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Eur J Med Chem ; 209: 112884, 2021 Jan 01.
Article in English | MEDLINE | ID: covidwho-800277

ABSTRACT

A novel methodology to access alkynyl nucleoside analogues is elaborated. Highly fluorescent 5-alkynylfuropyrimidines were synthesized (97-46%) and their antiviral properties investigated in vitro. Regiochemistry of the functionalization was achieved with the aid of 5-endo-dig electrophilic halocyclization of acetyl 5-p-tolyl- or 5-p-pentylphenyl-2'-deoxyuridine. Structure of one of the resulting nucleosides, 6-p-tolyl-5-iodo-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one, was confirmed by X-ray crystallography, and its conformation was compared to related nucleosides. Diverse alkynyl substituents were introduced at the heterobicyclic base C-5 position via Sonogashira coupling of 5-iodo-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-ones. The resulting compounds had fluorescence emissions of 452-481 nm. High quantum yields of 0.53-0.60 were observed for 9-ethynyl-9-fluorenol and propargyl alcohol/methyl ether-modified furopyrimidines. These modified nucleosides, designed in the form of ribose acetyl esters, are potential tools for fluorescent tagging, studying nucleoside metabolism, 2'-deoxyribonucleoside kinase activity, and antiviral activity. Antiviral assays against a broad spectrum of DNA and RNA viruses showed that in human embryonic lung (HEL) cell cultures some of the compounds posess antiviral activity (EC50 1.3-13.2 µM) against varicella-zoster virus (VZV). The alkynyl furopyrimidine with two p-pentylphenyl substituents emerged as the best compound with reasonable and selective anti-VZV activity, confirming p-pentylphenyl potency as a pharmacophore.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Antiviral Agents/chemical synthesis , Cell Line , Fluorescence , Halogenation , Herpesvirus 3, Human/drug effects , Humans , Models, Molecular , Pyrimidine Nucleosides/chemical synthesis , Varicella Zoster Virus Infection/drug therapy , Varicella Zoster Virus Infection/virology
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