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](/media/client/orcid_16x16.png)
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.
References
[1] M. Houghton, Liver Int. 2009, 29, 82.| Crossref | GoogleScholarGoogle Scholar | 19207970PubMed |
[2] R. G. Gish, K. P. Qian, S. Quan, Y. L. Xu, I. Pike, A. Polito, R. DiNello, J. Y. Lau, J. Viral Hepat. 1997, 4, 421.
| Crossref | GoogleScholarGoogle Scholar | 9430363PubMed |
[3] M. G. Ghany, D. B. Strader, D. L. Thomas, L. B. Seeff, Hepatology 2009, 49, 1335.
| Crossref | GoogleScholarGoogle Scholar | 19330875PubMed |
[4] S. Bruno, J. M. Vierling, R. Esteban, L. M. Nyberg, H. Tanno, Z. Goodman, F. Poordad, B. Bacon, K. Gottesdiener, L. D. Pedicone, J. K. Albrecht, C. A. Brass, S. Thompson, M. H. Burroughs, J. Hepatol. 2013, 58, 479.
| Crossref | GoogleScholarGoogle Scholar | 23183529PubMed |
[5] K. E. Reed, C. M. Rice, Curr. Top. Microbiol. Immunol. 2000, 242, 55.
| Crossref | GoogleScholarGoogle Scholar | 10592656PubMed |
[6] T. Suzuki, H. Aizaki, K. Murakami, I. Shoji, T. Wakita, J. Gastroenterol. 2007, 42, 411.
| Crossref | GoogleScholarGoogle Scholar | 17671755PubMed |
[7] F. Poordad, J. McCone, B. R. Bacon, S. Bruno, M. P. Manns, M. S. Sulkowski, I. M. Jacobson, K. R. Reddy, Z. D. Goodman, N. Boparai, M. J. DiNubile, V. Sniukiene, C. A. Brass, J. K. Albrecht, J.-P. Bronowicki, N. Engl. J. Med. 2011, 364, 1195.
| Crossref | GoogleScholarGoogle Scholar | 21449783PubMed |
[8] Q. L. Choo, G. Kuo, A. J. Weiner, L. R. Overby, D. W. Bradley, M. Houghton, Science 1989, 244, 359.
| Crossref | GoogleScholarGoogle Scholar | 2523562PubMed |
[9] K. J. Blight, C. M. Rice, J. Virol. 1997, 71, 7345.
| Crossref | GoogleScholarGoogle Scholar | 9311812PubMed |
[10] M. Honda, M. R. Beard, L.-H. Ping, S. M. Lemon, J. Virol. 1999, 73, 1165.
| Crossref | GoogleScholarGoogle Scholar | 9882318PubMed |
[11] I. M. Jacobson, J. G. McHutchison, G. Dusheiko, A. M. Di Bisceglie, K. R. Reddy, N. H. Bzowej, P. Marcellin, A. J. Muir, P. Ferenci, R. Flisiak, J. George, M. Rizzetto, D. Shouval, R. Sola, R. A. Terg, E. M. Yoshida, N. Adda, L. Bengtsson, A. J. Sankoh, T. L. Kieffer, S. George, R. S. Kauffman, S. Zeuzem, N. Engl. J. Med. 2011, 364, 2405.
| Crossref | GoogleScholarGoogle Scholar | 21696307PubMed |
[12] M. J. Sofia, W. Chang, P. A. Furman, R. T. Mosley, B. S. Ross, J. Med. Chem. 2012, 55, 2481.
| Crossref | GoogleScholarGoogle Scholar | 22185586PubMed |
[13] M. J. Sofia, D. Bao, W. Chang, J. Du, D. Nagarathnam, S. Rachakonda, P. G. Reddy, B. S. Ross, P. Wang, H. R. Zhang, S. Bansal, C. Espiritu, M. Keilman, A. M. Lam, H. M. Steuer, C. Niu, M. J. Otto, P. A. Furman, J. Med. Chem. 2010, 53, 7202.
| Crossref | GoogleScholarGoogle Scholar | 20845908PubMed |
[14] D. L. Wyles, J. A. Gutierrez, J. Viral Hepat. 2014, 21, 229.
| Crossref | GoogleScholarGoogle Scholar | 24597691PubMed |
[15] B. Rehermann, M. Nascimbeni, Nat. Rev. Immunol. 2005, 5, 215.
| Crossref | GoogleScholarGoogle Scholar | 15738952PubMed |
[16] K. Tsukiyama-Kohara, N. Iizuka, M. Kohara, A. Nomoto, J. Virol. 1992, 66, 1476.
| Crossref | GoogleScholarGoogle Scholar | 1310759PubMed |
[17] C. Wang, P. Sarnow, A. Siddiqui, J. Virol. 1993, 67, 3338.
| Crossref | GoogleScholarGoogle Scholar | 8388503PubMed |
[18] J. L. Kim, K. A. Morgenstern, C. Lin, T. Fox, M. D. Dwyer, J. A. Landro, S. P. Chambers, W. Markland, C. A. Lepre, E. T. O’Malley, S. L. Harbeson, C. M. Rice, M. A. Murcko, P. R. Caron, J. A. Thomson, Cell 1996, 87, 343.
| Crossref | GoogleScholarGoogle Scholar | 8861917PubMed |
[19] P. P. Seth, A. Miyaji, E. A. Jefferson, K. A. Sannes-Lowery, S. A. Osgood, S. S. Propp, R. Ranken, C. Massire, R. Sampath, D. J. Ecker, E. E. Swayze, R. H. Griffey, J. Med. Chem. 2005, 48, 7099.
| Crossref | GoogleScholarGoogle Scholar | 16279767PubMed |
[20] S. M. Dibrov, K. Ding, N. Brunn, M. Parker, B. M. Bergdahl, D. L. Wyles, T. Hermann, Proc. Natl. Acad. Sci. USA 2012, 109, 5223.
| Crossref | GoogleScholarGoogle Scholar | 22431596PubMed |
[21] M. Zając, I. Muszalska, A. Sobczak, A. Dadej, S. Tomczak, A. Jelińska, Eur. J. Med. Chem. 2019, 165, 225.
| Crossref | GoogleScholarGoogle Scholar | 30685524PubMed |
[22] J. Parsons, M. P. Castaldi, S. Dutta, S. M. Dibrov, D. L. Wyles, T. Hermann, Nat. Chem. Biol. 2009, 5, 823.
| Crossref | GoogleScholarGoogle Scholar | 19767736PubMed |
[23] F. Aboul-ela, Future Med. Chem. 2010, 2, 93.
| Crossref | GoogleScholarGoogle Scholar | 21426048PubMed |
[24] F. Franceschi, E. M. Duffy, Biochem. Pharmacol. 2006, 71, 1016.
| Crossref | GoogleScholarGoogle Scholar | 16443192PubMed |
[25] T. Hermann, D. J. Patel, Science 2000, 287, 820.
| Crossref | GoogleScholarGoogle Scholar | 10657289PubMed |
[26] A. Serganov, RNA Biol. 2010, 7, 98.
| Crossref | GoogleScholarGoogle Scholar | 20061809PubMed |
[27] K. D. Rynearson, B. Charrette, C. Gabriel, J. Moreno, M. A. Boerneke, S. M. Dibrov, T. Hermann, Bioorg. Med. Chem. Lett. 2014, 24, 3521.
| Crossref | GoogleScholarGoogle Scholar | 24930829PubMed |
[28] K. Ding, A. Wang, M. A. Boerneke, S. M. Dibrov, T. Hermann, Bioorg. Med. Chem. Lett. 2014, 24, 3113.
| Crossref | GoogleScholarGoogle Scholar | 24856063PubMed |
[29] M. A. Parker, T. Hermann, E. Satkiewicz, B. M. Bergdahl, Molecules 2011, 16, 281.
| Crossref | GoogleScholarGoogle Scholar |
[30] S. Zhou, K. D. Rynearson, K. Ding, N. D. Brunn, T. Hermann, Bioorg. Med. Chem. 2013, 21, 6139.
| Crossref | GoogleScholarGoogle Scholar | 23602522PubMed |
[31] For detailed FRET assay data, see Supplementary Material.
[32] For docking studies of quinoxaline derivatives with HCV-IRES RNA, see: J. Chakraborty, A. Kanungo, M. Tribid, K. Kumar, G. Sharma, R. Pal, K. S. Ahammed, D. Patra, B. Majhi, S. Chakrabarti, S. Das, S. Dutta, Chem. Commun. 2019, 55, 14027.
| Crossref | GoogleScholarGoogle Scholar |
[33] S. F. Martin, J. H. Clements, Annu. Rev. Biochem. 2013, 82, 267.
| Crossref | GoogleScholarGoogle Scholar | 23746256PubMed |
[34] G. Zimmermann, C. Schultz-Fademrecht, P. Küchler, S. Murarka, S. Ismail, G. Triola, P. Nussbaumer, A. Wittinghofer, H. Waldmann, J. Med. Chem. 2014, 57, 5435.
| Crossref | GoogleScholarGoogle Scholar | 24884780PubMed |
[35] K. S. Korach, P. Sarver, K. Chae, J. A. McLachlan, J. D. McKinney, Mol. Pharm. 1988, 33, 120.
[36] D. B. Kitchen, H. Decornez, J. R. Furr, J. Bajorath, Nat. Rev. Drug Discov. 2004, 3, 935.
| Crossref | GoogleScholarGoogle Scholar | 15520816PubMed |
[37] N. Moitessier, P. Englebienne, D. Lee, J. Lawandi, C. R. Corbeil, Br. J. Pharmacol. 2008, 153, S7.
| Crossref | GoogleScholarGoogle Scholar | 18037925PubMed |
[38] W. Duch, K. Swaminathan, J. Meller, Curr. Pharm. Des. 2007, 13, 1497.
| Crossref | GoogleScholarGoogle Scholar | 17504169PubMed |
[39] D. Hecht, G. Fogel, Curr. Comput.-Aided Drug Des. 2009, 5, 56.
| Crossref | GoogleScholarGoogle Scholar |
[40] D. Hecht, Drug Dev. Res. 2011, 72, 53.
| Crossref | GoogleScholarGoogle Scholar |