Novel small molecule inhibitors targeting the "switch region" of bacterial RNAP: Structure-based optimization of a virtual screening hit

European Journal of Medicinal Chemistry

Volumn 65, Issue , 2013, Pages 223-231

  Sahner, J Henning ^a   Groh, Matthias ^a   Negri, Matthias ^a   Haupenthal, Jörg ^a   Hartmann, Rolf W ^a  

^a SAARLAND UNIVERSITY   (Germany)

Author keywords

Antibacterial agent; Bacterial RNAP inhibitor; Myxopyronin; QSAR; Switch region; Ureidothiophene carboxylic acid

Indexed keywords

5 PHENYL 3 UREIDOTHIOPHENE 2 CARBOXYLIC ACID; ANTIBIOTIC AGENT; RIFAMPICIN; RNA POLYMERASE; UNCLASSIFIED DRUG;

ANTIBACTERIAL ACTIVITY; ARTICLE; DRUG SCREENING; DRUG TARGETING; ESCHERICHIA COLI; LIPOPHILICITY; NONHUMAN; QUANTITATIVE STRUCTURE ACTIVITY RELATION; VIRTUAL REALITY;

EID: 84878150208     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2013.04.060     Document Type: Article

References (40)

1. A. Srivastava, M. Talaue, S. Liu, D. Degen, R.Y. Ebright, E. Sineva, A. Chakraborty, S.Y. Druzhinin, S. Chatterjee, J. Mukhopadhyay, Y.W. Ebright, A. Zozula, J. Shen, S. Sengupta, R.R. Niedfeldt, C. Xin, T. Kaneko, H. Irschik, R. Jansen, S. Donadio, N. Connell, R.H. Ebright, New target for inhibition of bacterial RNA polymerase: 'switch region', Curr. Opin. Microbiol. 14 (2011) 532-543.
2. I. Chopra, Bacterial RNA polymerase: a promising target for the discovery of new antimicrobial agents, Curr. Opin. Invest. Drugs 8 (2007) 600-607. (Pubitemid 47205244)
3. R. Mariani, S.I. Maffioli, Bacterial RNA polymerase inhibitors: an organized overview of their structure, derivatives, biological activity and current clinical development status, Curr. Med. Chem. 16 (2009) 430-454.
4. J.Mukhopadhyay, K. Das, S. Ismail, D. Koppstein, M. Jang, B. Hudson, S. Sarafianos, S. Tuske, J. Patel, R. Jansen, H. Irschik, E. Arnold, R.H. Ebright, The RNA polymerase "switch region" is a target for inhibitors, Cell 135 (2008) 295-307.
5. P. Cramer, Multisubunit RNA polymerases, Curr. Opin. Struct. Biol. 12 (2002) 89-97. (Pubitemid 34142726)
6. R.H. Ebright, RNA polymerase: structural similarities between bacterial RNA polymerase and eukaryotic RNA polymerase II, J. Mol. Biol. 304 (2000) 687-698. (Pubitemid 32047073)
7. I. Artsimovitch, J. Seddon, P. Sears, Fidaxomicin is an inhibitor of the initiation of bacterial RNA synthesis, Clin. Infect. Dis. 55 (Suppl. 2) (2012) S127-S131.
8. T. Schaberg, M. Forßbohm, B. Hauer, D. Kirsten, R. Kropp, R. Loddenkemper, K. Magdorf, H. Rieder, D. Sagebiel, R. Urbanczik, Richtlinien zur medikamentösen Behandlung der Tuberkulose im Erwachsenen- und Kindesalter, Pneumologie 55 (2001) 494-511. (Pubitemid 33141021)
9. A. Pablos-Méndez, M.C. Raviglione, A. Laszlo, N. Binkin, H.L. Rieder, F. Bustreo, D.L. Cohn, C.S. Lambregts-van Weezenbeek, S.J. Kim, P. Chaulet, P. Nunn, Global surveillance for antituberculosis-drug resistance, 1994-1997. World Health OrganizationeInternational Union against tuberculosis and Lung disease working group on anti-tuberculosis drug resistance surveillance, N. Engl. J. Med. 338 (1998) 1641-1649.
10. M.A. Espinal, A. Laszlo, L. Simonsen, F. Boulahbal, S.J. Kim, A. Reniero, S. Hoffner, H.L. Rieder, N. Binkin, C. Dye, R. Williams, M.C. Raviglione, Global trends in resistance to antituberculosis drugs. World Health Organization-International Union against tuberculosis and lung disease working group on anti-tuberculosis drug resistance surveillance, N. Engl. J. Med. 344 (2001) 1294-1303.
11. L.B. Rice, Unmet medical needs in antibacterial therapy, Biochem. Pharmacol. 71 (2006) 991-995.
12. Q. Al-Balas, N.G. Anthony, B. Al-Jaidi, A. Alnimr, G. Abbott, A.K. Brown, R.C. Taylor, G.S. Besra, T.D. McHugh, S.H. Gillespie, B.F. Johnston, S.P. Mackay, G.D. Coxon, Identification of 2-aminothiazole-4-carboxylate derivatives active against Mycobacterium tuberculosis H37Rv and the β-ketoacyl-ACP synthase mtFabH, PLoS ONE 4 (2009) e5617.
13. H. Irschik, K. Gerth, G. Höfle, W. Kohl, H. Reichenbach, The myxopyronins, new inhibitors of bacterial RNA synthesis from Myxococcus fulvus (Myxobacterales), J. Antibiot. 36 (1983) 1651-1658. (Pubitemid 14182425)
14. T. Doundoulakis, A.X. Xiang, R. Lira, K.A. Agrios, S.E. Webber, W. Sisson, R.M. Aust, A.M. Shah, R.E. Showalter, J.R. Appleman, K.B. Simonsen, Myxopyronin B analogs as inhibitors of RNA polymerase, synthesis and biological evaluation, Bioorg. Med. Chem. Lett. 14 (2004) 5667-5672. (Pubitemid 39346365)
15. G.A. Belogurov, M.N. Vassylyeva, A. Sevostyanova, J.R. Appleman, A.X. Xiang, R. Lira, S.E. Webber, S. Klyuyev, E. Nudler, I. Artsimovitch, D.G. Vassylyev, Transcription inactivation through local refolding of the RNA polymerase structure, Nature 457 (2009) 332-335.
16. A. O' Neill, B. Oliva, C. Storey, A. Hoyle, C. Fishwick, I. Chopra, RNA polymerase inhibitors with activity against rifampin-resistant mutants of Staphylococcus aureus, Antimicrob. Agents Chemother. 44 (2000) 3163-3166.
17. T.I. Moy, A. Daniel, C. Hardy, A. Jackson, O. Rehrauer, Y.S. Hwang, D. Zou, K. Nguyen, J.A. Silverman, Q. Li, C. Murphy, Evaluating the activity of the RNA polymerase inhibitor myxopyronin B against Staphylococcus aureus, FEMS Microbiol. Lett. 319 (2011) 176-179.
18. D. Haebich, F. von Nussbaum, Lost in transcription - inhibition of RNA polymerase, Angew. Chem. Int. Ed. 48 (2009) 3397-3400.
19. R. O'Shea, H.E. Moser, Physicochemical properties of antibacterial compounds: implications for drug discovery, J. Med. Chem. 51 (2008) 2871-2878. (Pubitemid 351706014)
20. S. Hinsberger, M. Groh, M. Negri, J. Haupenthal, R.W. Hartmann, unpublished results.
21. M.J. McPhillie, R. Trowbridge, K.R. Mariner, A.J. O'Neill, A.P. Johnson, I. Chopra, C.W.G. Fishwick, Structure-based ligand design of novel bacterial RNA polymerase inhibitors, ACS Med. Chem. Lett. 2 (2011) 729-734.
22. E.T. Buurman, M.A. Foulk, N. Gao, V.A. Laganas, D.C. McKinney, D.T. Moustakas, J.A. Rose, A.B. Shapiro, P.R. Fleming, Novel rapidly diversifiable antimicrobial RNA polymerase switch region inhibitors with confirmed mode of action in Haemophilus influenza, J. Bacteriol. 194 (2012) 5504-5512.
23. Y.S. Li, L. Zhou, X. Ma, H. Song, X.Y. Tang, Pharmacophore modeling and structure-based virtual screening for a novel "switch region" target of bacterial RNA polymerase, Med. Chem. Res. (2011) 1-11.
24. M. Negri, J. Haupenthal, R.W. Hartmann, unpublished results.
25. F. Arhin, O. Bélanger, S. Ciblat, M. Dehbi, D. Delorme, E. Dietrich, D. Dixit, Y. Lafontaine, D. Lehoux, J. Liu, G.A. McKay, G. Moeck, R. Reddy, Y. Rose, R. Srikumar, K.S.E. Tanaka, D.M. Williams, P. Gros, J. Pelletier, T.R. Parr, A.R. Far, A new class of small molecule RNA polymerase inhibitors with activity against rifampicin-resistant Staphylococcus aureus, Bioorg.Med. Chem. 14 (2006) 5812-5832. (Pubitemid 44164278)
26. H. Hartmann, J. Liebscher, A simple method for the synthesis of 5-aryl-3-amino-2-alkoxycarbonylthiophenes, Synthesis (1984) 275-276.
27. F. Fabis, S. Jolivet-Fouchet, M. Robba, H. Landelle, S. Rault, Thiaisatoic anhydrides: efficient synthesis under microwave heating conditions and study of their reactivity, Tetrahedron 54 (1998) 10789-10800. (Pubitemid 28383760)
28. L. Foulon, E. Braud, F. Fabis, J.C. Lancelot, S. Rault, Synthesis and combinatorial approach of the reactivity of 6- and 7-arylthieno [3,2-d ][1,3] oxazine-2,4-diones, Tetrahedron 59 (2003) 10051-10057. (Pubitemid 37434059)
29. F.X. Le Foulon, E. Braud, F. Fabis, J.C. Lancelot, S. Rault, Solution-phase parallel synthesis of a 1140-member ureidothiophene carboxylic acid library, J. Comb. Chem. 7 (2005) 253-257. (Pubitemid 40522008)
30. J.G. Topliss, Utilization of operational schemes for analog synthesis in drug design, J. Med. Chem. 15 (1972) 1006-1011.
31. Molecular Operating Environment (MOE), 2011.10, Chemical Computing Group Inc., 1010 Sherbooke St.West, Suite #910, Montreal, QC, Canada, H3A 2R7, 2011.
32. H. Nikaido, Molecular basis of bacterial outer membrane permeability revisited, Microbiol. Mol. Biol. Rev. 67 (2003) 593-656. (Pubitemid 37549772)
33. C.M. Morris, A. George, W.W. Wilson, F.R. Champlin, Effect of polymyxin B nonapeptide on daptomycin permeability and cell surface properties in Pseudomonas aeruginosa, Escherichia coli, and Pasteurella multocida, J. Antibiot. 48 (1995) 67-72.
34. H. Nikaido, Outer membrane of Salmonella typhimurium. Transmembrane diffusion of some hydrophobic substances, Biochim. Biophys. Acta 433 (1976) 118-132.
35. A. Srivastava, D. Degen, Y.W. Ebright, R.H. Ebright, Frequency, spectrum, and fitness costs of resistance to myxopyronin in Staphylococcus aureus: myxopyronin resistance has non-zero fitness cost, Antimicrob. Agents Chemother. 56 (2012) 6250-6255.
36. S. Cabani, P. Gianni, V. Mollica, L. Lepori, Group contributions to the thermodynamic properties of non-ionic organic solutes in dilute aqueous solution, J. Sol. Chem. 10 (1981) 563-595.
37. E. Freire, Do enthalpy and entropy distinguish first in class from best in class? Drug Discov. Today 13 (2008) 869-874.
38. J. Haupenthal, K. Hüsecken, M. Negri, C.K. Maurer, R.W. Hartmann, Influence of DNA template choice on transcription and inhibition of E. coli RNA polymerase, Antimicrob. Agents Chemother. 56 (2012) 4536-4539.
39. H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, Gaussian 03, Revision c.02, Gaussian Inc., Wallingford CT, 2004.
40. Compound 23 was synthesized via the following route: (Chemical Equation Presented)