3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations

Journal of Medicinal Chemistry

Volumn 59, Issue 6, 2016, Pages 2648-2659

  Tang, Jing ^a   Liu, Feng ^a   Nagy, Eva ^b   Miller, Lena ^b   Kirby, Karen A ^c   Wilson, Daniel J ^a   Wu, Bulan ^a   Sarafianos, Stefan G ^c   Parniak, Michael A ^b   Wang, Zhengqiang ^a  

^a UNIVERSITY OF MINNESOTA   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^c University of Missouri   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 HYDROXY 1 METHYL 6 [[3 (PYRIMIDIN 5 YL)PHENYL]AMINO]PYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 1 METHYL 6 [[3 (TETRAHYDROFURAN 3 YL)PHENYL]AMINO]PYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 1 METHYL 6 [[4' (TRIFLUOROMETHYL) (1,1' BIPHENYL) 4 YL]AMINO]PYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 1 METHYL 6 [[4' METHYL (1,1' BIPHENYL) 3 YL]AMINO]PYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 1 METHYL 6 [[4' METHYL (1,1' BIPHENYL) 4 YL]AMINO]PYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 6 [[2' METHOXY (1,1' BIPHENYL) 3 YL]AMINO] 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 6 [[2' METHOXY (1,1' BIPHENYL) 4 YL]AMINO] 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 6 [[3' METHOXY (1,1' BIPHENYL) 3 YL]AMINO] 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 6 [[3' METHOXY (1,1' BIPHENYL) 4 YL]AMINO] 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 6 [[4' HYDROXY (1,1' BIPHENYL) 3 YL]AMINO] 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 6 [[4' METHOXY (1,1' BIPHENYL) 3 YL]AMINO] 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXY 6 [[4' METHOXY (1,1' BIPHENYL) 4 YL]AMINO] 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 3 HYDROXYPYRIMIDINE 2,4 DIONE DERIVATIVE; 3' [(1 HYDROXY 3 METHYL 2,6 DIOXO 1,2,3,6 TETRAHYDROPYRIMIDIN 4 YL)AMINO] [1,1' BIPHENYL] 3 CARBONITRILE; 3' [(1 HYDROXY 3 METHYL 2,6 DIOXO 1,2,3,6 TETRAHYDROPYRIMIDIN 4 YL)AMINO] [1,1' BIPHENYL] 4 CARBONITRILE; 4' [(1 HYDROXY 3 METHYL 2,6 DIOXO 1,2,3,6 TETRAHYDROPYRIMIDIN 4 YL)AMINO] [1,1' BIPHENYL] 4 CARBONITRILE; 4' [(1 HYDROXY 3 METHYL 2,6 DIOXO 1,2,3,6 TETRAHYDROPYRIMIDIN 4 YL)] [1,1' BIPHENYL] 4 CARBONITRILE; 6 [(1,1' BIPHENYL) 3 YLAMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4 (1H,3H) DIONE; 6 [(1,1' BIPHENYL) 4 YLAMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4 (1H,3H)DIONE; 6 [(1,1' BIPHENYL) 4 YLOXY] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4 (1H,3H) DIONE; 6 [[2 (3,5 DIMETHYLISOXAZOL 4 YL)PHENYL]AMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 6 [[2',4' DIMETHOXY (1,1' BIPHENYL) 3 YL]AMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 6 [[2',4' DIMETHOXY (1,1' BIPHENYL) 4 YL]AMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 6 [[2',6' DIMETHOXY (1,1' BIPHENYL) 4 YL]AMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 6 [[3',4' DIMETHOXY (1,1' BIPHENYL) 4 YL]AMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 6 [[3',5' DIMETHOXY (1,1' BIPHENYL) 3 YL]AMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 6 [[3',5' DIMETHOXY (1,1' BIPHENYL) 4 YL]AMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; 6 [[4 (3,5 DIMETHYLISOXAZOL 4 YL)PHENYL]AMINO] 3 HYDROXY 1 METHYLPYRIMIDINE 2,4(1H,3H) DIONE; RNA DIRECTED DNA POLYMERASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; DNA DIRECTED RNA POLYMERASE; RIBONUCLEASE H; RNA DIRECTED DNA POLYMERASE; URACIL;

ANTIVIRAL ACTIVITY; ARTICLE; CELL VIABILITY ASSAY; CYTOTOXICITY; DRUG DESIGN; DRUG SCREENING; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS 1; STRUCTURE ACTIVITY RELATION; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; ENZYME ACTIVE SITE; HUMAN; MOLECULAR MODEL; POLYMERASE CHAIN REACTION; SYNTHESIS;

ANTI-HIV AGENTS; CATALYTIC DOMAIN; DNA-DIRECTED RNA POLYMERASES; DRUG DESIGN; HIV REVERSE TRANSCRIPTASE; HIV-1; HUMANS; MODELS, MOLECULAR; POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTASE INHIBITORS; RIBONUCLEASE H, HUMAN IMMUNODEFICIENCY VIRUS; STRUCTURE-ACTIVITY RELATIONSHIP; URACIL;

EID: 84962144439     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01879     Document Type: Article

References (32)

1. Hill, M.; Tachedjian, G.; Mak, J. The packaging and maturation of the HIV-1 pol proteins Curr. HIV Res. 2005, 3, 73-85 10.2174/1570162052772942
2. Richman, D. D. HIV chemotherapy Nature 2001, 410, 995-1001 10.1038/35073673
3. UNAIDS Aids Information; UNAIDS: Geneva, Switzerland. http://www.unaids.org/en/dataanalysis/datatools/aidsinfo/.
4. Beilhartz, G. L.; Gotte, M. HIV-1 Ribonuclease H: Structure, Catalytic Mechanism and Inhibitors Viruses 2010, 2, 900-926 10.3390/v2040900
5. Sarafianos, S. G.; Marchand, B.; Das, K.; Himmel, D. M.; Parniak, M. A.; Hughes, S. H.; Arnold, E. Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition J. Mol. Biol. 2009, 385, 693-713 10.1016/j.jmb.2008.10.071
6. Cihlar, T.; Ray, A. S. Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine Antiviral Res. 2010, 85, 39-58 10.1016/j.antiviral.2009.09.014
7. de Bethune, M. P. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009) Antiviral Res. 2010, 85, 75-90 10.1016/j.antiviral.2009.09.008
8. Parniak, M. A. Unpublishd data.
9. Nowotny, M. Retroviral integrase superfamily: the structural perspective EMBO Rep. 2009, 10, 144-151 10.1038/embor.2008.256
10. Cao, L.; Song, W.; De Clercq, E.; Zhan, P.; Liu, X. Recent progress in the research of small molecule HIV-1 RNase H inhibitors Curr. Med. Chem. 2014, 21, 1956-1967 10.2174/0929867321666140120121158
11. Klumpp, K.; Hang, J. Q.; Rajendran, S.; Yang, Y. L.; Derosier, A.; In, P. W. K.; Overton, H.; Parkes, K. E. B.; Cammack, N.; Martin, J. A. Two-metal ion mechanism of RNA cleavage by HIV RNase H and mechanism-based design of selective HIV RNase H inhibitors Nucleic Acids Res. 2003, 31, 6852-6859 10.1093/nar/gkg881
12. Himmel, D. M.; Maegley, K. A.; Pauly, T. A.; Bauman, J. D.; Das, K.; Dharia, C.; Clark, A. D., Jr.; Ryan, K.; Hickey, M. J.; Love, R. A.; Hughes, S. H.; Bergqvist, S.; Arnold, E. Structure of HIV-1 reverse transcriptase with the inhibitor beta-Thujaplicinol bound at the RNase H active site Structure 2009, 17, 1625-1635 10.1016/j.str.2009.09.016
13. Himmel, D. M.; Myshakina, N. S.; Ilina, T.; Van Ry, A.; Ho, W. C.; Parniak, M. A.; Arnold, E. Structure of a dihydroxycoumarin active-site inhibitor in complex with the RNase H domain of HIV-1 reverse transcriptase and structure-activity analysis of inhibitor analogs J. Mol. Biol. 2014, 426, 2617-2631 10.1016/j.jmb.2014.05.006
14. Shaw-Reid, C. A.; Munshi, V.; Graham, P.; Wolfe, A.; Witmer, M.; Danzeisen, R.; Olsen, D. B.; Carroll, S. S.; Embrey, M.; Wai, J. S.; Miller, M. D.; Cole, J. L.; Hazuda, D. J. Inhibition of HIV-1 ribonuclease H by a novel diketo acid, 4-[5-(benzoylamino)thien-2-yl]-2,4-dioxobutanoic acid J. Biol. Chem. 2003, 278, 2777-2780 10.1074/jbc.C200621200
15. Kirschberg, T. A.; Balakrishnan, M.; Squires, N. H.; Barnes, T.; Brendza, K. M.; Chen, X.; Eisenberg, E. J.; Jin, W.; Kutty, N.; Leavitt, S.; Liclican, A.; Liu, Q.; Liu, X.; Mak, J.; Perry, J. K.; Wang, M.; Watkins, W. J.; Lansdon, E. B. RNase H active site inhibitors of human immunodeficiency virus type 1 reverse transcriptase: design, biochemical activity, and structural information J. Med. Chem. 2009, 52, 5781-5784 10.1021/jm900597q
16. Williams, P. D.; Staas, D. D.; Venkatraman, S.; Loughran, H. M.; Ruzek, R. D.; Booth, T. M.; Lyle, T. A.; Wai, J. S.; Vacca, J. P.; Feuston, B. P.; Ecto, L. T.; Flynn, J. A.; DiStefano, D. J.; Hazuda, D. J.; Bahnck, C. M.; Himmelberger, A. L.; Dornadula, G.; Hrin, R. C.; Stillmock, K. A.; Witmer, M. V.; Miller, M. D.; Grobler, J. A. Potent and selective HIV-1 ribonuclease H inhibitors based on a 1-hydroxy-1,8-naphthyridin-2(1H)-one scaffold Bioorg. Med. Chem. Lett. 2010, 20, 6754-6757 10.1016/j.bmcl.2010.08.135
17. Beilhartz, G. L.; Ngure, M.; Johns, B. A.; Deanda, F.; Gerondelis, P.; Gotte, M. Inhibition of the Ribonuclease H Activity of HIV-1 Reverse Transcriptase by GSK5750 Correlates with Slow Enzyme-Inhibitor Dissociation J. Biol. Chem. 2014, 289, 16270-16277 10.1074/jbc.M114.569707
18. Corona, A.; Di Leva, F. S.; Thierry, S.; Pescatori, L.; Crucitti, G. C.; Subra, F.; Delelis, O.; Esposito, F.; Rigogliuso, G.; Costi, R.; Cosconati, S.; Novellino, E.; Di Santo, R.; Tramontano, E. Identification of Highly Conserved Residues Involved in Inhibition of HIV-1 RNase H Function by Diketo Acid Derivatives Antimicrob. Agents Chemother. 2014, 58, 6101-6110 10.1128/AAC.03605-14
19. Vernekar, S. K.; Liu, Z.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z. Design, synthesis, biochemical, and antiviral evaluations of C6 benzyl and C6 biarylmethyl substituted 2-hydroxylisoquinoline-1,3-diones: dual inhibition against HIV reverse transcriptase-associated RNase H and polymerase with antiviral activities J. Med. Chem. 2015, 58, 651-664 10.1021/jm501132s
20. Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z. N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase ACS Med. Chem. Lett. 2011, 2, 63-67 10.1021/ml1002162
21. Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z. Q. 6-Benzoyl-3-hydroxypyrimidine-2,4-diones as dual inhibitors of HIV reverse transcriptase and integrase Bioorg. Med. Chem. Lett. 2011, 21, 2400-2402 10.1016/j.bmcl.2011.02.069
22. Tang, J.; Maddali, K.; Metifiot, M.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z. Q. 3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase J. Med. Chem. 2011, 54, 2282-2292 10.1021/jm1014378
23. Adrian, G.; Mignonac, S.; Lecoutteux, F. Preparation of 5-(1-methylethyl)-6-(phenylmethyl)pyrimidine-2,4(1H,3H)-dione. WO 2000003999, January 27, 2000.
24. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells Science 2000, 287, 646-650 10.1126/science.287.5453.646
25. Su, H.-P.; Yan, Y.; Prasad, G. S.; Smith, R. F.; Daniels, C. L.; Abeywickrema, P. D.; Reid, J. C.; Loughran, H. M.; Kornienko, M.; Sharma, S.; Grobler, J. A.; Xu, B.; Sardana, V.; Allison, T. J.; Williams, P. D.; Darke, P. L.; Hazuda, D. J.; Munshi, S. Structural Basis for the Inhibition of RNase H Activity of HIV-1 Reverse Transcriptase by RNase H Active Site-Directed Inhibitors J. Virol. 2010, 84, 7625-7633 10.1128/JVI.00353-10
26. Fletcher, R. S.; Holleschak, G.; Nagy, E.; Arion, D.; Borkow, G.; Gu, Z.; Wainberg, M. A.; Parniak, M. A. Single-step purification of recombinant wild-type and mutant HIV-1 reverse transcriptase Protein Expression Purif. 1996, 7, 27-32 10.1006/prep.1996.0004
27. Gong, Q.; Menon, L.; Ilina, T.; Miller, L. G.; Ahn, J.; Parniak, M. A.; Ishima, R. Interaction of HIV-1 reverse transcriptase ribonuclease H with an acylhydrazone inhibitor Chem. Biol. Drug Des. 2011, 77, 39-47 10.1111/j.1747-0285.2010.01052.x
28. Parniak, M. A.; Min, K. L.; Budihas, S. R.; Le Grice, S. F.; Beutler, J. A. A fluorescence-based high-throughput screening assay for inhibitors of human immunodeficiency virus-1 reverse transcriptase-associated ribonuclease H activity Anal. Biochem. 2003, 322, 33-9 10.1016/j.ab.2003.06.001
29. Wang, Z.; Bennett, E. M.; Wilson, D. J.; Salomon, C.; Vince, R. Rationally designed dual inhibitors of HIV reverse transcriptase and integrase J. Med. Chem. 2007, 50, 3416-3419 10.1021/jm070512p
30. Sirivolu, V. R.; Vernekar, S. K. V.; Ilina, T.; Myshakina, N. S.; Parniak, M. A.; Wang, Z. Q. Clicking 3 '-Azidothymidine into Novel Potent Inhibitors of Human Immunodeficiency Virus J. Med. Chem. 2013, 56, 8765-8780 10.1021/jm401232v
31. Abram, M. E.; Parniak, M. A. Virion instability of human immunodeficiency virus type 1 reverse transcriptase (RT) mutated in the protease cleavage site between RT p51 and the RT RNase H domain J. Virol. 2005, 79, 11952-11961 10.1128/JVI.79.18.11952-11961.2005
32. Emsley, P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and development of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501 10.1107/S0907444910007493