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

ABSTRACT: 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??M for wild-type and thymidine kinase deficient strains, respectively, and a selectivity index ?200??M. This breakthrough approach paves the way for new purine and pyrimidine (E)-but-2-enyl phosphonoamidate analogs.

SUBMITTER: Bessieres M

PROVIDER: S-EPMC7115695 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Bessières Maxime M Hervin Vincent V Roy Vincent V Chartier Agnès A Snoeck Robert R Andrei Graciela G Lohier Jean-François JF Agrofoglio Luigi A LA

European journal of medicinal chemistry 20180131

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 EC<sub>50</sub> values of 0.33 and 0.39 μ ...[more]

PMID: 29407990

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