N. C. P. Araújo et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2038–2043
2043
Wang, X. F.; Karle, J. M.; Tang, Y. Q.; Wittlin, S.; Brun, R.; Vennerstrom, J. L. J.
Med. Chem. 2005, 48, 4953.
OZ439, an analogue of OZ277, which has an improved metabolic stability and
PK profile.
81.4, 74.0, 52.6, 49.9, 49.4, 44.5, 44.3, 37.8, 36.9, 34.7, 30.8, 29.9, 27.6, 26.4,
25.2, 25.0, 20.6, 13.2. MS m/z (CI, +ve): 530 ([M+H]+, 2) 512(17) 179 (75) 145
(100); (FAB): 530 [M+]. Found [M+H]+ 530.2804, C29H41O4N3 requires
530.2785.
33. Compound 8c: yellow solid; mp 133–134 °C;
m
(film)/cmꢂ1 1711, 1612, 1582,
18. Dong, Y. X.; Tang, Y. Q.; Chollet, J.; Matile, H.; Wittlin, S.; Charman, S. A.;
Charman, W. N.; Tomas, J. S.; Scheurer, C.; Snyder, C.; Scorneaux, B.; Bajpai, S.;
Alexander, S. A.; Wang, X. F.; Padmanilayam, M.; Cheruku, S. R.; Brun, R.;
Vennerstrom, J. L. Bioorg. Med. Chem. 2006, 14, 6368.
19. Tang, Y. Q.; Dong, Y. X.; Wittlin, S.; Charman, S. A.; Chollet, J.; Chiu, F. C. K.;
Charman, W. N.; Matile, H.; Urwyler, H.; Dorn, A.; Bajpai, S.; Wang, X. F.;
Padmanilayam, M.; Karle, J. M.; Brun, R.; Vennerstrom, J. L. Bioorg. Med. Chem.
2007, 17, 1260.
1453, 1376, 1056, 878, 853. 1H NMR (400 MHz, CDCl3) d 8.49 (d, J = 5.3 Hz, 1H),
7.96 (br s, 1H), 7.52 (br d, 1H), 7.00 (br d, 1H), 6.39 (d, J = 5.5 Hz, 1H), 5.23 (s,
1H), 3.47 (m, 4H), 2.63 (m, 2H), 2.28 (m, 2H) 2.15–0.80 (m, 30H) including 1.39
(s, 3H, C-3-Me), 0.93 (d, 3H, J = 6.0 Hz, C-6-Me), 0.80 (d, 3H, J = 7.6 Hz, C-9-Me).
MS m/z (FAB, +ve): Found [M+H]+ 544.29430, C30H43O4N3 requires 544.2942.
34. Compound 9f: Reductive amination of adamantane-2-spiro-30-80-oxo-10, 40-
trioxaspiro[4.5] decane 17 (0.62 g, 2.2 mmol) with 6-chloro-2-methoxy-9-
piperazin-1-yl-acridine (0.87 g, 2.8 mmol) and sodium trioacetoxyborohydride
20. Dechy-Cabaret, O.; Benoit-Vical, F.; Robert, A.; Meunier, B. ChemBioChem 2000,
1, 281.
21. Basco, L. K.; Dechy-Cabaret, O.; Ndounga, M.; Meche, F. S.; Robert, A.; Meunier,
B. Antimicrob. Agents Chemother. 2001, 45, 1886.
22. Robert, A.; Dechy-Cabaret, O.;Cazelles, J.;Meunier, B. Acc. Chem. Res. 2002, 35, 167.
23. Meunier, B. Acc. Chem. Res. 2008, 41, 69.
24. Dechy-Cabaret, O.; Benoit-Vical, F.; Loup, C.; Robert, A.; Gornitzka, H.;
Bonhoure, A.; Vial, H.; Magnaval, J. F.; Seguela, J. P.; Meunier, B. Chem. Eur. J.
2004, 10, 1625.
25. Benoit-Vical, F.; Lelievre, J.; Berry, A.; Deymier, C.; Dechy-Cabaret, O.; Cazelles,
J.; Loup, C.; Robert, A.; Magnaval, J. F.; Meunier, B. Antimicrob. Agents
Chemother. 2007, 51, 1463.
26. Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. 2004, 12, 1177.
27. O’Neill, P. M.; Bishop, L. P.; Storr, R. C.; Hawley, S. R.; Maggs, J. L.; Ward, S. A.;
Park, B. K. J. Med. Chem. 1996, 39, 4511.
(0.6 g, 2.8 mmol) afforded the required trioxolaquine as a mixture of
diastereomers. Orange solid (0.67 g, 52%). Mp 112 °C. mmax (film)/cmꢂ1 1211
(R–O–CH3), 1116 (C30–O–C50), 754 (C30–O–O–C50). 1H NMR (400 MHz, CDCl3) d
8.31–8.02 (m, 3H), 7.54–7.35 (m, 3H), 3.98 and 3.97 (2 ꢃ s, 3H), 3.62–3.60 (m,
4H) 2.90–2.88 (m, 5H), 2.55–2.49 (m, 1H), 2.03–1.70 (m, 21H). 13C (100 MHz,
CDCl3) d 157.1, 152.5, 149.2, 149.1, 148.4, 134.9, 132.0, 129.2, 128.9, 126.9,
126.3, 126.1, 125.5, 112.1111.8, 108.7, 108.6, 107.3, 100.8, 68.3, 62.6, 55.9,
53.9, 51.2, 50.9, 38.1, 37.1, 36.7, 35.2, 33.4, 32.4, 27.2, 26.8; MS (CI, +ve) 590
([M+H]+, 100), 360 (30). Found [M+H]+ 590.2786, C34H41N3O4Cl requires
590.2776. The two diastereomers were separated by HPLC using a 151/152
Gilson HPLC; mobile phase: ethyl acetate (channel A, 40%) and n-hexane
(channel B, 60%); ramp time: 1 min; flow: 1.0 ml/minꢂ1; column: H1Chrom
(normal phase), serial no. KR100-10-250004; detector: UV, 254 nm. For the
less polar diastereomer; 1H NMR (400 MHz, CDCl3) d 8.31 (d, J = 9.2 Hz, 1H),
8.16 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 9.4 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.46 (dd,
J = 9.4 Hz, J = 2.7 Hz, 1H), 7.40 (dd, J = 9.3 Hz, J = 2.10 Hz, 1H), 3.99 (s, 3H), 3.64
(m, 4H), 2.91 (m, 4H), 2.56 (m, 1H), 2.04–1.68 (m, 22H). 13C (100 MHz, CDCl3) d
157.2, 152.5, 148.4, 134.9, 132.1, 129.0, 126.1, 125.5, 123.5, 112.1, 108.7, 100.9,
66.2,62.3,55.9,53.0,51.3, 37.1, 36.8, 35.1, 33.2, 27.3, 26.8, 26.2, 15.6. For the
more polar diastereomer; 1H NMR (400 MHz, CDCl3) d 8.30 (d, J = 9.2 Hz, 1H),
8.16 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 9.3 and J = 2.7 Hz, 1H), 7.53 (d, J = 2.7 Hz,
1H), 7.45 (d, J = 9.4 Hz, 1H), 7.39 (dd, J = 9.30 Hz, J = 2.7 Hz, 1H), 3.98 (s, 3H),
3.61 (m, 4H), 2.89 (m, 4H), 2.55 (m, 1H), 2.05–1.70 (m, 22H). 13C (100 MHz,
CDCl3) d 156.8, 148.8, 148.0, 134.5, 131.7, 128.6, 126.0, 125.3, 125.1, 123.1,
111.5, 108.3, 100.5, 65.8, 62.3, 55.6, 52.6, 50.5, 36.4, 34.8, 34.8, 33.3, 26.9, 25.5,
15.2.
28. Hindley, S.; Ward, S. A.; Storr, R. C.; Searle, N. L.; Bray, P. G.; Park, B. K.; Davies,
J.; O’Neill, P. M. J. Med. Chem. 2002, 45, 1052.
29. Stocks, P. A.; Bray, P. G.; Barton, V. E.; Al-Helal, M.; Jones, M.; Araujo, N. C.;
Gibbons, P.; Ward, S. A.; Hughes, R. H.; Biagini, G. A.; Davies, J.; Amewu, R.;
Mercer, A. E.; Ellis, G.; O’Neill, P. M. Angew. Chem., Int. Ed. 2007, 46, 6278.
30. O’Neill, P. M.; Pugh, M.; Stachulski, A. V.; Ward, S. A.; Davies, J.; Park, B. K. J.
Chem. Soc., Perkin Trans. 1 2001, 2682.
31. Jeyadevan, J. P.; Bray, P. G.; Chadwick, J.; Mercer, A. E.; Byrne, A.; Ward, S. A.;
Park, B. K.; Williams, D. P.; Cosstick, R.; Davies, J.; Higson, A. P.; Irving, E.;
Posner, G. H.; O’Neill, P. M. J. Med. Chem. 2004, 47, 1290.
32. Compound 8b was obtained as a light yellow solid (0.19 g, 17% from 10b-carba
aldehyde
14
(0.52 g,
2.21 mmol),
N2-(-chloro-4-quinolinyl)-1,2-
35. Trager, W.; Jensien, J. B. Nature 1978, 273, 621.
diaminopropane (0.55 g, 1.77 mmol) and sodium triacetoxyborohydride
(0.38 g, 1.77 mmol). The mixture was allowed to stir for 22 h at room
temperature and then washed with distilled water. The organic layer was
dried and evaporated under vacuum to dryness. The residue was purified by
flash chromatography using ethyl acetate/methanol (5–25%) mp 115 °C. mmax
(film)/cmꢂ1 1611, 1582, 1451, 1370, 1055, 877, 853. 1H NMR (250 MHz, CDCl3)
d 8.47 (d, J = 5.8 Hz, 1H), 8.00 (m,1H), 7.91 (d, J = 3.3 Hz, 1H), 7.36 (m, 1H), 6.29
(d, J = 5.8 Hz, 1H), 5.20 (s, 1H), 3.65 (m, 1H), 3.40 (m, 2H), 2.99 (m, 2H), 2.87 (m,
2H), 2.45 (m. 2H), 2.10–0.82 (m, 25H) including 1.41 (s, 3H, C-3-Me), 0.96 (d,
J = 6.4 Hz, 3H, C-6-Me), 0.82 (d, J = 7.6 Hz, 3H, C-9-Me). 13C (100 MHz, CDCl3) d
152.4, 150.9, 149.6, 134.9, 128.9, 125.0, 122.6, 118.0, 103.4, 98.6, 92.1, 89.7,
36. Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chulay, J. D. Antimicrob. Agents
Chemother. 1979, 16, 710.
37. Warhurst, D. C.; Steele, J. C. P.; Adagu, I. S.; Craig, J. C.; Cullander, C. J.
Antimicrob. Chemother. 2003, 52, 188.
38. Eckstein-Ludwig, U.; Webb, R. J.; van Goethem, I. D. A.; East, J. M.; Lee, A. G.;
Kimura, M.; O’Neill, P. M.; Bray, P. G.; Ward, S. A.; Krishna, S. Nature 2003, 424,
957.
39. Tang, Y. Q.; Dong, Y. X.; Wang, X. F.; Sriraghavan, K.; Wood, J. K.; Vennerstrom,
J. L. J. Org. Chem. 2005, 70, 5103.
40. Coslédan, F.; Fraisse, L.; Pellet, A.; Guillou, F.; Mordmüller, B.; Kremsner, P. G.;
Moreno, A.; Mazier, D.; Maffrand, J.-P.; Meunier, B. PNAS 2008, 105, 17579.