Synthesis and Biological Evaluation of Phthalazinone Inhibitors of ...

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(3.79, s, 3H), (3.40, s, 2H, J= 10 Hz), (3.14, s, 2H), (2.56, s, 3H), (2.46, s, 3H), (2.31, s, 1H), (1.40, s, 3H), (1.28, s, 1H), (1.24, d, 3H, J= 10 Hz). (59) N-(9H-carbazol-3-yl)-2-(3-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)acetamide. 1 H NMR (DMSO-d6, 400 MHz): (11.19, s, 1H), (10.26, s, 1H), (8.38, s, 1H), (8.31, d, 1H, J= 8 Hz), (8.04, d, 1H, J= 8 Hz), (7.97, q, 2H, J= 8 Hz), (7.88, t, 1H, J= 8 Hz), (7.49, t, 1H, J= 8 Hz), (7.43, m, 2H, J= 7-8 Hz), (7.36, t, 1H, J= 8 Hz), (7.11, t, 1H, J= 6 Hz), (4.13, s, 2H), (3.75, s, 3H). (60) N-(9-ethyl-9H-carbazol-3-yl)-2-(3-methyl-4-oxo-3,4-dihydrophthalazin- 1-yl)acetamide. 1 H NMR (DMSO-d6, 400 MHz): (10.39, s, 1H), (8.41, s, 1H), (8.31, d, 1H, J= 8 Hz), (8.03, t, 2H, J= 8 Hz), (7.96, t, 1H, J= 8 Hz), (7.97, t, 1H, J= 8 Hz), (7.56, d, 2H, J= 10 Hz), 7.43, t, 1H, J= 8 Hz), (7.15, t, 1H, J= 8 Hz), (4.40, q, 2H, J= 8 Hz), (4.14, s, 2H), (3.74, s, 3H), (1.29, t, 3H, J= 8 Hz). 32
Bibliography 1. Huang, D.R.; White, A.C. Gastroenterol. Clin . North Am. 2006, 35, 291-314; Corso, P.S; Kramer, M.H.; Blair, K.A.; Addiss, D.G.; Davis, J.P.; Haddix, A.C. Emerg. Infect. Dis. 2003, 9, 426-31. 2. Dupont, H.L.; Chappell, C.L.; Sterling, C.R.; Okhuysen, P.C.; Rose, J.B.; Kakubowski, W. N. Engl. J. Med. 1995, 332, 855-59. 3. Abrahamsen, M.S.; Templeton, T.J.; Enomoto, S.; Abrahante, J.E.; Zhu, G.; Lancto, C.A.; Deng, M.; Liu, C.; Widmer, G.; Tzipori, S. et al. Science 2004, 304, 441-45; Striepen, B.; Pruijssers, A.J.; Huang, J.; Li, C.; Gubbels, M.J.; Umejiego, N.N.; Hedstrom, L.; Kissinger, J.C. Proc. Natl. Acad. Sci. USA 2004, 101, 3154- 59; Xu, P.; Widmer, G.; Wang, Y.; Ozaki, L.S.; Alves, J.M.; Serrano, M.G.; Puiu, D.; Manque, P.; Akiyoshi, D.; Mackey, A.J. et al. Nature 2004, 431, 1107-12. 4. Ratcliffe, A.J. Drug Discov. Dev. 2006, 9, 595-605. 5. Umejiego, N.N.; Gollapalli, D.; Sharling, L.; Volftsun, A.; Lu, J.; Benjamin, N.N.; Stroupe, A.H.; Riera, T.V.; Striepen, B.; Hedstrom, L. Chemistry and Biology 2008, 15, 70-77. 6. Maurya, S. K.; Gollapalli, D. R.; Kirubakaran, S.; Zhang, M.; Johnson, C. R.; Benjamin, N. N.; Hedstrom, L.; Cuny, G. D. J Med Chem 2009, 52, 4623; MacPherson, I.S.; Kirubakaran, S.; Gorla, S.K.; Riera, T.V.; Alejandro D’Aquino, J.; Zhang, M.; Cuny, G.D.; Hedstrom, L. J. Am. Chem. Soc. 2010, 132, 1230-31. 7. Mylari, B.L., Larson, E.R., Beyer, T.A., Zembrowski, W.J., Aldinger, C.E., Dee, M.F., Siegel, T.W., Singleton, D.H. J. Med. Chem. 1991, 34, 108-122; Niebel, C., Lokshin, V., Sigalov, M., Krief, P., Khodorkovsky, V. Eur J. Org. Chem. 2008, 3689-3699. 8. Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res. 2005, 38, 386-395. 9. Brammer, L.; Bruton, E.A.; Sherwood, P. Crystal Growth & Design. 2001, 1, 277-90; Schwӧbel, J.; Ebert, R.; Kȕhne, R.; Schȕȕrmann, G. J. Chem. Inf. Model. 2009, 49, 956-62. 10. Topliss, J.G. J. Med. Chem. 1972, 15, 1007-1011. 11. Bondi, A. J. Phys. Chem. 1964, 68, 441-451. 12. Ravtndranath, V.; Burka, T., Boyd, M. R., Pharmacologist, 1983, 25, 171 ;Ravindranath, V.; Boyd, M. R., Toxicol. Appl. Pharmacol., 1985, 78, 370-376; Adam, W.; Hadjiarapoglou, L.; Peters, K.; Sauter, M. J. Am. Chem. Soc., 1993, 115, 8603–8608. 13. Kistiakowsky, G. B.; Ruhoffh, J. R.; Smith, A.; Vaughan, W. E. J. Am. Chem. Soc., 1936, 58, 146–153. 33
Page 1 and 2: Synthesis and Biological Evaluation
Page 3 and 4: inducing enzyme inhibition. Further
Page 5 and 6: List of Tables Table I. Table II. I
Page 7 and 8: Introduction Outbreaks worldwide ha
Page 9 and 10: Compound 7 and its analogs were pre
Page 11 and 12: D21 9 Me 2-OMePh >5000 ND D23 10 Me
Page 13 and 14: D35 51 Me thiazolyl) 2-(5-Me(1,3,4-
Page 15 and 16: Figure III. Intramolecular interact
Page 17 and 18: Figure IV. Ball-and-stick model of
Page 19 and 20: methoxy group. We believe that this
Page 21 and 22: enzofuran series of inhibitors. How
Page 23 and 24: Trends in potency seemed to increas
Page 25 and 26: Conclusion We have hypothesized, ap
Page 27 and 28: chemical shift values are also repo
Page 29 and 30: General procedure for the synthesis
Page 31 and 32: (15) N-(4-bromophenyl)-2-(3-methyl-
Page 33 and 34: 1H, J= 7 Hz), (8.17, d, 1H, J= 9 Hz
Page 35 and 36: (7.95, q, 2H, J= 7-8 Hz), (7.87, t,
Page 37: 1H, J= 8 Hz), (7.31, d, 1H, J= 8 Hz

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