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

Journal of Medicinal Chemistry

Volumn 55, Issue 5, 2012, Pages 2242-2250

  Wang, Xiaowei ^a   Zhang, Jianfang ^d   Huang, Yang ^c   Wang, Ruiping ^d   Zhang, Liang ^a   Qiao, Kang ^a   Li, Li ^a   Liu, Chang ^d   Ouyang, Yabo ^c   Xu, Weisi ^c   Zhang, Zhili ^a   Zhang, Liangren ^b   Shao, Yiming ^c   Jiang, Shibo ^e   Ma, Liying ^c   Liu, Junyi ^a,b  

^a School of Pharmaceutical Sciences   (China)

^b PEKING UNIVERSITY   (China)

^c CHINESE CENTER FOR DISEASE CONTROL AND PREVENTION   (China)

^d CAPITAL MEDICAL UNIVERSITY   (China)

^e FUDAN UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

1 [(2 BENZYLOXYL)METHYL] 5 IODO 6 ARYLURACIL; 1 BENZYLOXYMETHYL 6 (3,5 DIMETHYLBENZYL) 5 IODOURACIL; 6 (3,5 DIFLUOROBENZYL) 1 BENZYLOXYMETHYL 5 IODOURACIL; 6 (3,5 DIMETHYLBENZYL) 1 BENZYLOXYMETHYL 5 BROMOURACIL; 6 (3,5 DIMETHYLBENZYL) 1 ETHOXYMETHYL 5 IODOURACIL; 6 (ARYLMETHYL) 1 ALKYL 5 DIMETHYLAMINOURACIL; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; HALOGEN; NEVIRAPINE; RNA DIRECTED DNA POLYMERASE INHIBITOR; TNK 651; UNCLASSIFIED DRUG;

ARTICLE; BIOLOGICAL ACTIVITY; CONTROLLED STUDY; DRUG DESIGN; DRUG SYNTHESIS; HUMAN;

ANTI-HIV AGENTS; CELL LINE, TUMOR; DRUG DESIGN; DRUG RESISTANCE, VIRAL; HIV REVERSE TRANSCRIPTASE; HIV-1; HUMANS; HYDROGEN BONDING; MODELS, MOLECULAR; STRUCTURE-ACTIVITY RELATIONSHIP; URACIL;

EID: 84863290357     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm201506e     Document Type: Article

References (38)

1. Tronchet, J. M.; Seman, M. Nonnucleoside inhibitors of HIV-1 reverse transcriptase: from the biology of reverse transcription to molecular design Curr. Top. Med. Chem. 2003, 3, 1496-1511
2. Tarby, C. M. Recent advances in the development of next generation non-nucleoside reverse transcriptase inhibitors Curr. Top. Med. Chem. 2004, 4, 1045-1057
3. Sluis-Cremer, N.; Temiz, N. A.; Bahar, I. Conformational changes in HIV-1 reverse transcriptase induced by nonnucleoside reverse transcriptase inhibitor binding Curr. HIV Res. 2004, 2, 323-332
4. De Clercq, E. New developments in anti-HIV chemotherapy Biochim. Biophys. Acta 2002, 1587, 258-275
5. Ren, J.; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, I.; Keeling, J.; Darby, G.; Jones, Y.; Stuart, D.; Stammers, D. High resolution structures of HIV-1 RT from four RT-inhibitor complexes Nat. Struct. Biol. 1995, 2, 293-302
6. Esnouf, R.; Ren, J.; Ross, C.; Jones, Y.; Stammers, D.; Stuart, D. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors Nat. Struct. Biol. 1995, 2, 303-308
7. 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. U.S.A. 1994, 91, 3911-3915
8. Jonckheere, H.; Anne, J.; De Clercq, E. The HIV-1 reverse transcription (RT) process as target for RT inhibitors Med. Res. Rev. 2000, 20, 129-154
9. Das, K.; Clark, A. D., Jr.; Lewi, P. J.; Heeres, J.; de Jonge, M. R.; Koymans, L. M. H.; Vinkers, H. M.; Daeyaert, F.; Ludovici, D. W.; Kukla, M. J.; De Corte, B.; Kavash, R. W.; Ho, C. Y.; Ye, H.; Lichtenstein, M. A.; Andries, K.; Pauwels, R.; de Bethune, M.-P.; Boyer, P. L.; Clark, P.; Hughes, S. H.; Janssen, P. A. J.; Arnold, E. Roles of Conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug- resistant HIV-1 variants J. Med. Chem. 2004, 47, 2550-2560
10. Ding, J.; Das, K.; Tantillo, C.; Zhang, W.; Clark, A. J.; Jessen, S.; Lu, X.; Hsiou, Y.; Jacobo-Molina, A.; Andries, K.; Et, A. Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor alpha-APA R 95845 at 2.8 Å resolution Structure 1995, 3, 365-379
11. Ding, J.; Das, K.; Moereels, H.; Koymans, L.; Andries, K.; Janssen, P. A.; Hughes, S. H.; Arnold, E. Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors Nat. Struct. Biol. 1995, 2, 407-415
12. Esnouf, R. M.; Stuart, D. I.; De Clercq, E.; Schwartz, E.; Balzarini, J. Models which explain the inhibition of reverse transcriptase by HIV-1-specific (thio)carboxanilide derivatives Biochem. Biophys. Res. Commun. 1997, 234, 458-464
13. Coffin, J. M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy Science 1995, 267, 483-489
14. Ma, L.; Huang, J.; Xing, H.; Yuan, L.; Yu, X.; Sun, J.; Huang, Y.; Qu, S.; Feng, Y.; Liao, L.; Liu, S.; Shao, Y. Genotypic and phenotypic cross-drug resistance of harboring drug-resistant HIV type 1 subtype B′ strains from former blood donors in central Chinese provinces AIDS Res. Hum. Retroviruses 2010, 26, 1007-1013.10
15. Arnold, E.; Das, K.; Ding, J.; Yadav, P. N.; Hsiou, Y.; Boyer, P. L.; Hughes, S. H. Targeting HIV reverse transcriptase for anti-AIDS drug design: structural and biological considerations for chemotherapeutic strategies Drug Des. Discovery 1996, 13, 29-47
16. Ren, J.; Stammers, D. K. HIV reverse transcriptase structures: designing new inhibitors and understanding mechanisms of drug resistance Trends Pharmacol. Sci. 2005, 26, 4-7
17. Das, K.; Lewi, P. J.; Hughes, S. H.; Arnold, E. Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors Prog. Biophys. Mol. Biol. 2005, 88, 209-231
18. Ma, L.; Sun, J.; Xing, H.; Si, X.; Yuan, L.; Guo, Y.; Cheng, H.; Shao, Y. Genotype and phenotype patterns of drug-resistant HIV-1 subtype B′ (Thai B) isolated from patients failing antiretroviral therapy in China J. Acquired Immune Defic. Syndr. 2007, 44, 14-19
19. Baba, M.; De Clercq, E.; Tanaka, H.; Ubasawa, M.; Takashima, H.; Sekiya, K.; Nitta, I.; Umezu, K.; Nakashima, H.; Mori, S.; Et, A. Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 2356-2360
20. Campiani, G.; Ramunno, A.; Maga, G.; Nacci, V.; Fattorusso, C.; Catalanotti, B.; Morelli, E.; Novellino, E. Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: past, present, and future perspectives Curr. Pharm. Des. 2002, 8, 615-657
21. Baba, M.; Tanaka, H.; Miyasaka, T.; Yuasa, S.; Ubasawa, M.; Walker, R. T.; De Clercq, E. Hept derivatives: 6-Benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442) Nucleosides Nucleotides 1995, 14, 575-583
22. Sankatsing, S. U.; Weverling, G. J.; Peeters, M.; Van'T, K. G.; Gruzdev, B.; Rakhmanova, A.; Danner, S. A.; Jurriaans, S.; Prins, J. M.; Lange, J. M. TMC125 exerts similar initial antiviral potency as a five-drug, triple class antiretroviral regimen AIDS 2003, 17, 2623-2627
23. Hopkins, A. L.; Ren, J.; Esnouf, R. M.; Willcox, B. E.; Jones, E. Y.; Ross, C.; Miyasaka, T.; Walker, R. T.; Tanaka, H.; Stammers, D. K.; Stuart, D. I. Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors J. Med. Chem. 1996, 39, 1589-1600
24. Kireev, D. B.; Chretien, J. R.; Grierson, D. S.; Monneret, C. A 3D QSAR study of a series of HEPT analogues: the influence of conformational mobility on HIV-1 reverse transcriptase inhibition J. Med. Chem. 1997, 40, 4257-4264
25. Esnouf, R. M.; Ren, J.; Hopkins, A. L.; Ross, C. K.; Jones, E. Y.; Stammers, D. K.; Stuart, D. I. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 3984-3989
26. Mai, A.; Artico, M.; Sbardella, G.; Massa, S.; Novellino, E.; Greco, G.; Loi, A. G.; Tramontano, E.; Marongiu, M. E.; La Colla, P. 5-Alkyl-2-(alkylthio)- 6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3 H)-ones: novel potent and selective dihydro-alkoxy-benzyl-oxopyrimidine derivatives J. Med. Chem. 1999, 42, 619-627
27. Hannick, S. M.; Kishi, Y. An improved procedure for the Blaise reaction: a short, practical route to the key intermediates of the saxitoxin synthesis J. Org. Chem. 1983, 48, 3833-3835
28. Danel, K.; Larsen, E.; Pedersen, E. B. Easy synthesis of 5,6-disubstituted acyclouridine derivatives Synthesis 1995, 8, 934-936
29. Petersen, L.; Pedersen, E. B.; Nielsen, C. Three routes for the synthesis of 6-benzyl-1-ethoxymethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- carbaldehyde Synthesis 2001, 4, 559-564
30. Wamberg, M.; Pedersen, E. B.; Nielsen, C. Synthesis of furoannelated analogues of Emivirine (MKC-442) Arch. Pharm. (Weinheim) 2004, 337, 148-151
31. Danel, K.; Larsen, E.; Pedersen, E. B.; Vestergaard, B. F.; Nielsen, C. Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine J. Med. Chem. 1996, 39, 2427-2431
32. Muller, C. E.; Thorand, M.; Qurishi, R.; Diekmann, M.; Jacobson, K. A.; Padgett, W. L.; Daly, J. W. Imidazo[2,1- i ]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A(2A)- and A(3)-adenosine receptor antagonists J. Med. Chem. 2002, 45, 3440-3450
33. Elderfield, R.; Jesse, W. Application of the Mannich reaction with β,β-dichlorodiethylamine to derivatives of uracil J. Org. Chem. 1961, 26, 3042-3043
34. Sung, W. L. Synthesis of 4-(1,2,4-triazol-1-yl)-pyrimidin-2(1 H)-one ribonucleotide and its application in synthesis of oligoribonucleotides J. Org. Chem. 1982, 47, 3623-3628
35. Lavandera, I.; Fernández, S.; M., F.; Gotor, V. Novel and efficient syntheses of 3′,5′-diamino derivatives of 2′,3′,5′-trideoxycytidine and 2′,3′,5′- trideoxyadenosine. Protonation behavior of 3′,5′-diaminonucleosides Tetrahedron 2003, 59, 5449-5456
36. Evelina, C.; Antonella, C.; Liguori, A.; Napoli, A.; Siciliano, C.; Sindona, G. Simple and efficient routes for the preparation of isoxazolidinyl nucleosides containing cytosine and 5-methyl-cytosine as new potential anti-HIV drugs Tetrahedron 2001, 57, 8551-8557
37. Lu, X.; Chen, Y.; Guo, Y.; Liu, Z.; Shi, Y.; Xu, Y.; Wang, X.; Zhang, Z.; Liu, J. The design and synthesis of N-1-alkylated-5-aminoarylalkylsubstituted- 6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors Bioorg. Med. Chem. 2007, 15, 7399-7407
38. Jiang, S.; Lu, H.; Liu, S.; Zhao, Q.; He, Y.; Debnath, A. K. N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion Antimicrob. Agents Chemother. 2004, 48, 4349-4359