Recent advances in the discovery and development of novel HIV-1 NNRTI platforms (Part II): 2009-2013 update

Current Medicinal Chemistry

Volumn 21, Issue 3, 2014, Pages 329-355

  Song, Yu'Ning ^a   Fang, Zengjun ^a   Zhan, Peng ^a   Liu, Xinyong ^a  

^a BEIJING UNIVERSITY OF POSTS AND TELECOMMUNICATIONS   (China)

Author keywords

AIDS; Drug design; Drug resistance; HIV; Inhibitor; NNRTIs; RT

Indexed keywords

1 [(2 HYDROXYETHOXY)METHYL] 6 (PHENYLTHIO)THYMINE; ACETANILIDE DERIVATIVE; ALKYLBENZENE; BENZOPHENONE DERIVATIVE; BENZOXAZOLE DERIVATIVE; CAPRAVIRINE; CHROMENE DERIVATIVE; ETRAVIRINE; IMIDAZO[1,2 A]PYRIDINE DERIVATIVE; IMIDAZOLE DERIVATIVE; ISOXAZOLIDINE DERIVATIVE; MOLECULAR SCAFFOLD; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; NUCLEOTIDE DERIVATIVE; PYRIDONE DERIVATIVE; PYRIMIDINE DERIVATIVE; RILPIVIRINE; SULFIDE; SULFONE DERIVATIVE; THIAZOLIDINE DERIVATIVE;

ANTIVIRAL THERAPY; ARTICLE; CHEMICAL MODIFICATION; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG SCREENING; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROPHOBICITY; MOLECULAR DOCKING; SEXUAL TRANSMISSION; VIRUS REPLICATION; VIRUS RESISTANCE;

DRUG DISCOVERY; DRUG RESISTANCE, VIRAL; HIV INFECTIONS; HIV REVERSE TRANSCRIPTASE; HIV-1; HUMANS; MOLECULAR DOCKING SIMULATION; REVERSE TRANSCRIPTASE INHIBITORS;

EID: 84893310295     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/09298673113206660298     Document Type: Article

References (173)

1. UNAIDS Report on the Global Aids Epidemic, 2012. See: http://www.unaids.org/en/media/unaids/contentassets/documents/e pidemiology/2012/gr2012/20121120-UNAIDS-Global-Report- 2012-en.pdf (Accessed: December 5, 2012).
2. Martins, S.; Ramos, M.J.; Fernandes, P.A. The current status of the NNRTI family of antiretrovirals used in the HAART regime against HIV infection. Curr. Med. Chem., 2008, 15, 1083-95.
3. Asahchop, E.L.; Wainberg, M.A.; Sloan, R.D.; Tremblay, C.L. Antiviral drug resistance and the need for development of new HIV-1 reverse transcriptase inhibitors. Antimicrob. Agents. Chemother., 2012, 56, 5000-8.
4. La Regina, G.; Coluccia, A.; Silvestri, R. Looking for an active conformation of the future HIV type-1 non-nucleoside reverse transcriptase inhibitors. Antivir. Chem. Chemother., 2010, 20, 213-37.
5. Adams, J.; Patel, N.; Mankaryous, N.; Tadros, M.; Miller, C.D. Nonnucleoside reverse transcriptase inhibitor resistance and the role of the second-generation agents. Ann. Pharmacother., 2010, 44, 157-65.
6. de Béthune, 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.
7. Reynolds, C.; de Koning, C.B.; Pelly, S.C.; van Otterlo, W.A.; Bode, M.L. In search of a treatment for HIV - current therapies and the role of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Chem. Soc. Rev., 2012, 41, 4657-70.
8. Alcaro, S.; Alteri, C.; Artese, A.; Ceccherini-Silberstein, F.; Costa, G.; Ortuso, F.; Parrotta, L.; Perno, C.F.; Svicher, V. Molecular and structural aspects of clinically relevant mutations related to the approved non-nucleoside inhibitors of HIV-1 reverse transcriptase. Drug Resist. Updat. 2011, 14, 141-9.
9. Jayaweera, D.; Dilanchian, P. New therapeutic landscape of NNRTIs for treatment of HIV: a look at recent data. Expert Opin. Pharmacother., 2012, 13, 2601-12.
10. Rawal, R.K.; Murugesan, V.; Katti, S.B. Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs. Curr. Med. Chem., 2012, 19, 5364-80.
11. Prajapati, D.G.; Ramajayam, R.; Yadav, M.R.; Giridhar, R. The search for potent, small molecule NNRTIs: A review. Bioorg. Med. Chem., 2009, 17, 5744-62.
12. FDA. Intelence (etravirine). http://www.fda.gov/Safety/ MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProdu cts/ucm180579.htm (2011 July 19).
13. Croxtall, J.D. Etravirine: a review of its use in the management of treatment-experienced patients with HIV-1 infection. Drugs, 2012, 72, 847-69.
14. FDA. Approval of Edurant (rilpivirine) a new NNRTI) for the treatment of HIV in treatment naive patients. http://www.fda.gov/ ForConsumers/ByAudience/ ForPatientAdvocates/HIVandAIDSAct ivities/ucm256151.htm (2011 July 19).
15. Schafer, J.J.; Short, W.R. Rilpivirine, a novel non-nucleoside reverse transcriptase inhibitor for the management of HIV-1 infection: a systematic review. Antivir. Ther., 2012, 17, 1495-502.
16. Zhan, P.; Liu, X.; Li, Z. Recent advances in the discovery and development of novel HIV-1 NNRTI platforms: 2006-2008 update. Curr. Med. Chem., 2009, 16, 2876-89.
17. Zhan, P.; Chen, X.; Li, D.; Fang, Z.; De Clercq, E.; Liu, X. HIV-1 NNRTIs: Structural diversity, pharmacophore similarity, and implications for drug design. Med. Res. Rev., 2013, 33, E1-E72.
18. Zhan, P.; Liu, X. Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2005 - 2010). Expert Opin. Ther. Pat., 2011, 21, 717-96.
19. Zhan, P.; Liu, X.; Li, Z.; Pannecouque, C.; De Clercq, E. Design strategies of novel NNRTIs to overcome drug resistance. Curr. Med. Chem., 2009, 16, 3903-17.
20. Li, D.; Zhan, P.; De Clercq, E.; Liu, X. Strategies for the design of HIV-1 non-nucleoside reverse transcriptase inhibitors: lessons from the development of seven representative paradigms. J. Med. Chem., 2012, 55, 3595-613.
21. Kim, J.; Park, C.; Ok, T.; So, W.; Jo, M.; Seo, M.; Kim, Y.; Sohn, J.H.; Park, Y.; Ju, M.K.; Kim, J.; Han, S.J.; Kim, T.H.; Cechetto, J.; Nam, J.; Sommer, P.; No, Z. Discovery of 3,4- dihydropyrimidin-2(1H)-ones with inhibitory activity against HIV- 1 replication. Bioorg. Med. Chem. Lett., 2012, 22, 2119-24.
22. Kim, J.; Ok, T.; Park, C.; So, W.; Jo, M.; Kim, Y.; Seo, M.; Lee, D.; Jo, S.; Ko, Y.; Choi, I.; Park, Y.; Yoon, J.; Ju, M.K.; Ahn, J.; Kim, J.; Han, S.J.; Kim, T.H.; Cechetto, J.; Nam, J.; Liuzzi, M.; Sommer, P.; No, Z. A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability. Bioorg. Med. Chem. Lett., 2012, 22, 2522-6.
23. Kim, J.; Cechetto, J.; No, Z.; Christophe, T,; Kim, T.; Nam, Y.J.; So, W.; Jo, M.; Ok, T.; Park, C.; Seo, J.M.; Sohn, J.-H.; Sommer, P.; Boese, S.A.; Han, S.-J. Park, S.Y.; Kim, P.H. Antiviral compounds. WO2010046780A2.
24. Kim, J.; Lee, D.; Park, C.; So, W.; Jo, M.; Ok, T.; Kwon, J.; Kong, S.; Jo, S.; Kim, Y.; Choi, J.; Kim, H.C.; Ko, Y.; Choi, I.; Park, Y.; Yoon, J.; Ju, M.K.; Kim, J.; Han, S.-J.; Kim, T.-H.; Cechetto, J.; Nam, J.; Sommer, P.; Liuzzi, M.; Lee, J.; No, Z. Discovery of phenylaminopyridine derivatives as novel HIV-1 non-nucleoside reverse transcriptase inhibitors. ACS Med. Chem. Lett., 2012, 3, 678-682.
25. Liu, B.; Lee, Y.; Zou, J.; Petrassi, H.M.; Joseph, R.W.; Chao, W.; Michelotti, E.L.; Bukhtiyarova, M.; Springman, E.B.; Dorsey, B.D. Discovery and SAR of a series of 4,6-diamino-1,3,5-triazin-2-ol as novel non-nucleoside reverse transcriptase inhibitors of HIV-1. Bioorg. Med. Chem. Lett., 2010, 20, 6592-6.
26. Kitchen, D.B.; Decornez, H.; Furr, J.R.; Bajorath, J. Docking and scoring in virtual screening for drug discovery: methods and applications. Nat. Rev. Drug Discov., 2004, 3, 935-949.
27. Bustanji, Y.; Al-Masri, I.M.; Qasem, A.; Al-Bakri, A.G.; Taha, M.O. In silico screening for non-nucleoside HIV-1 reverse transcriptase inhibitors using physicochemical filters and highthroughput docking followed by in vitro evaluation. Chem. Biol. Drug Des., 2009, 74, 258-265.
28. Nichols, S.E.; Domaoal, R.A.; Thakur, V.V.; Tirado-Rives, J.; Anderson, K.S.; Jorgensen, W.L. Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures. J. Chem. Inf. Model, 2009, 49, 1272-9.
29. Bollini, M.; Domaoal, R.A.; Thakur, V.V.; Gallardo-Macias, R.; Spasov, K.A.; Anderson, K.S.; Jorgensen, W.L. Computationallyguided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents. J. Med. Chem., 2011, 54, 8582-91.
30. Frey, K.M.; Bollini, M.; Mislak, A.C.; Cisneros, J.A.; Gallardo-Macias, R.; Jorgensen, W.L.; Anderson, K.S. Crystal structures of HIV-1 reverse transcriptase with picomolar inhibitors reveal key interactions for drug design. J. Am. Chem. Soc., 2012, 134, 19501-3.
31. Raju, T.N. The Nobel chronicles. 1988: James Whyte Black, (b 1924), Gertrude Elion (1918-99), and George H Hitchings (1905- 98). Lancet, 2000, 355:1022.
32. Zhao, H.; Guo, Z. Medicinal chemistry strategies in follow-on drug discovery. Drug Discov. Today, 2009, 14, 516-22.
33. Fischer, J., Ganellin, C.R. Analogue-based Drug Discovery 2006, ISBN: 978-3-527-31257-3.
34. Fischer, J., Ganellin, C.R. Analogue-based Drug Discovery II 2010, ISBN: 978-3-527-32549-8.
35. Fischer, J., Ganellin, C.R. Rotella, D.P. Analogue-based Drug Discovery III. 2012, ISBN: 978-3-527-33073-7.
36. Chen, X.; Zhan, P.; Li, D.; De Clercq, E.; Liu, X. Recent advances in DAPYs and related analogues as HIV-1 NNRTIs. Curr. Med. Chem., 2011, 18, 359-76.
37. Patani, G.A.; LaVoie, E.J. Bioisosterism: A rational approach in drug design. Chem. Rev., 1996, 96, 3147-3176.
38. Olesen, P.H. The use of bioisosteric groups in lead optimization. Curr. Opin. Drug Discov. Devel., 2001, 4, 471-478.
39. Lima, L.M.; Barreiro, E.J. Bioisosterism: a useful strategy for molecular modification and drug design. Curr. Med. Chem., 2005, 12, 23-49.
40. Tian, X.; Qin, B.; Lu, H.; Lai, W.; Jiang, S.; Lee, K.H.; Chen, C.H.; Xie, L. Discovery of diarylpyridine derivatives as novel nonnucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 5482-5.
41. Tian, X.T.; Qin, B.J.; Wu, Z.Y.; Wang, X.F.; Lu, H.; Morris-Natschke, S.L.; Chen, C.H.; Jiang, S.; Lee, K.H.; Xie, L. Design, synthesis, and evaluation of diarylpyridines and diarylanilines as potent non-nucleoside HIV-1 reverse transcriptase inhibitors, J. Med. Chem., 2010, 53, 8287-8297.
42. Qin, B.; Jiang, X.; Lu, H.; Tian, X.; Barbault, F.; Huang, L.; Qian, K.; Chen, C.H.; Huang, R.; Jiang, S.; Lee, K.H.; Xie, L. Diarylaniline derivatives as a distinct class of HIV-1 non-nucleoside reverse transcriptase inhibitors. J. Med. Chem., 2010, 53, 4906-16.
43. Sun, L.Q.; Qin, B.; Huang, L.; Qian, K.; Chen, C.H.; Lee, K.H.; Xie, L. Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 2012, 22, 2376-9.
44. Sun, L.Q.; Zhu, L.; Qian, K.; Qin, B.; Huang, L.; Chen, C.H.; Lee, K.H.; Xie, L. Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 nonnucleoside reverse transcriptase inhibitor (NNRTI) drug candidates. J. Med. Chem., 2012, 55, 7219-29.
45. Ribone, S.R.; Leen, V.; Madrid, M.; Dehaen, W.; Daelemans, D.; Pannecouque, C.; Briñón, M.C. Synthesis, biological evaluation and molecular modeling of 4,6-diarylpyrimidines and diarylbenzenes as novel non-nucleosides HIV-1 reverse transcriptase inhibitors. Eur. J. Med. Chem., 2012, 58, 485-92.
46. Venkatraj, M.; Ariën, K.K.; Heeres, J.; Dirié, B.; Joossens, J.; Van Goethem, S.; Van der Veken, P.; Michiels, J.; Vande Velde, C.M.; Vanham, G.; Lewi, P.J.; Augustyns, K. Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Bioorg. Med. Chem., 2011, 19, 5924-34.
47. Li, D.; Zhan, P.; Liu, H.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Liu, X. Synthesis and biological evaluation of pyridazine derivatives as novel HIV-1 NNRTIs. Bioorg. Med. Chem., 2013, 21, 2128-34.
48. Zeng, Z.S.; He, Q.Q.; Liang, Y.H.; Feng, X.Q.; Chen, F.E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Hybrid diarylbenzopyrimidine non-nucleoside reverse transcriptase inhibitors as promising new leads for improved anti-HIV-1 chemotherapy. Bioorg. Med. Chem., 2010, 18, 5039-47.
49. Zeng, Z.S.; Liang, Y.H.; Feng, X.Q.; Chen, F.E.; Pannecouque, C.; Balzarini, J.; De Clercq, E. Lead optimization of diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. ChemMedChem., 2010, 5, 837-40.
50. Feng, X.Q.; Zeng, Z.S.; Liang, Y.H.; Chen, F.E.; Pannecouque, C.; Balzarini, J.; De Clercq, E. Synthesis and biological evaluation of 4- (hydroxyimino)arylmethyl diarylpyrimidine analogues as potential non-nucleoside reverse transcriptase inhibitors against HIV. Bioorg. Med. Chem., 2010, 18, 2370-4.
51. Ma, X.D.; Yang, S.Q.; Gu, S.X.; He, Q.Q.; Chen, F.E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Synthesis and anti-HIV activity of aryl-2-[(4- cyanophenyl)amino]-4-pyrimidinone hydrazones as potent nonnucleoside reverse transcriptase inhibitors. ChemMedChem., 2011, 6, 2225-32.
52. Gu, S.X.; He, Q.Q.; Yang, S.Q.; Ma, X.D.; Chen, F.E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Synthesis and structure-activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs. Bioorg. Med. Chem., 2011, 19, 5117-24.
53. Gu, S.X.; Li, Z.M.; Ma, X.D.; Yang, S.Q.; He, Q.Q.; Chen, F.E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Chiral resolution, absolute configuration assignment and biological activity of racemic diarylpyrimidine CH(OH)- DAPY as potent nonnucleoside HIV-1 reverse transcriptase inhibitors. Eur. J. Med. Chem., 2012, 53, 229-34.
54. Liang, Y.H.; He, Q.Q.; Zeng, Z.S.; Liu, Z.Q.; Feng, X.Q.; Chen, F.E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Synthesis and anti-HIV activity of 2-naphthyl substituted DAPY analogues as non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2010, 18, 4601-5.
55. Gu, S.X.; Yang, S.Q.; He, Q.Q.; Ma, X.D.; Chen, F.E.; Dai, H.F.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Design, synthesis and biological evaluation of cycloalkyl arylpyrimidines (CAPYs) as HIV-1 NNRTIs. Bioorg. Med. Chem., 2011, 19, 7093-9.
56. Rotili, D.; Samuele, A.; Tarantino, D.; Ragno, R.; Musmuca, I.; Ballante, F.; Botta, G.; Morera, L.; Pierini, M.; Cirilli, R.; Nawrozkij, M.B.; Gonzalez, E.; Clotet, B.; Artico, M.; Esté, J.A.; Maga, G.; Mai, A. 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies. J. Med. Chem., 2012, 55, 3558-62.
57. Kertesz, D.J.; Brotherton-Pleiss, C.; Yang, M.; Wang, Z.; Lin, X.; Qiu, Z.; Hirschfeld, D.R.; Gleason, S.; Mirzadegan, T.; Dunten, P.W.; Harris, S.F.; Villaseñor, A.G.; Hang, J.Q.; Heilek, G.M.; Klumpp, K. Discovery of piperidin-4-yl-aminopyrimidines as HIV- 1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses. Bioorg. Med. Chem. Lett., 2010, 20, 4215-8.
58. Tang, G.; Kertesz, D.J.; Yang, M.; Lin, X.; Wang, Z.; Li, W.; Qiu, Z.; Chen, J.; Mei, J.; Chen, L.; Mirzadegan, T.; Harris, S.F.; Villaseñor, A.G.; Fretland, J.; Fitch, W.L.; Hang, J.Q.; Heilek, G.; Klumpp, K. Exploration of piperidine-4-ylaminopyrimidines as HIV-1 reverse transcriptase inhibitors. NPhenyl derivatives with broad potency against resistant mutant viruses. Bioorg. Med. Chem. Lett., 2010, 20, 6020-3.
59. Chen, X.; Zhan, P.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Liu, X. Synthesis and biological evaluation of piperidinesubstituted triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors. Eur. J. Med. Chem., 2012, 51, 60-6.
60. Chen, X.; Zhan, P.; Liu, X.; Cheng, Z.; Meng, C.; Shao, S.; Pannecouque, C.; De Clercq, E.; Liu, X. Design, synthesis, anti-HIV evaluation and molecular modeling of piperidine-linked aminotriazine derivatives as potent non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2012, 20, 3856-64.
61. Venkatraj, M.; Ariën, K.K.; Heeres, J.; Joossens, J.; Messagie, J.; Michiels, J.; Van der Veken, P.; Vanham, G.; Lewi, P.J.; Augustyns, K. Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents. Bioorg. Med. Chem. Lett., 2012, 22, 7174-8.
62. Johnson, B.C.; Pauly, G.T.; Rai, G.; Patel, D.; Bauman, J.D.; Baker, H.L.; Das, K.; Schneider, J.P.; Maloney, D.J.; Arnold, E.; Thomas, C.J.; Hughes, S.H. A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants. Retrovirology, 2012, 9, 99.
63. Ribone, S.R.; Quevedo, M.A.; Madrid, M.; Briñón, M.C. Rational approaches for the design of effective human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitors. J. Chem. Inf. Model, 2011, 51, 130-8.
64. Gallicchio, E. Role of Ligand Reorganization and Conformational Restraints on the Binding Free Energies of DAPY Non-Nucleoside Inhibitors to HIV Reverse Transcriptase. Comput. Mol. Biosci., 2012, 2, 7-22.
65. Lansdon, E.B.; Brendza, K.M.; Hung, M.; Wang, R.; Mukund, S.; Jin, D.; Birkus, G.; Kutty, N.; Liu, X. Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design. J. Med. Chem., 2010, 53, 4295-9.
66. Bailey, C.M.; Sullivan, T.J.; Iyidogan, P.; Tirado-Rives, J.; Chung, R.; Ruiz-Caro, J.; Mohamed, E.; Jorgensen, W.; Hunter, R.; Anderson, K.S. Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of- Concept as a Novel Therapeutic Design Strategy. J. Med. Chem., 2013, 56, 3959-68.
67. Zhan, P.; Li, Z.; Liu, X.; De Clercq, E.Sulfanyltriazole/ tetrazoles: a promising class of HIV-1 NNRTIs. Mini. Rev. Med. Chem., 2009, 9, 1014-1023.
68. Song, Y. ; Zhan, P. ; Liu, X. Heterocyclethioacetic acid motif: a privileged molecular scaffold with potent, broad-ranging pharmacological activities. Curr. Pharm. Des., 2013 [Epub ahead of print].
69. Zhang, Z.; Xu, W.; Koh, Y.H.; Shim, J.H.; Girardet, J.L.; Yeh, L.T.; Hamatake, R.K.; Hong, Z. A novel nonnucleoside analogue that inhibits human immunodeficiency virus type 1 isolates resistant to current nonnucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother., 2007, 51, 429-437.
70. Moyle, G.; Boffito, M.; Stoehr, A.; Rieger, A.; Shen, Z.; Manhard, K.; Sheedy, B.; Hingorani, V.; Raney, A.; Nguyen, M.; Nguyen, T.; Ong, V.; Yeh, L.T.; Quart, B. Phase 2a randomized controlled trial of short-term activity, safety, and pharmacokinetics of a novel nonnucleoside reverse transcriptase inhibitor, RDEA806, in HIV-1- positive, antiretroviral-naive subjects. Antimicrob. Agents Chemother., 2010, 54, 3170-3178.
71. Zhan, P.; Liu, X.; Cao, Y.; Wang, Y.; Pannecouque, C.; De Clercq, E. 1,2,3-Thiadiazole thioacetanilides as a novel class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 5368-71.
72. Zhan, P.; Liu, X.; Li, Z.; Fang, Z.; Li, Z.; Wang, D.; Pannecouque, C.; De Clercq, E. Novel 1,2,3-thiadiazole derivatives as HIV-1 NNRTIs with improved potency: synthesis and preliminary SAR studies. Bioorg. Med. Chem., 2009, 17, 5920-7.
73. Zhan, P.; Liu, X.; Fang, Z.; Li, Z.; Pannecouque, C.; De Clercq, E. Synthesis and anti-HIV activity evaluation of 2-(4-(naphthalen-2- yl)-1,2,3-thiadiazol-5-ylthio)-N-acetamides as novel non- nucleoside HIV-1 reverse transcriptase inhibitors. Eur. J. Med. Chem., 2009, 44, 4648-53.
74. Zhan, P.; Liu, X.; Li, Z.; Fang, Z.; Pannecouque, C.; De Clercq, E. 1,2,3-thiadiazole thioacetanilides. Part 2: Synthesis and biological evaluation of a new series of 2-{[4-(3,4-dichlorophenyl)-1,2,3- thiadiazol-5-yl]sulfanyl} acetanilides as HIV-1 inhibitors. Chem. Biodivers., 2010, 7, 1717-27.
75. Jiang, X.; Zhan, P.; Liu, X.; De Clercq, E. Synthesis and anti-HIV activity evaluation of 2-(5-(naphthalen-1-yl)-1,2,3-thiadiazol-4- ylthio)-N-acetamides derivatives. Lat. Am. J. Pharm., 2012, 31, 751-5.
76. Zhan, P.; Chen, X.; Li, X.; Li, D.; Tian, Y.; Chen, W.; Pannecouque, C.; De Clercq, E.; Liu, X. Arylazolylthioacetanilide. part 8: Design, Synthesis and Biological Evaluation of Novel 2-(2-(2,4- Dichlorophenyl)-2H-1,2,4-triazol-3- ylthio)-N-arylacetamides As Potent HIV-1 Inhibitors. Eur. J. Med. Chem., 2011, 46, 5039-5045.
77. Zhan, P.; Liu, X.; Fang, Z.; Pannecouque, C.; De Clercq, E. 1,2,3- Selenadiazole thioacetanilides: Synthesis and anti-HIV activity evaluation. Bioorg. Med. Chem., 2009, 17, 6374-9.
78. Zhan, P.; Liu, X.; Zhu, J.; Fang, Z.; Li, Z.; Pannecouque, C.; De Clercq, E. Synthesis and biological evaluation of imidazole thioacetanilides as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2009, 17, 5775-5781.
79. Zhan, P.; Wang, L.; Liu, H.; Chen, X.; Li, X.; Jiang, X.; Zhang, Q.; Liu, X.; Pannecouque, C.; Naesens, L.; De Clercq, E.; Liu A.; Du, G. Arylazolyl(azinyl)thioacetanilide. part 9 : Synthesis and biological investigation of thiazolylthioacetamides derivatives as a novel class of potential antiviral agents. Arch. Pharm. Res., 2012, 35, 1037-1048.
80. Zhan, P.; Chen, W.; Li, Z.; Li, X.; Chen, X.; Tian, Y.; Pannecouque, C.; De Clercq, E.; Liu, X. Discovery of novel 2-(3-(2- chlorophenyl)pyrazin-2- ylthio)-N-arylacetamides as potent HIV-1 inhibitors using a structure-based bioisosterism approach. Bioorg. Med. Chem., 2012, 20, 6795-802.
81. Zhan, P.; Li, X.; Li, Z.; Chen, X.; Tian, Y.; Chen, W.; Liu, X.; Pannecouque, C.; De Clercq, E. Structure-based bioisosterism design, synthesis and biological evaluation of novel 1,2,4-triazin-6- ylthioacetamides as potent HIV-1 NNRTIs. Bioorg. Med. Chem. Lett., 2012, 22, 7155-62.
82. Song, Y.; Zhan, P.; Kang, D.; Li, X.; Tian, Y.; Li, Z.; Chen, X.; Chen, W.; Pannecouque, C.; De Clercq, E.; Liu, X. Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach. Med. Chem. Commun., 2013, 4, 810-816.
83. Li, X.; Zhan, P.; Liu, H.; Li, D.; Wang, L.; Chen, X.; Liu, H.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Liu X. Arylazolyl( azinyl)thioacetanilides. Part 10: Design, synthesis and biological evaluation of novel substituted imidazopyridinylthioacetanilides as potent HIV-1 inhibitors. Bioorg. Med. Chem., 2012, 20, 5527-36.
84. Zhan, P.; Liu, H.; Liu, X.; Wang, Y.; Pannecouque, C.; Witvrouw, M.; De Clercq, E. Synthesis and anti-HIV activity evaluation of novel N'-arylidene-2-[1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio] acetohy drazides. Med. Chem. Res., 2009, 19, 652-663.
85. Yu, M.; Fan, E.; Wu, J.; Liu, X. Recent advances in the DABOs family as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr. Med. Chem., 2011, 18, 2376-85.
86. Zhang, J.; Zhan, P.; Wu, J.; Li, Z.; Jiang, Y.; Ge, W.; Pannecouque, C.; De Clercq, E.; Liu, X. Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl) pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2011, 19, 4366-76.
87. Qin, H.; Liu, C.; Guo, Y.; Wang, R.; Zhang, J.; Ma, L.; Zhang, Z.; Wang, X.; Cui, Y.; Liu, J. Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 nonnucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2010, 18, 3231-7.
88. He, Y.P.; Long, J.; Zhang, S.S.; Li, C.; Lai, C.C.; Zhang, C.S.; Li, D.X.; Zhang, D.H.; Wang, H.; Cai, Q.Q.; Zheng, Y.T. Synthesis and biological evaluation of novel dihydro-aryl/alkylsulfanylcyclohexylmethyl- oxopyrimidines (S-DACOs) as high active anti- HIV agents. Bioorg. Med. Chem. Lett., 2011, 21, 694-7.
89. Wu, D.C.; Zhuang, D.M.; Liu, X.F.; Lu, L.H.; Wang, H.; Li, C.; Cong Lai, C.; Li J.Y.; He, Y.P. Synthesis and biological evaluation of novel hydroxylphenethyl-S DACOs as high active anti-HIV agents. Lett. Drug Des. Discov., 2013, 10, 271-276.
90. Radi, M.; Pagano, M.; Franchi, L.; Castagnolo, D.; Schenone, S.; Casaluce, G.; Zamperini, C.; Dreassi, E.; Maga, G.; Samuele, A.; Gonzalo, E.; Clotet, B.; Esté, J.A.; Botta, M. Synthesis, biological activity, and ADME properties of novel S-DABOs/NDABOs as HIV reverse transcriptase inhibitors. ChemMedChem., 2012, 7, 883-96.
91. Rotili, D.; Tarantino, D.; Artico, M.; Nawrozkij, M.B.; Gonzalez-Ortega, E.; Clotet, B.; Samuele, A.; Esté, J.A.; Maga, G.; Mai, A. Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)- nanomolar level. J. Med. Chem., 2011, 54, 3091-6.
92. Chen, W.; Zhan, P.; Wu, J.; Li, Z.; Liu, X. The development of HEPT-type HIV non-nucleoside reverse transcriptase inhibitors and its implications for DABO family. Curr. Pharm. Des., 2012, 18, 4165-86.
93. Puig-de-la-Bellacasa, R.; Giménez, L.; Pettersson, S.; Pascual, R.; Gonzalo, E.; Esté, J.A.; Clotet, B.; Borrell, J.I.; Teixidó, J. Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors. Eur. J. Med. Chem., 2012, 54, 159-74.
94. Wang, X.; Zhang, J.; Huang, Y.; Wang, R.; Zhang, L.; Qiao, K.; Li, L.; Liu, C.; Ouyang, Y.; Xu, W.; Zhang, Z.; Zhang, L.; Shao, Y.; Jiang, S.; Ma, L.; Liu, J. Design, synthesis, and biological evaluation of 1-[(2-benzyloxyl/ alkoxyl)methyl]-5-halo-6-aryluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile. J. Med. Chem., 2012, 55, 2242-50.
95. Mitchell, M.L.; Son, J.C.; Guo, H.; Im, Y.A.; Cho, E.J.; Wang, J.; Hayes, J.; Wang, M.; Paul, A.; Lansdon, E.B.; Chen, J.M.; Graupe, D.; Rhodes, G.; He, G.X.; Geleziunas, R.; Xu, L.; Kim, C.U. N1-Alkyl pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett., 2010, 20, 1589-92.
96. Mitchell, M.L.; Son, J.C.; Lee, I.Y.; Lee, C.K.; Kim, H.S.; Guo, H.; Wang, J.; Hayes, J.; Wang, M.; Paul, A.; Lansdon, E.B.; Chen, J.M.; Eisenberg, G.; Geleziunas, R.; Xu, L.; Kim, C.U. N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett., 2010, 20, 1585-8.
97. Johnson, T.J.; Srinivasan, P.; Albright, T.H.; Watson-Buckheit, K.; Rabe, L.; Martin, A.; Pau, C.P.; Hendry, R.M.; Otten, R.; McNicholl, J.; Buckheit R, Jr.; Smith, J.; Kiser, P.F. Safe and sustained vaginal delivery of pyrimidinedione HIV-1 inhibitors from polyurethane intravaginal rings. Antimicrob. Agents Chemother., 2012, 56, 1291-9.
98. Watson Buckheit, K.; Yang, L.; Buckheit RW, Jr. Development of dual-acting pyrimidinediones as novel and highly potent topical anti-HIV microbicides. Antimicrob. Agents Chemother., 2011, 55, 5243-54.
99. Zhan, P.; Liu, X. Rationally designed multitarget anti-HIV agents. Curr. Med. Chem., 2013, 20, 1743-58.
100. Zhan, P.; Liu, X. Designed multiple ligands: an emerging anti-HIV drug discovery paradigm. Curr. Pharm. Des., 2009, 15, 1893-917.
101. 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.
102. Tang, J.; Maddali, K.; Metifiot, M.; Sham, Y.Y.; Vince, R.; Pommier, Y.; Wang, Z. 3- Hydroxypyrimidine-2,4-diones as an inhibitor scaffold of HIV integrase. J. Med. Chem., 2011, 54, 2282-92.
103. (c) Tang, J.; Maddali, K.; Dreis, C.D.; Sham, Y.Y.; Vince, R.; Pommier, Y.; Wang, Z. 6- Benzoyl-3-hydroxypyrimidine-2,4-diones as dual inhibitors of HIV reverse transcriptase and integrase. Bioorg. Med. Chem. Lett., 2011, 21, 2400-2.
104. Isono, Y.; Sakakibara, N.; Ordonez, P.; Hamasaki, T.; Baba, M.; Ikejiri, M.; Maruyama, T. Synthesis of 1-benzyl-3-(3,5- dimethylbenzyl)uracil derivatives with potential anti-HIV activity. Antivir. Chem. Chemother., 2011, 22, 57-65.
105. Ordonez, P.; Hamasaki, T.; Isono, Y.; Sakakibara, N.; Ikejiri, M.; Maruyama, T.; Baba, M. Anti-human immunodeficiency virus type 1 activity of novel 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl)uracil derivatives. Antimicrob. Agents Chemother., 2012, 56, 2581-9.
106. Novikov, M.S.; Valuev-Elliston, V.T.; Babkov, D.A.; Paramonova, M.P.; Ivanov, A.V.; Gavryushov, S.A.; Khandazhinskaya, A.L.; Kochetkov, S.N.; Pannecouque, C.; Andrei, G.; Snoeck, R.; Balzarini, J.; Seley-Radtke, K.L. N(1),N(3)-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem., 2013, 21, 1150-8.
107. Guillemont, J.; Benjahad, A.; Oumouch, S.; Decrane, L.; Palandjian, P.; Vernier, D.; Queguiner, L.; Andries, K.; de Béthune, M.P.; Hertogs, K.; Grierson, D.S.; Nguyen, C.H. Synthesis and biological evaluation of C-5 methyl substituted 4-arylthio and 4-aryloxy-3- Iodopyridin-2(1H)-one type anti-HIV agents. J. Med. Chem., 2009, 52, 7473-87.
108. Le Van, K.; Cauvin, C.; de Walque, S.; Georges, B.; Boland, S.; Martinelli, V.; Demonté, D.; Durant, F.; Hevesi, L.; Van Lint, C. New pyridinone derivatives as potent HIV-1 nonnucleoside reverse transcriptase inhibitors. J. Med. Chem., 2009, 52, 3636-43.
109. Li, A.; Ouyang, Y.; Wang, Z.; Cao, Y.; Liu, X.; Ran, L.; Li, C.; Li, L.; Zhang, L.; Qiao, K.; Xu, W.; Huang, Y.; Zhang, Z.; Tian, C.; Liu, Z.; Jiang, S.; Shao, Y.; Du, Y.; Ma, L.; Wang, X.; Liu, J. Novel pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) with high potency against NNRTIresistant HIV-1 strains. J. Med. Chem., 2013, 56, 3593-608.
110. Ma, X.D.; Zhang, X.; Dai, H.F.; Yang, S.Q.; Yang, L.M.; Gu, S.X.; Zheng, Y.T.; He, Q.Q.; Chen, F.E. Synthesis and biological activity of naphthyl-substituted (B-ring) benzophenone derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2011, 19, 4601-7.
111. Ma, X.D.; Zhang, X.; Yang, S.Q.; Dai, H.F.; Yang, L.M.; Gu, S.X.; Zheng, Y.T.; He, Q.Q.; Chen FE. Synthesis and biological evaluation of (±)- benzhydrol derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2011, 19, 4704-9.
112. Ma, X.D.; He, Q.Q.; Zhang, X.; Yang, S.Q.; Yang, L.M.; Gu, S.X.; Zheng, Y.T.; Chen, F.E.; Dai, H.F. Synthesis, structure-activity relationships, and docking studies of N-phenylarylformamide derivatives (PAFAs) as non-nucleoside HIV reverse transcriptase inhibitors. Eur. J. Med. Chem., 2012, 58, 504-12.
113. Novikov, M.S.; Ivanova, O.N.; Ivanov, A.V.; Ozerov, A.A.; Valuev-Elliston, V.T.; Temburnikar, K.; Gurskaya, G.V.; Kochetkov, S.N.; Pannecouque, C.; Balzarini, J.; Seley-Radtke, K.L. 1-[2-(2- Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents. Bioorg. Med. Chem., 2011, 19, 5794-802.
114. Prokofjeva, M.M.; Valuev-Elliston, V.T.; Ivanov, A.V.; Kochetkov, S.N.; Novikov, M.S.; Prassolov, V.S. Benzophenone derivatives of pyrimidines as effective non-nucleoside inhibitors of wildtype and drug-resistant HIV-1 reverse transcriptase. Dokl. Biochem. Biophys., 2012, 447, 280-1.
115. Chen, X.; Ding, S.; Zhan, P.; Liu, X. Recent advances of diaryl ether family as HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr. Pharm. Des., 2013, 19, 2829-38.
116. Lai, M.T.; Munshi, V.; Touch, S.; Tynebor, R.M.; Tucker, T.J.; McKenna, P.M.; Williams, T.M.; DiStefano, D.J.; Hazuda, D.J.; Miller, M.D. Antiviral activity of MK-4965, a novel nonnucleoside reverse transcriptase inhibitor. Antimicrob. Agents Chemother., 2009, 53, 2424-31.
117. Gomez, R.; Jolly, S.J.; Williams, T.; Vacca, J.P.; Torrent, M.; McGaughey, G.; Lai, M.T.; Felock, P.; Munshi, V.; Distefano, D.; Flynn, J.; Miller, M.; Yan, Y.; Reid, J.; Sanchez, R.; Liang, Y.; Paton, B.; Wan, B.L.; Anthony, N. Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptase. J. Med. Chem., 2011, 54, 7920-33.
118. Lu, M.; Felock, P.J.; Munshi, V.; Hrin, R.C.; Wang, Y.J.; Yan, Y.; Munshi, S.; McGaughey, G.B.; Gomez, R.; Anthony, N.J.; Williams, T.M.; Grobler, J.A.; Hazuda, D.J.; McKenna, P.M.; Miller, M.D.; Lai, M.T. Antiviral activity and in vitro mutation development pathways of MK-6186, a novel nonnucleoside reverse transcriptase inhibitor. Antimicrob. Agents Chemother., 2012, 56, 3324-35.
119. Gomez, R.; Jolly, S.; Williams, T.; Tucker, T.; Tynebor, R.; Vacca, J.; McGaughey, G.; Lai, M.T.; Felock, P.; Munshi, V.; DeStefano, D.; Touch, S.; Miller, M.; Yan, Y.; Sanchez, R.; Liang, Y.; Paton, B.; Wan, B.L.; Anthony, N. Design and synthesis of pyridone inhibitors of non-nucleoside reverse transcriptase. Bioorg. Med. Chem. Lett., 2011, 21, 7344-50.
120. Javanbakht, H.; Ptak, R.G.; Chow, E.; Yan, J.M.; Russell, J.D.; Mankowski, M.K.; Hogan, P.A.; Hogg, J.H.; Vora, H.; Hang, J.Q.; Li, Y.; Su, G.; Paul, A.; Cammack, N.; Klumpp, K.; Heilek, G. In vitro resistance development for RO-0335, a novel diphenylether nonnucleoside reverse transcriptase inhibitor. Antiviral Res., 2010, 86, 212-9.
121. Gu, S.X.; Zhang, X.; He, Q.Q.; Yang, L.M.; Ma, X.D.; Zheng, Y.T.; Yang, S.Q.; Chen, F.E. Synthesis and biological evaluation of naphthyl phenyl ethers (NPEs) as novel nonnucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2011, 19, 4220-6.
122. Kennedy-Smith, J.J.; Arora, N.; Billedeau, J.R.; Fretland, J.; Hang, J.Q.; Heilek, G.M.; Harris, S.F.; Hirschfeld, D.; Javanbakht, H.; Li, Y.; Liang, W.; Roetz, R.; Smith, M.; Su, G.; Suh, J.M.; Villaseñor, A.G.; Wu, J.; Yasuda, D.; Klumpp, K.; Sweeney, Z.K. Synthesis and biological activity of new pyridone diaryl ether non-nucleoside inhibitors of HIV-1 reverse transcriptase. Med. Chem. Commun., 2010, 1, 79-83
123. Sweeney, Z.K.; Kennedy-Smith, J.J.; Wu, J.; Arora, N.; Billedeau, J.R.; Davidson, J.P.; Fretland, J.; Hang, J.Q.; Heilek, G.M.; Harris, S.F.; Hirschfeld, D.; Inbar, P.; Javanbakht, H.; Jernelius, J.A.; Jin, Q.; Li, Y.; Liang, W.; Roetz, R.; Sarma, K.; Smith, M.; Stefanidis, D.; Su, G.; Suh, J.M.; Villaseñor, A.G.; Welch, M.; Zhang, F.J.; Klumpp, K. Diphenyl ether non-nucleoside reverse transcriptase inhibitors with excellent potency against resistant mutant viruses and promising pharmacokinetic properties. ChemMedChem, 2009, 4, 88-99.
124. Su, D.S.; Lim, J.J.; Tinney, E.; Tucker, T.J.; Saggar, S.; Sisko, J.T.; Wan, B.L.; Young, M.B.; Anderson, K.D.; Rudd, D.; Munshi, V.; Bahnck, C.; Felock, P.J.; Lu, M.; Lai, M.T.; Touch, S.; Moyer, G.; Distefano, D.J.; Flynn, J.A.; Liang, Y.; Sanchez, R.; Perlow-Poehnelt, R.; Miller, M.; Vacca, J.P.; Williams, T.M.; Anthony, N.J. Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif. Bioorg. Med. Chem. Lett., 2010, 20, 4328-32.
125. Chong, P.; Sebahar, P.; Youngman, M.; Garrido, D.; Zhang, H.; Stewart, E.L.; Nolte, R.T.; Wang, L.; Ferris, R.G.; Edelstein, M.; Weaver, K.; Mathis, A.; Peat, A. Rational design of potent nonnucleoside inhibitors of HIV-1 reverse transcriptase. J. Med. Chem., 2012, 55, 10601-9.
126. Silvestri, R.; Artico, M. Indolyl aryl sulfones (IASs): development of highly potent NNRTIs active against wt-HIV-1 and clinically relevant drug resistant mutants. Curr. Pharm. Des., 2005, 11, 3779-806.
127. Zala, C.; St Clair, M.; Dudas, K.; Kim, J.; Lou, Y.; White, S.; Piscitelli, S.; Dumont, E.; Pietropaolo, K.; Zhou, X.J.; Mayers, D. Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1- infected subjects. Antimicrob. Agents Chemother., 2012, 56, 2570-5.
128. Klibanov, O.M.; Kaczor, R.L. IDX-899, an aryl phosphinate-indole non-nucleoside reverse transcriptase inhibitor for the potential treatment of HIV infection. Curr. Opin. Investig. Drugs, 2010, 11, 237-45.
129. Zhou, X.J.; Pietropaolo, K.; Damphousse, D.; Belanger, B.; Chen, J.; Sullivan-Bólyai, J.; Mayers, D. Single-dose escalation and multiple- dose safety, tolerability, and pharmacokinetics of IDX899, a candidate human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor, in healthy subjects. Antimicrob. Agents Chemother., 2009, 53, 1739-46.
130. Piscitelli, F.; Coluccia, A.; Brancale, A.; La Regina, G.; Sansone, A.; Giordano, C.; Balzarini, J.; Maga, G.; Zanoli, S.; Samuele, A.; Cirilli, R.; La Torre, F.; Lavecchia, A.; Novellino, E.; Silvestri, R. Indolylarylsulfones bearing natural and unnatural amino acids. Discovery of potent inhibitors of HIV-1 non-nucleoside wild type and resistant mutant strains reverse transcriptase and coxsackie B4 virus. J. Med. Chem., 2009, 52, 1922-34.
131. La Regina, G.; Coluccia, A.; Brancale, A.; Piscitelli, F.; Gatti, V.; Maga, G.; Samuele, A.; Pannecouque, C.; Schols, D.; Balzarini, J.; Novellino, E.; Silvestri, R. Indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: new cyclic substituents at indole-2- carboxamide. J. Med. Chem., 2011, 54, 1587-98.
132. La Regina, G.; Coluccia, A.; Brancale, A.; Piscitelli, F.; Famiglini, V.; Cosconati, S.; Maga, G.; Samuele, A.; Gonzalez, E.; Clotet, B.; Schols, D.; Esté, J.A.; Novellino, E.; Silvestri, R. New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors. J. Med. Chem., 2012, 55, 6634-8.
133. Samuele, A.; Kataropoulou, A.; Viola, M.; Zanoli, S.; La Regina, G.; Piscitelli, F.; Silvestri, R.; Maga, G. Non-nucleoside HIV-1 reverse transcriptase inhibitors di-halo-indolyl aryl sulfones achieve tight binding to drug-resistant mutants by targeting the enzyme-substrate complex. Antiviral Res., 2009, 81, 47-55.
134. Hassam, M.; Basson, A.E.; Liotta, D.C.; Morris, Lynn.; van Otterlo, W.A.L..; Pelly, S.C. Novel cyclopropyl-indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors. ACS Med. Chem. Lett., 2012, 3, 470-475.
135. Monforte, A.M.; Logoteta, P.; De Luca, L.; Iraci, N.; Ferro, S.; Maga, G.; De Clercq, E.; Pannecouque, C.; Chimirri, A. Novel 1,3- dihydro- benzimidazol-2-ones and their analogues as potent nonnucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2010, 18, 1702-10.
136. Samuele, A.; Crespan, E.; Vitellaro, S.; Monforte, A.M.; Logoteta, P.; Chimirri, A.; Maga, G. Slow binding-tight binding interaction between benzimidazol-2-one inhibitors and HIV-1 reverse transcriptase containing the lysine 103 to asparagine mutation. Antiviral Res., 2010, 86, 268-75.
137. Monforte, A.M.; Logoteta, P.; Ferro, S.; De Luca, L.; Iraci, N.; Maga, G.; Clercq, E.D.; Pannecouque, C.; Chimirri, A. Design, synthesis, and structure-activity relationships of 1,3-dihydrobenzimidazol-2- one analogues as anti-HIV agents. Bioorg. Med. Chem., 2009, 17, 5962-7.
138. Cheng, P.; Gu, Q.; Liu, W.; Zou, J.F.; Ou, Y.Y.; Luo, Z.Y.; Zeng, J.G. Synthesis of quinolin-2-one alkaloid derivatives and their inhibitory activities against HIV-1 reverse transcriptase. Molecules, 2011, 16, 7649-61.
139. Xu, B.; Sun, Y.; Guo, Y.; Cao, Y.; Yu, T. Synthesis and biological evaluation of N4-(hetero)arylsulfonylquinoxalinones as HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2009, 17, 2767-74.
140. Ran, J.Q.; Huang, N.; Xu, H.; Yang, L.M.; Lv, M.; Zheng, Y.T. Anti HIV-1 agents 5: synthesis and anti-HIV-1 activity of some Narylsulfonyl- 3-acetylindoles in vitro. Bioorg. Med. Chem. Lett., 2010, 20, 3534-6.
141. Tian, Y.; Zhan, P.; Rai, D.; Zhang, J.; De Clercq, E.; Liu, X. Recent advances in the research of 2,3-diaryl-1,3-thiazolidin-4-one derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr. Med. Chem., 2012, 19, 2026-37.
142. Murugesan, V.; Tiwari, V.S.; Saxena, R.; Tripathi, R.; Paranjape, R.; Kulkarni, S.; Makwana, N.; Suryawanshi, R.; Katti, S.B. Lead optimization at C-2 and N-3 positions of thiazolidin-4-ones as HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2011, 19, 6919-26.
143. Ravichandran, V.; Jain, A.; Kumar, K.S.; Rajak, H.; Agrawal, R.K. Design, synthesis, and evaluation of thiazolidinone derivatives as antimicrobial and anti-viral agents. Chem. Biol. Drug Des., 2011, 78, 464-70.
144. Li, X.; Zhan, P.; De Clercq, E.; Liu, X. The HIV-1 non-nucleoside reverse transcriptase inhibitors (part V): capravirine and its analogues. Curr. Med. Chem., 2012, 19, 6138-49.
145. Mowbray, C.E.; Burt, C.; Corbau, R.; Perros, M.; Tran, I.; Stupple, P.A.; Webster, R.; Wood, A. Pyrazole NNRTIs 1: design and initial optimisation of a novel template. Bioorg. Med. Chem. Lett., 2009, 19, 5599-5602.
146. (b) Mowbray, C.E.; Corbau, R.; Hawes, M.; Jones, L.H.; Mills, J.E.; Perros, M.; Selby, M.D.; Stupple, P.A.; Webster, R.; Wood, A. Pyrazole NNRTIs 3: optimisation of physicochemical properties. Bioorg. Med. Chem. Lett., 2009, 19, 5603-5606.
147. (c) Mowbray, C.E.; Burt, C.; Corbau, R.; Gayton, S.; Hawes, M.; Perros, M.; Tran, I.; Price, D.A.; Quinton, F.J.; Selby, M.D.; Stupple, P.A.; Webster, R.; Wood, A. Pyrazole NNRTIs 4: selection of UK-453,061 (lersivirine) as a development candidate. Bioorg. Med. Chem. Lett., 2009, 19, 5857-5860.
148. Fätkenheuer, G.; Staszewski, S.; Plettenburg, A.; Hackman, F.; Layton, G.; McFadyen, L.; Davis, J.; Jenkins, T.M. Activity, pharmacokinetics and safety of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, during 7-day monotherapy in HIV-1-infected patients. AIDS, 2009, 23, 2115-22.
149. Corbau, R.; Mori, J.; Phillips, C.; Fishburn, L.; Martin, A.; Mowbray, C.; Panton, W.; Smith-Burchnell, C.; Thornberry, A.; Ringrose, H.; Knöchel, T.; Irving, S.; Westby, M.; Wood, A.; Perros, M. Lersivirine: a non-nucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus-1. Antimicrob. Agents Chemother., 2010, 54, 4451-63.
150. (a) Nugent, R.A.; Schlachter, S.T.; Murphy, M.J.; Cleek, G.J.; Poel, T.J.; Wishka, D.G.; Graber, D.R.; Yagi, Y.; Keiser, B.J.; Olmsted, R.A.; Kopta, L.A.; Swaney, S.M.; Poppe, S.M.; Morris, J.; Tarpley, W.G.; Thomas, R.C. Pyrimidine thioethers: a novel class of HIV-1 reverse transcriptase inhibitors with activity against BHAPresistant HIV. J. Med. Chem., 1998, 41, 3793-803.
151. Althaus, I. W.; Chou, K.-C.; Lemay, R. J.; Franks, K. M.; Deibel, M. R.; Kezdy, F. J.; Resnick, L.; Busso, M. E.; So, A. G.; Downey, K. M.; Romero, D. L.; Thomas, R. C.; Aristoff, P. A.; Tarpley, W. G.; Reusser, F. The benzylthio-pyrimidine U-31, 355, a potent inhibitor of HIV-1 reverse transcriptase. Biochem. Pharmacol., 1996, 51, 743-750.
152. Boyer, J.; Arnoult, E.; Médebielle, M.; Guillemont, J.; Unge, J.; Jochmans, D. Difluoromethylbenzoxazole pyrimidine thioether derivatives: a novel class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors. J. Med. Chem., 2011, 54, 7974-85.
153. Elleder, D.; Baiga, T.J.; Russell, R.L.; Naughton, J.A.; Hughes, S.H.; Noel, J.P.; Young, J.A. Identification of a 3-aminoimidazo[ 1.;2-a]pyridine inhibitor of HIV-1 reverse transcriptase. Virol. J., 2012, 9, 305.
154. Chen, H.; Yang, T.; Wei, S.; Zhang, H.; Li, R.; Qin, Z.; Li, X. Synthetic bicyclic iminosugar derivatives fused thiazolidin-4-one as new potential HIV-RT inhibitors. Bioorg. Med. Chem. Lett., 2012, 22, 7041-4.
155. Mokale, S.N.; Lokwani, D.; Shinde, D.B. Synthesis, biological activity and docking study of imidazol-5-one as novel nonnucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem., 2012, 20, 3119-27.
156. Romeo, R.; Giofrè, S.V.; Macchi, B.; Balestrieri, E.; Mastino, A.; Merino, P.; Carnovale, C.; Romeo, G.; Chiacchio, U. Truncated reverse isoxazolidinyl nucleosides: a new class of allosteric HIV-1 reverse transcriptase inhibitors. ChemMedChem, 2012, 7, 565-9.
157. Xue, H.; Lu, X.; Zheng, P.; Liu, L.; Han, C.; Hu, J.; Liu, Z.; Ma, T.; Li, Y.; Wang, L.; Chen, Z.; Liu, G. Highly suppressing wildtype HIV-1 and Y181C mutant HIV-1 strains by 10-chloromethyl- 11-demethyl-12-oxo-calanolide A with druggable profile. J. Med. Chem., 2010, 53, 1397-401.
158. (b) Lu, X.; Liu, L.; Zhang, X.; Lau, T.C.; Tsui, S.K.; Kang, Y.; Zheng, P.; Zheng, B.; Liu, G.; Chen, Z. F18, a novel small-molecule nonnucleoside reverse transcriptase inhibitor, inhibits HIV-1 replication using distinct binding motifs as demonstrated by resistance selection and docking analysis. Antimicrob. Agents Chemother., 2012, 56, 341-51.
159. Zhou, T.; Shi, Q.; Chen, C.H.; Zhu, H.; Huang, L.; Ho, P.; Lee, K.H. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2',2'- dimethyldihydropyranochromone (DCP) analogs as potent anti- HIV agents. Bioorg. Med. Chem., 2010, 18, 6678-89.
160. (b) Xu, S.Q.; Yan, X.; Chen, Y.; Xia, P.; Qian, K.; Yu, D.; Xia, Y.; Yang, Z.Y.; Morris-Natschke, S.L.; Lee, K.H. Anti-AIDS agents 84. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2'- monomethyl-4-methyl- and 1'-thia-4-methyl-(3'R,4'R)-3',4'-di-O- (S)-camphanoyl-(+)-cis-khellactone (DCK) analogs. Bioorg. Med. Chem., 2010, 18, 7203-11.
161. Cullen, M.D.; Ho, W.C.; Bauman, J.D.; Das, K.; Arnold, E.; Hartman, T.L.; Watson, K.M.; Buckheit, R.W.; Pannecouque, C.; De Clercq, E.; Cushman, M. Crystallographic study of a novel subnanomolar inhibitor provides insight on the binding interactions of alkenyldiarylmethanes with human immunodeficiency virus-1 reverse transcriptase. J. Med. Chem., 2009, 52, 6467-73.
162. Das, K.; Bauman, J.D.; Rim, A.S.; Dharia, C.; Clark AD, Jr.; Camarasa, M.J.; Balzarini, J.; Arnold, E. Crystal structure of tertbutyldimethylsilyl- spiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket. J. Med. Chem., 2011, 54, 2727-37.
163. Weitman, M.; Lerman, K.; Nudelman, A.; Major, D.T.; Hizi, A.; Herschhorn, A. Structure - activity relationship studies of 1-(4- chloro-2,5- dimethoxyphenyl)-3-(3-propoxypropyl)thiourea, a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type-1. Eur. J. Med. Chem., 2011, 46, 447-67.
164. Ekkati, A.R.; Bollini, M.; Domaoal, R.A.; Spasov, K.A.; Anderson, K.S.; Jorgensen, W.L. Discovery of dimeric inhibitors by extension into the entrance channel of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett., 2012, 22, 1565-8.
165. (b) Jorgensen, W.L.; Bollini, M.; Thakur, V.V.; Domaoal, R.A.; Spasov, K.A.; Anderson, K.S. Efficient discovery of potent anti-HIV agents targeting the Tyr181Cys variant of HIV reverse transcriptase. J. Am. Chem. Soc., 2011, 133, 15686-96.
166. (c) Bollini, M.; Gallardo-Macias, R.; Spasov, K.A.; Tirado-Rives, J.; Anderson, K.S.; Jorgensen, W.L. Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency. Bioorg. Med. Chem. Lett., 2013, 23, 1110-3.
167. (d) Leung, C.S.; Zeevaart, J.G.; Domaoal, R.A.; Bollini, M.; Thakur, V.V.; Spasov, K.A.; Anderson. K.S.; Jorgensen WL. Eastern extension of azoles as nonnucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives. Bioorg. Med. Chem. Lett., 2010, 20, 2485-8.
168. Maga, G.; Radi, M.; Gerard, M.A.; Botta, M.; Ennifar, E. HIV-1 RT inhibitors with a novel mechanism of action: NNRTIs that compete with the nucleotide substrate. Viruses, 2010, 2, 880-99.
169. Jegede, O.; Khodyakova, A.; Chernov, M.; Weber, J.; Menéndez- Arias, L.; Gudkov, A.; Quiñones-Mateu, M.E. Identification of low-molecular weight inhibitors of HIV-1 reverse transcriptase using a cell-based high-throughput screening system. Antiviral Res., 2011, 91, 94-8.
170. Ehteshami, M.; Nijhuis, M.; Bernatchez, J.A.; Ablenas, C.J.; Mc-Cormick, S.; de Jong, D.; Jochmans, D.; Götte, M. Formation of a quaternary complex of HIV-1 reverse transcriptase with a nucleotide- competing inhibitor and its ATP enhancer. J. Biol. Chem., 2013 [Epub ahead of print].
171. Tremblay, M.; Bethell, R.C.; Cordingley, M.G.; Deroy, P.; Duan, J.; Duplessis, M.; Edwards, P.J.; Faucher, A.M.; Halmos, T.; James, C.A.; Kuhn, C.; Lacoste, J.É.; Lamorte, L.; Laplante, S.R.; Malenfant, E.; Minville, J.; Morency, L.; Morin, S.; Rajotte, D.; Salois, P.; Simoneau, B.; Tremblay, S.; Sturino, C.F. Identification of benzofurano[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide- competing reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 2013, 23, 2775-80.
172. James, C.A.; Deroy, P.; Duplessis, M.; Edwards, P.J.; Halmos, T.; Minville, J.; Morency, L.; Morin, S.; Simoneau, B.; Tremblay, M.; Bethell, R.; Cordingley, M.; Duan, J.; Lamorte, L.; Pelletier, A.; Rajotte, D.; Salois, P.; Tremblay, S.; Sturino, C.F. Nucleotide competing reverse transcriptase inhibitors: Discovery of a series of non-basic benzofurano[ 3,2-d]pyrimidin-2- one derived inhibitors. Bioorg. Med. Chem. Lett., 2013, 23, 2781-6.
173. (c) Rajotte, D.; Tremblay, S.; Pelletier, A.; Salois, P.; Bourgon, L.; Coulombe, R.; Mason, S.; Lamorte, L.; Sturino, C.; Bethell, R. Identification and characterization of a novel HIV-1 nucleotide competing RT inhibitor series. Antimicrob. Agents Chemother., 2013, 57, 2712-8.