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Structure activity relationship of novel antiviral nucleosides against Enterovirus A71

Authors
  • Tosh, Dilip K.1
  • Toti, Kiran S.1
  • Hurst, Brett L.2
  • Julander, Justin G.2
  • Jacobson, Kenneth A.1
  • 1 Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, MA 20892, USA
  • 2 Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, VSB 305, Logan, UT 84322-5600, USA
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Oct 05, 2020
Volume
30
Issue
23
Pages
127599–127599
Identifiers
DOI: 10.1016/j.bmcl.2020.127599
PMID: 33031923
PMCID: PMC7534897
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Unknown

Abstract

Various (North)-methanocarba adenosine derivatives, containing rigid bicyclo[3.1.0]hexane ribose substitution, were screened for activity against representative viruses, and inhibition was observed after treatment of Enterovirus A71 with a 2-chloro- N 6-1-cyclopropyl-2-methylpropan-1-yl derivative ( 17 ). µM activity was also seen when testing 17 against other enteroviruses in the Picornaviridae family. Based on this hit, structural congeners of 17 , containing other N 6-alkyl groups and 5′ modifications, were synthesized and tested. The structure activity relationship is relatively narrow, with most modifications of the adenine or the methanocarba ring reducing or abolishing the inhibitory potency. 4′-Truncated 31 (MRS5474), 4′-fluoromethyl 48 (MRS7704) and 4′-chloromethyl 49 nucleosides displayed EC50 ~3–4 µM, and 31 and 48 achieved SI ≥10. However, methanocarba analogues of ribavirin and N 6-benzyladenosine, shown previously to have anti-EV-A71 activity, were inactive. Thus, we identified methanocarba nucleosides as a new scaffold for enterovirus inhibition with a narrow structure activity relationship and no similarity to previously published anti-enteroviral nucleosides.

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