were synthesized and characterized.
► The hetero-coupling reaction between two terminal alkynes through C–H activation has been studied.
► All these synthesized molecules (18–31) were evaluated for their antiviral activity against a wide variety of virus.
► EC50 value of 26 was in sub-micromolar range against VZV (OKA) in HEL cell lines.