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RESEARCH ARTICLE
Contents Vol 73(3)

Syntheses and Binding Testing of N1-Alkylamino-Substituted 2-Aminobenzimidazole Analogues Targeting the Hepatitis C Virus Internal Ribosome Entry Site*

David Schmit A , Urszula Milewicz A , Mark A. Boerneke B , Scott Burley A , Kevin Walsworth A , Joann Um C , David Hecht A C , Thomas Hermann B and B. Mikael Bergdahl https://orcid.org/0000-0002-7104-927X A D
+ Author Affiliations
- Author Affiliations

A Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, USA.

B Department of Chemistry and Biochemistry and Center for Drug Discovery Innovation, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

C Department of Chemistry, Southwestern College, 900 Otay Lakes Road, Chula Vista, CA 91913, USA.

D Corresponding author. Email: bbergdahl@sdsu.edu

Australian Journal of Chemistry 73(3) 212-221 https://doi.org/10.1071/CH19526
Submitted: 17 October 2019  Accepted: 4 December 2019   Published: 31 January 2020

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.


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