C. Sheng et al. / European Journal of Medicinal Chemistry 45 (2010) 3531e3540
3539
6.1.30. General procedure for the synthesis of compounds 20aee
3-(Aminomethyl)pyridine (0.28 mol) was added to a solution of
compound 19aee (0.28 mmol) in absolute EtOH (5 mL). The reac-
tion mixture was stirred at 80 ꢀC for 12 h and evaporated under
reduced pressure. The residue was dissolved in EtOAc (50 mL) and
H2O (50 mL). The organic layer was separated, washed with satu-
rated NH4Cl (50 mL), dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (CH2Cl2/MeOH ¼ 20:1, v/v) to give
compounds 20aee.
OCH2CH2CH2NH), 3.76 (s, 2H, NHCH2Pyridinyl), 2.74 (t, 2H, J ¼ 7.0
Hz, OCH2CH2CH2NH), 1.98 (p, 2H, J ¼ 6.5 Hz, OCH2CH2CH2NH).
HRMS (m/z): calcd. for C24H23ClN4O2: 434.1510; found: 434.1494.
Anal. calcd. for C24H23ClN4O2: C, 66.28; H, 5.33; N, 12.88. Found: C,
66.01; H, 5.34; N, 12.90.
6.2. Molecular docking
ꢀ
The crystallographic coordinates of CaNMT [25] (0.32 A resolu-
tion, Rcryst ¼ 0.284) were obtained from the Brookheaven Protein
Databank as entries 1IYL. The chemical structures of compounds 8f
and 16a were built by InsightII 2000 software package. Followed by
energy minimization, compounds 8f and 16a were docked into the
active site of CaNMT using the Affinity module within InsightII
2000 software package. The detailed docking protocols are similar
to that in our previous modeling studies on CaNMT [26].
6.1.31. N-(3-Fluorophenyl)-4-[3-(pyridin-3-ylmethylamino)-
propoxy]-1H-indole-2-carboxamide (20a)
Yellow solid (30 mg, 25% yield). 1H NMR
d (ppm): 11.77 (s, 1H,
indole-NH), 10.35 (s, 1H, CONH), 8.55 (s, 1H, pyridinyl-C2H), 8.42 (d,
1H, J ¼ 4.5 Hz, pyridinyl-C6H), 7.81 (d, 1H, J ¼ 7.0 Hz, pyridinyl-
C4H), 6.54e7.75 (m, 9H, Ar-H), 4.18 (t, 2H,
J
¼
6.0 Hz,
OCH2CH2CH2NH), 3.75 (s, 2H, NHCH2Pyridinyl), 2.73 (t, 2H, J ¼ 6.5
Hz, OCH2CH2CH2NH), 1.98 (p, 2H, J ¼ 6.5 Hz, OCH2CH2CH2NH).
HRMS (m/z): calcd. for C24H23FN4O2: 418.1805; found: 418.1817.
Anal. calcd. for C24H23FN4O2: C, 68.88; H, 5.54; N, 13.39. Found: C,
69.01; H, 5.52; N, 13.40.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 30973640), Shanghai Rising-Star
Program (Grant Nos. 09QA1407000), National Major Special Project
for the Creation of New Drugs (Grant Nos. 2009ZX09301-011) and
Shanghai Leading Academic Discipline Project (Project Nos. B906).
6.1.32. N-(4-Chlorophenyl)-4-[3-(pyridin-3-ylmethylamino)-
propoxy]-1H-indole-2-carboxamide (20b)
Yellow solid (36 mg, 30% yield). 1H NMR
d (ppm): 11.74 (s, 1H,
Appendix. Supplementary data
indole-NH), 10.29 (s, 1H, CONH), 8.54 (s, 1H, pyridinyl-C2H), 8.42 (d,
1H, J ¼ 4.5 Hz, pyridinyl-C6H), 7.86 (d, 1H, J ¼ 9.0 Hz, pyridinyl-
Supplementary data associated with this article can be found, in
C4H), 6.53e7.75 (m, 9H, Ar-H), 4.18 (t, 2H,
J
¼
6.5 Hz,
OCH2CH2CH2NH), 3.75 (s, 2H, NHCH2Pyridinyl), 2.73 (t, 2H, J ¼ 6.5
Hz, OCH2CH2CH2NH), 1.98 (p, 2H, J ¼ 6.0 Hz, OCH2CH2CH2NH).
HRMS (m/z): calcd. for C24H23ClN4O2: 434.1510; found: 434.1499.
Anal. calcd. for C24H23ClN4O2: C, 66.28; H, 5.33; N, 12.88. Found: C,
66.08; H, 5.32; N, 12.91.
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1H-indole-2-carboxamide (20c)
Pale yellow solid (32 mg, 29% yield). 1H NMR
d (ppm): 11.71 (s,
1H, indole-NH), 10.17 (s, 1H, CONH), 8.54 (s, 1H, pyridinyl-C2H),
8.42 (d, 1H, J ¼ 4.5 Hz, pyridinyl-C6H), 7.82 (d, 1H, J ¼ 8.5 Hz, pyr-
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6.1.34. N-(3,4-Difluorophenyl)-4-[3-(pyridin-3-ylmethylamino)-
propoxy]-1H-indole-2-carboxamide (20d)
Yellow solid (39 mg, 32% yield). 1H NMR
d (ppm): 11.79 (s, 1H,
indole-NH), 10.38 (s, 1H, CONH), 8.55 (s, 1H, pyridinyl-C2H), 8.43 (d,
1H, J ¼ 3.5 Hz, pyridinyl-C6H), 7.98e8.02 (m, 1H, J ¼ 8.5 Hz, pyr-
idinyl-C4H), 6.54e7.76 (m, 8H, Ar-H), 4.18 (t, 2H, J ¼ 6.0 Hz,
OCH2CH2CH2NH), 3.76 (s, 2H, NHCH2Pyridinyl), 2.74 (t, 2H, J ¼ 6.5
Hz, OCH2CH2CH2NH), 1.99 (p, 2H, J ¼ 6.5 Hz, OCH2CH2CH2NH).
HRMS (m/z): calcd. for C24H22F2N4O2: 436.1711; found: 436.1700.
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66.18; H, 5.06; N, 12.42.
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6.1.35. N-(2-Chlorophenyl)-4-[3-(pyridin-3-ylmethylamino)-
propoxy]-1H-indole-2-carboxamide (20e)
Flavo-green solid (22 mg, 18% yield). 1H NMR
d (ppm): 11.75 (s,
1H, indole-NH), 10.04 (s, 1H, CONH), 8.54 (s, 1H, pyridinyl-C2H),
8.42 (d, 1H, J ¼ 3.5 Hz, pyridinyl-C6H), 7.75 (d, 1H, J ¼ 8.0 Hz, pyr-
idinyl-C4H), 6.53e7.59 (m, 9H, Ar-H), 4.18 (t, 2H, J ¼ 6.0 Hz,