Syntheses and Binding Testing of N 1-Alkylamino-Substituted 2-Aminobenzimidazole Analogues Targeting the Hepatitis C Virus Internal Ribosome Entry Site

David Schmit, Urszula Milewicz, Mark A. Boerneke, Scott Burley, Kevin Walsworth, Joann Um, David Hecht, Thomas Hermann, B. Mikael Bergdahl

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

A series of 2-aminobenzimidazole analogues have been synthesised and tested for binding to a previously established RNA target for viral translation inhibitors in the internal ribosome entry site (IRES) of the hepatitis C virus (HCV). Synthesis of new inhibitor compounds followed a highly convergent strategy which allowed for incorporation of diverse tertiary amino substituents in high overall yields (eight-steps, 4-22 %). Structure-activity relationship (SAR) studies focussed on the tertiary amine substituent involved in hydrogen bonding with the RNA backbone at the inhibitor binding site. The SAR study was further correlated with in silico docking experiments. Analogous compounds showed promising activities (half maximal effective concentration, EC50: 21-89 µM). Structures of the synthesised analogues and a correlation to their mode of binding, provided the opportunity to explore parameters required for selective targeting of the HCV IRES at the subdomain IIa which acts as an RNA conformational switch in HCV translation.

Original languageEnglish (US)
Pages (from-to)212-221
Number of pages10
JournalAustralian Journal of Chemistry
Volume73
Issue number3
DOIs
StatePublished - Mar 2020

Bibliographical note

Funding Information:
This work was supported by the San Diego State University Foundation and the California State University Program for Education and Research (CSUPERB). M. A. B. was supported by a GAANN fellowship from the US Department of Education. T. H. acknowledges support by the UCSD Academic Senate, grant No. RM069B. The authors thank Dr LeRoy Lafferty for NMR support, and former Dendreon Inc., and ChemDiv, Inc., for generous donation of equipment and supplies.

Publisher Copyright:
© 2020 CSIRO.

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