Dihydro-alkoxyl-benzyl-oxopyrimidine derivatives (DABOs) as non-nucleoside reverse transcriptase inhibitors: An update review (2001-2011)

Current Medicinal Chemistry

Volumn 19, Issue 2, 2012, Pages 152-162

  Yang, Shiqiong ^a   Chen, Fen Er ^a   De Clercq, Erik ^b  

^a FUDAN UNIVERSITY   (China)

^b REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

DABOs; Drug resistance mutations; HIV 1; HIV 2; NNRTIs; RT

Indexed keywords

1 [(2 HYDROXYETHOXY)METHYL] 6 (PHENYLTHIO)THYMINE; DELAVIRDINE; DIDANOSINE; DIHYDRO ALKOXYL BENZYL OXOPYRIMIDINE DERIVATIVE; EFAVIRENZ; ETRAVIRINE; LAMIVUDINE; NEVIRAPINE; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; PYRIMIDINE DERIVATIVE; RILPIVIRINE; RNA DIRECTED DNA POLYMERASE; STAVUDINE; UNCLASSIFIED DRUG; ZIDOVUDINE;

CHEMICAL MODIFICATION; CYTOTOXICITY; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; ENZYME STRUCTURE; REVIEW; STRUCTURE ACTIVITY RELATION; VIRUS REPLICATION;

EID: 84863231119     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986712803414169     Document Type: Review

References (65)

1. http://www.aids-prevention.info/facts-about-aids/ (Accessed May 15, 2011
2. WHO/UNAIDS AIDS Epidemic Update. December 2009 (Accessed May 15, 2011
3. Darke, P.L.; Huff, J.R. HIV protease as an inhibitor target for the treatment of AIDS. Adv. Pharmacol. (San Diego, Calif.), 1994, 25, 399-454.
4. De Clercq, E.; Neyts, J. Antiviral agents acting as DNA or RNA chain terminators. Handb. Exp. Pharmacol., 2009, 189, 53-84.
5. Öberg, B. Rational design of polymerase inhibitors as antiviral drugs. Antiviral Res., 2006, 71, 90-95. (Pubitemid 44223772)
6. De Clercq, E. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Past, present, and future. Chem. & Biodiversity, 2004, 1, 44-64.
7. Menéndez-Arias, L. Mechanisms of resistance to nucleoside analog inhibitors of HIV-1 reverse transcriptase. Virus Res., 2008, 134, 124-146.
8. Wensing, A.M.J.; van Maarseveen, N.M.;Nijhuis, M. Fifteen years of HIV protease inhibitors: Raising the barrier to resistance. Antiviral Res., 2010, 85, 59-74.
9. Carvalho, A.P.; Fernandes, P.A.; Ramos, M.J. Molecular insights into the mechanisms of HIV-1 reverse transcriptase resistance to nucleoside analogs. Mini-Rev. Med. Chem., 2006, 6, 549-555.
10. 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.
11. Zhan, P.; Chen, X.; Li, Do.; Fang, Z.; De Clercq, E.; Liu, X. HIV-1 NNRTIs: Structural diversity, pharmacophore similarity, and implications for drug design. Med. Res. Rev., 2011, doi:10.1002/med.20241.
12. Sluis-Cremer, N.; Tachedjian, G. Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res., 2008, 134, 147-156.
13. Sahlberg, C.; Zhou, X.-X. Development of non-nucleoside reverse transcriptase inhibitors for anti-HIV therapy. Anti-infective Agents Med Chem., 2008, 7, 101-117. (Pubitemid 351761450)
14. D'Cruz, O.J.; Uckun, F.M. Novel tight binding PETT, HEPT and DABObased non-nucleoside inhibitors of HIV-1 reverse transcriptase. J. Enzyme Inhib. Med. Chem., 2006, 21, 329-350. (Pubitemid 44355782)
15. Camarasa, M.J.; Velazquez, S.; San-Felix, A.; Perez-Perez, M.J.; Bonache, M.C.; De Castro, S. TSAO derivatives, inhibitors of HIV-1 reverse transcriptase dimerization: Recent progress. Curr. Pharm. Des., 2006, 12, 1895-1907.
16. Lv, M.; Xu, H. Dipyridodiazepinone analogs as human immunodeficiency virus type 1-specific non-nucleoside reverse transcriptase inhibitors: An overview. Curr. Med. Chem., 2010, 17, 1874-1898.
17. Xu, H. Progress of bis(heteroaryl)piperazines (BHAPs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) against human immunodeficiency virus type 1 (HIV-1). Mini-Rev. Med. Chem., 2010, 10, 62-72.
18. Botta, M.; Artico M.; Massa, S.; Gambacorta, A.; Marongiu, M. E.; Pani, A.; La Colla, P. Synthesis, antimicrobial and antiviral activities of isotrimethoprim and some related derivatives. Eur. J. Med. Chem., 1992, 27, 251-257.
19. Marongiu, M.E.; Pani, A.; Musiu, C.; La Colla, P.; Mai, A.; Sbardella, G.; Massa, S.; Artico, M. 3,4-Dihydro-2-alkoxy-6-benzyl-oxopyrimidines [DABO]: Development of a potent class of non-nucleoside reverse transcriptase inhibitors. Recent Res. Dev. Med. Chem., 2001, 1, 65-92.
20. Artico, M.; Istituto, P.; Fondazione, C.B. Selected non-nucleoside reverse transcriptase inhibitors: The DABOs family. Drugs Future, 2002, 27, 159-175. (Pubitemid 34475137)
21. Meng, G.; Chen, F.-E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Nonnucleoside HIV-1 reverse transcriptase inhibitors: Part I. Synthesis and structure-activity relationship of 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils as HEPT analogs. Chem. Pharm. Bull., 2003, 51, 779-789. (Pubitemid 41694779)
22. He, Y.-P.; Chen, F.-E.; Sun, G.-F.; Wang, Y.-P.; De Clercq, E.; Balzarini, J.; Pannecouque, C. 5-Alkyl-2-[(aryl and alkyloxylcarbonylmethyl) thio]-6-(1-naphthylmethyl) pyrimidin-4(3H)-ones as an unique HIV reverse transcriptase inhibitors of S-DABO series. Bioorg. Med. Chem. Lett., 2004, 14, 3173-3176. (Pubitemid 38624587)
23. Sun, G.-F. Kuang, Y.-Y.; Chen, F.-E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Non-nucleoside HIV reverse transcriptase inhibitors, Part 6[1]: Synthesis and anti-HIV activity of novel 2-[(arylcarbonylmethyl)thio]-6-arylthio DABO analogs. Arch. Pharm. Chem. Life Sci., 2005, 338, 457-461. (Pubitemid 41564255)
24. Ji, L.; Chen, F.-E.; Xie, B.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Synthesis and anti-HIV activity evaluation of 1-[(alkenyl or alkynyl or alkyloxy)methyl]-5-alkyl-6-(1-naphthoyl)-2,4-pyrimidinediones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur. J. Med. Chem., 2007, 42, 198-204. (Pubitemid 46282232)
25. Ji, L.; Chen, F.-E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Synthesis and anti-HIV-1 activity evaluation of 5-alkyl-2-alkylthio-6- (arylcarbonyl or α-cyanoarylmethyl)-3,4-dihydropyrimidin-4(3H)-ones as novel nonnucleoside HIV-1 reverse transcriptase inhibitors. J. Med. Chem., 2007, 50, 1778-1786. (Pubitemid 46626589)
26. Wang, Y.-P.; Chen, F.-E.; Balzarini, J.; De Clercq, E.; Pannecouque, C. Nonnucleoside HIV-1 reverse-transcriptase inhibitors. Part 10. Synthesis and anti-HIV activity of 5-alkyl-6-(1-naphthylmethyl)pyrimidin-4(3H)-ones with a mono-or disubstituted 2-amino function as novel 'dihydro-alkoxy- benzyloxopyrimidine' (DABO) analogs. Chem. & Biodiversity., 2008, 5, 168-176. (Pubitemid 351201004)
27. Wang, Y.-P.; Chen, F.-E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Synthesis and in vitro anti-HIV evaluation of a new series of 6-arylmethylsubstituted S-DABOs as potential non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur. J. Med. Chem., 2009, 44, 1016-1023.
28. Nawrozkij, M.B.; Rotili, D.; Tarantino, D.; Botta, G.; Eremiychuk, A.S.; Musmuca, I.; Ragno, R.; Samuele, A.; Zanoli, S.; Armand-Ugón, M.; Clotet-Codina, I.; Novakov, I.A.; Orlinson, B.S.; Maga, G.; Esté, J.A.; Artico, M.; Mai, A. 5-Alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin- 4(3H)-ones, a series of anti-HIV-1 agents of the dihydro-alkoxy- benzyloxopyrimidine family with peculiar structure-activity relationship profile. J. Med. Chem., 2008, 51, 4641-4652.
29. Bartolini, S.; Mai, A.; Artico, M.; Paesano, N.; Rotili, D.; Spadafora, C.; Sbardella, G. 6-[1-(2,6-Difluorophenyl)ethyl]pyrimidinones antagonize cell proliferation and induce cell differentiation by inhibiting (a nontelomeric) endogenous reverse transcriptase. J. Med. Chem., 2005, 48, 6776-6778. (Pubitemid 41533097)
30. Mai, A.; Artico, M.; Rotili, D.; Tarantino, D.; Clotet-Codina, I.; Armand-Ugón, M.; Ragno, R.; Simeoni, S.; Sbardella, G.; Nawrozkij, M.B.; Samuele, A.; Maga, G.; Esté, J.A. Synthesis and biological properties of novel 2-aminopyrimidin-4(3H)-ones highly potent against HIV-1 mutant strains. J. Med. Chem., 2007, 50, 5412-5424. (Pubitemid 350057851)
31. Sarafianos, S.G.; Das, K.; Tantillo, C.; Clark Jr., A.D.; Ding, J.; Whitcomb, J.M.; Boyer, P.L.; Hughes, S.H.; Arnold, E. Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. EMBO J., 2001, 20, 1449-1461. (Pubitemid 32233984)
32. di Marzo Veronese, F.; Copeland, T.D.; DeVico, A.L.; Rahman, R.; Oroszlan, S.; Gallo, R.C.; Sarngadharan, M.G. Characterization of highly immunogenic p66/p51 as the reverse transcriptase of HTLV-III/LAV. Science, 1986, 231, 1289-1291. (Pubitemid 16036733)
33. Lowe, D.M.; Aitken, A.; Bradley, C.; Darby, G.K.; Larder, B.A.; Powell, K.L. HIV-1 reverse transcriptase: Crystallization and analysis of domain structure by limited proteolysis. Biochemistry, 1988, 27, 8884-8889. (Pubitemid 19021270)
34. 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.
35. Gopalakrishnan, V.; Peliska, J.A.; Benkovic, S.J. Human immunodeficiency virus type 1 reverse transcriptase: Spatial and temporal relationship between the polymerase and RNase H activities. Proc. Natl. Acad. Sci. USA, 1992, 89, 10763-10767.
36. Chiu, T.K.; Davies, D.R. Structure and function of HIV -1 integrase. Curr. Top. Med. Chem., 2004, 4, 965-977.
37. Ren, J.; Milton, J.; Weaver, K.L.; Short, S.A.; Stuart, D.I.; Stammers, D.K. Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. Structure, 2000, 8, 1089-1094. (Pubitemid 32667472)
38. Smerdon, S.J.; Jager, J.; Wang, J.; Kohlstaedt, L.A.; Chirino, A.J.; Friedman, J.M.; Rice, P. A.; Steitz, T.A. Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA, 1994, 91, 3911-3915. (Pubitemid 24139542)
39. Schafer, W.; Friebe, W.G.; Leinert, H.; Mertens, A.; Poll, T.; von der Saal, W.; Zilch, H.; Nuber, B.; Ziegler, M.L. Non-nucleoside inhibitors of HIV-1 reverse transcriptase: Molecular modeling and X-ray structure investigations. J. Med. Chem., 1993, 36, 726-732. (Pubitemid 23105726)
40. Hogberg, M.; Sahlberg, C.; Engelhardt, P.; Noreen, R.; Kangasmetsa, J.; Johansson, N.G.; Oberg, B.; Vrang, L.; Zhang, H.; Sahlberg, B.L.; Unge, T.; Lovgren, S.; Fridborg, K.; Backbro, K. Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3. Synthesis and further structure-activity relationship studies of PETT analogs. J. Med. Chem., 1999, 42, 4150-4160. (Pubitemid 29483032)
41. Esnouf, R.; Ren, J.-S.; Ross, C.; Jones, Y.; Stammers, D.; Stuart, D. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat. Struct. Biol., 1995, 2, 303-308.
42. de Brito M.A.; Rodrigues, C.R.; Cirino, J.J.V.; de Alencastro, R.B.; Castro,H.C.; Albuquerque, M.G. 3D-QSAR CoMFA of a series of DABO derivatives as HIV-1 reverse transcriptase non-nucleoside inhibitors. J. Chem. Inf. Model., 2008, 48, 1706-1715.
43. Radi, M.; Maga, G.; Alongi, M.; Angeli, L.; Samuele, A.; Zanoli, S.; Bellucci, L.; Tafi, A.; Casaluce, G.; Giorgi, G.; Armand-Ugón, M.; Gonzalez, E.; Esté, J.A; Baltzinger, M.; Bec, G.; Dumas, P.; Ennifar, E.; Botta, M. Discovery of chiral cyclopropyl dihydro-alkylthio-benzyloxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants. J. Med. Chem., 2009, 52, 840-851.
44. Spence, R. A.; Kati, W. M.; Anderson, K. S.; Johnson, K. A. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science, 1995, 267, 988-993.
45. Xia, Q.; Radzio, J.; Anderson, K.S.; Sluis-Cremer, N. Probing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analyses. Protein Sci., 2007, 16, 1728-1737. (Pubitemid 47195699)
46. Basavapathruni, A.; Bailey, C.M.; Anderson, K.S. Defining a molecular mechanism of synergy between nucleoside and nonnucleoside AIDS drugs. J Biol. Chem., 2004, 279, 6221-6224. (Pubitemid 38248754)
47. Cruchaga, C.; Odriozola, L.; Andreola, M.; Tarrago-Litvak, L.; Martinez-Irujo, J.J. Inhibition of phosphorolysis catalyzed by HIV-1 reverse transcriptase is responsible for the synergy found in combinations of 3'-azido-3'-deoxythymidine with nonnucleoside inhibitors. Biochemistry, 2005, 44, 3535-3546. (Pubitemid 40322023)
48. Radzio, J.; Sluis-Cremer, N. Efavirenz accelerates HIV-1 reverse transcriptase ribonuclease H cleavage, leading to diminished zidovudine excision. Mol. Pharmacol., 2008, 73, 601-606. (Pubitemid 351159228)
49. D'Cruz, O. J.; Uckun, F. M. Dawn of non-nucleoside inhibitor-based anti-HIV microbicides. J. Antimicrob. Chemother., 2006, 57, 411-423. (Pubitemid 43240192)
50. Blanca, G.; Baldanti, F.; Paolucci, S.; Skoblov, A.Y.; Victorova, L.; Hubscher, U.; Gerna, G.; Spadari, S.; Maga, G. Nevirapine resistance mutation at codon 181 of the HIV-1 reverse transcriptase confers stavudine resistance by increasing nucleotide substrate discrimination and phosphorolytic activity. J. Biol. Chem., 2003, 278, 15469-15472. (Pubitemid 36799653)
51. De Clercq, E. The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res., 1998, 38, 153-179. (Pubitemid 29065480)
52. Condra, J.H.; Emini, E.A.; Gotlib, L.; Graham, D.J.; Schlabach, A.J.; Wolfgang, J.A.; Colonno, R.J.; Sardana, V.V. Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors. Antimicrob. Agents Chemother., 1992, 36, 1441-1446.
53. Manetti, F.; Esté, J.A.; Clotet-Codina, I.; Armand-Ugón, M.; Maga, G.; Crespan, E.; Cancio, R.; Mugnaini, C.; Bernardini, C.; Togninelli, A.; Carmi, C.; Alongi, M.; Petricci, E.; Massa, S.; Corelli, F.; Botta, M. Parallel solution-phase and microwave-assisted synthesis of new S-DABO derivatives endowed with subnanomolar anti-HIV-1 activity. J. Med. Chem., 2005, 48, 8000-8008. (Pubitemid 41798430)
54. Mugnaini, C.; Manetti, F.; Esté, J.A.; Clotet-Codina, I.; Maga, G.; Cancio, R.; Botta, M.; Corelli, F. Synthesis and biological investigation of S-aryl-SDABO derivatives as HIV-1 inhibitors. Bioorg. Med. Chem. Lett., 2006, 16, 3541-3544. (Pubitemid 43777090)
55. Yu, M.-Y.; Li, Z.-Y; Liu, S.; Fan, E.-K; Pannecouque, C.; De Clercq, E.; Liu, X.-Y. Synthesis and biological evaluation of 6-substituted 5-alkyl-2-(phenylaminocarbonylmethylthio)pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs. ChemMedChem, 2011, 6, 826-833.
56. Denmark, S.E.; Edwards, J.P. A comparison of (chloromethyl)-and (iodomethyl)zinc cyclopropanation reagents. J. Org. Chem., 1991, 56, 6974-6981.
57. Denmark, S.E.; O'Connor, S.P. Enantioselective cyclopropanation of allylic alcohols. The effect of zinc iodide. J. Org. Chem., 1997, 62, 3390-3401.
58. Mugnaini, C.; Alongi, M.; Togninelli, A.; Gevariya, H.; Brizzi, A.; Manetti, F.; Bernardini, C.; Angeli, L.; Tafi, A.; Bellucci, L.; Corelli, F.; Massa, S.; Maga, G.; Samuele, A.; Facchini, M.; Clotet-Codina, I.; Armand-Ugón, M.; Esté, J. A.; Botta, M. Dihydro-alkylthio- benzyloxopyrimidines as inhibitors of reverse transcriptase: Synthesis and rationalization of the biological data on both wild-type enzyme and relevant clinical mutants. J. Med. Chem., 2007, 50, 6580-6595. (Pubitemid 350309097)
59. Qin, H.; Liu, C.; Zhang, J.-F.; Guo, Y.; Zhang, S.-W.; Zhang, Z.-L.; Wang, X.-W.; Zhang, L.-R.; Liu, J.-Y. Synthesis and biological evaluation of novel 2-arylalkylthio-4-amino-6-benzyl pyrimidines as potent HIV-1 nonnucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 2010, 20, 3003-3005.
60. Rotili, D.; Tarantino, D.; Artico, M.; Nawrozkij, M. B.; Gonzalez-Ortega, E.; Clotet, B.; Samuele, A.; Esté, J. A.; Maga, G.; Mai, A. Diarylpyrimidinedihydrobenzyloxopyrimidine hybrids: New, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level. J. Med. Chem., 2011, 54, 3091-3096.
61. Qin, H.; Liu, C.; Guo, Y.; Wang, R.-P.; Zhang, J.-F.; Ma, L.-Y.; Zhang, Z.-L.; Wang, X.W; Cui, Y.-X.; Liu, J.-Y. Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 2010, 18, 3231-3237.
62. Radi, M.; Contemori, L.; Castagnolo, D.; Spinosa, R.; Esté, J. A.; Massa, S.; Botta, M. A versatile route to C-6 arylmethyl-functionalized S-DABO and related analogs. Org. Lett., 2007, 9, 3157-3160.
63. 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/alkylsulfanyl-cyclohexylmethyloxopyrimidines (S-DACOs) as high active anti-HIV agents. Bioorg. Med. Chem. Lett., 2011, 21, 694-697.
64. Zhang J.; Zhan P.; Wu J.-D; Li Z.-Y; Jiang Y.; Ge W.-Y.; Pannecouque Christophe; De Clercq Erik; Liu X.-Y. 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, 4366-4376.
65. Rao, Z.-K.; Long, J.; Li, C.; Zhang, S.-S.; He, M.; Ou, L.-C.; Zheng, Y.-T.; He, Y.-P. Synthesis and anti-HIV-1 activity of Sdihydro( alkyloxy)benzyloxypyrimidine derivatives. Monatsh. Chem., 2008, 139, 967-974.