15. Bollini, M.; Frey, K. M.; Cisneros, J. A.; Spasov, K.
A.; Das, K.; Bauman, J. D.; Arnold, E.; Anderson, K.
S.; Jorgensen, W. L. Bioorg. Med. Chem. Lett. 2013,
23, accompanying article.
rilpivirine. Further fine-tuning of properties and
activities can be envisioned now that the benefits of
exploration of the NNRTI entrance channel are clear.
16. Ekkati, A. R.; Bollini, M.; Domaoal, R. A.; Spasov, K.
A.; Anderson, K. S.; Jorgensen, W. L. Bioorg. Med.
Chem. Lett. 2012, 22, 1565.
17. General procedure: 5 (0.34 g, 1.2 mmol) was
dissolved in anhydrous THF (10 mL), following by
addition of the corresponding aniline 6 (1.2 mmol) and
DIPEA (0.18 g, 1.44 mmol). The reaction mixture was
stirred at room temperature or refluxed overnight.
THF was removed under pressure; the crude was
purified on silica gel to afford the corresponding
Acknowledgements
Gratitude is expressed to the National Institutes of
Health (AI44616, GM32136, GM49551) for research
support. Receipt of reagents through the NIH AIDS
Research and Reference Reagent Program, Division of
AIDS, NIAID, NIH is also greatly appreciated.
References
1. Prajapati, D. G.; Ramajayam, R.; Yadav, M. R.;
Giridhar, R. Bioorg. Med. Chem. 2009, 17, 5744.
2. de Béthune, M.-P. Antiviral Res. 2010, 85, 75.
3. Guillemont, J.; Pasquier, E.; Palandijan, P.; Vernier,
D.; Gaurrand, S.; Lewi, P. J.; Heeres, J.; de Jonge, M.
R.; Koymans, L. M. H.; Daeyaert, F. F. D.; Vinker, M.
H.; Arnold, E.; Das. K.; Pauwels, R.; Andries, K.; de
Béthune, M.-P.; Bettens, E.; Hertogs, K.; Wigerinck,
P.; Timmerman, P.; Janssen, P. A. J. J. Med. Chem.
2005, 48, 2072.
4. Janssen, P. A. J.; Lewi, P. J.; Arnold, E.; Daeyaert, F.;
de Jonge, M.; Heeres, J.; Koymans, L.; Vinkers, M.;
Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.;
Andries, K.; de Bethune, M.-P.; Pauwels, R.; Das, K.;
Clark, A. D., Jr.; Frenkel, Y. V.; Hughes, S. H.;
Medaer, B.; De Knaep, F.; Bohets, H.; De Clerck, F.;
Lampo, A.; Williams, P.; Stoffels, P. J. Med. Chem.
2005, 48, 1901.
5. Permpalung, N.; Putcharoen, O. Avihingsanon, A.;
Ruxrungtham, K. Expert Opin. Pharmacotherapy
2012, 13, 2301.
6. Molina, J.-M.; Cahn, P.; Grinsztejn, B.; Lazzarin, A.;
Mills, A.; Saag, M.; Supparatpinyo, K.; Walmsley, S.;
Crauwels, H.; Rimsky, L. T.; Vanveggel, S.; Boven,
K. Lancet 2011, 378, 238.
7. Lyseng-Williamson, K. A.; Scott, L. J. Clin. Drug
Investig. 2012, 32, 715.
8. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.;
Feeney, P. J. Adv. Drug Deliv. Rev. 2001, 46, 3.
9. Jorgensen, W. L.; Duffy, E. M. Adv. Drug Deliv. Rev.
2002, 54, 355.
compounds 7. Then, to
a
solution of the
hydroxyalkylmorpholine (12.8 mmol) in anhydrous
THF, NaH (95 %, 7.1 mmol) was added in portions at
o
0 C. After 30 min, a solution of 7 in dioxane was
added dropwise and stirred at room temperature or at
o
80 C overnight. After this period, the solvent was
removed under pressure; the crude was purified on
silica gel to give the target compounds. For compound
4d: 1H NMR (500 MHz, CDCl3) δ 7.81 – 7.58 (m,
2H), 7.47-7.32 (m, 4H), 7.17 (s, 1H), 6.73 (s, 1H),
5.91 (d, J = 16.8 Hz, 1H), 4.42 (s, 2H), 4.22 (s, 1H),
3.72 (s, 4H), 2.46 (t, J = 33.9 Hz, 6H), 2.29 (d, J =
9.2 Hz, 6H), 1.98 (s, 2H). 13C NMR (101 MHz,
DMSO) δ 173.77, 166.10, 150.29, 143.64, 136.48,
132.60, 127.27, 119.45, 118.47, 66.17, 64.45, 55.21,
53.33, 48.58, 40.12, 39.91, 39.70, 39.49, 38.86, 18.24.
HR-MS (ES) calcd for C28H30 N8O2 [M+1]+ 511.0009,
found 511.0011.
18. Bollini, M.; Domaoal, R.A.; Thakur, V. V.; Gallardo-
Macias, R.; Spasov, K. A.; Anderson, K. S.;
Jorgensen, W. L. J. Med. Chem. 2011, 54, 8582.
19. Baka, E.; Comer, J. E. A; Takács-Novák, K. J. Pharm.
Biomed. Anal. 2008, 46, 335.
20. Ludovici, D. W.; Kavash, R. W.; Kukla, M. J.; Ho, C.
Y.; Ye, H.; De Corte, B. L.; Andries, K.; de Béthune,
M.-P.; Azijn, H.; Pauwels, R.; Moereels, H. E. L.;
Heeres, J.; Koymans, L. M. H.; de Jonge, M. R.; Van
Aken, K. J. A.; Daeyaert, F. F. D.; Lewi, P. J.; Das,
K.; Arnold, E.; Janssen, P. A. J. Bioorg. Med. Chem.
Lett. 2001, 11, 2229.
21. Sun, L.-Q.; Qin, B.; Huang, L.; Qian, K.; Chen, C.-H.;
Lee, K.-H.; Xie, L. Bioorg. Med. Chem. Lett. 2012,
22, 2376.
22. Jorgensen, W. L. Acc. Chem. Res. 2009, 42, 724.
23. Jorgensen, W. L.; Tirado-Rives, J. J. Comput. Chem.
2005, 26, 1689.
10. Frenkel, Y. V.; Clark, A. D., Jr.; Das, K.; Wang, Y.-
H.; Lewi, P. J.; Janssen, P. A. J.; Arnold, E. J. Med.
Chem. 2005, 48, 1974.
11. Weuts, I.; Van Dycke, F.; Voorspoels, J.; de Cort, S.;
Stokbroekx, S.; Leemans, R.; Brewster, M. E.; Xu, D.;
Segmuller, B.; Turner, Y. T. A.; Roberts, C. J.;
Davies, M. C.; Qi, S.; Craig, D. Q. M.; Reading, M. J.
Pharm. Sci. 2011, 100, 260.
24. Jorgensen, W. L.; Tirado-Rives, J. Proc. Natl. Acad.
Sci. U.S.A. 2005, 102, 6665.
25. 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 Béthune, M.-P.;
Boyer, P. L.; Clark, P.; Hughes, S. H.; Janssen, P. A.
J.; Arnold, E. J. Med. Chem. 2004, 47, 2550.
12. Saxena, B. B.; Han, Y. A.; Fu, D.; Rathnam, P.; Singh,
M.; Laurence, J.; Lerner, S. AIDS 2009, 23, 917.
13. Yang, Y.; Parniak, M. A.; Isaacs, C. E.; Hillier, S. L.;
Rohan, L. C. AAPS J. 2008, 10, 606.
14. Morelock, M. M.; Choi, L. L.; Bell, G. L.; Wright, J.
L. J. Pharm. Sci. 1994, 83, 948.