Plasmodium flaciparum Lactate Dehydrogenase Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 16 3849
(s, 3H), 3.82 (t, 2H), 2.28 (t, 2H), 2.1 (s, 1H, OH), 1.40 (t, 3H);
13C NMR (CDCl3) δ 160.8, 153.5, 148.5, 136.2, 124.3, 121.2, 119.8,
111.0, 63.41, 55.8, 53.8, 39.1, 13.9; LC-MS (APCI) 268.2.
Ethyl 7-[2-(4-{[Ethoxy(oxo)acetyl]amino}phenyl)ethoxy]-5-
hydroxy-4-oxo-4H-chromene-2-carboxylate (28a): DIAD (49 µL,
0.25 mmol) was added to a mixture of 20a (50 mg, 0.21 mmol),
triphenylphosphine (65 mg, 0.25 mmol), and compound 11 (62 mg,
0.25 mmol) in CH2Cl2 at 0 °C. After the reaction was completed,
a yellow solid (60 mg, 61%) was obtained as described in general
δ 182.6, 165.5, 162.3, 161.5, 161.2, 157.7, 156.1, 154.6, 149.4,
135.8, 124.5, 121.3, 120.4, 112.6, 112.4, 106.4, 99.4, 93.8, 69.4,
56.4, 34.9; DEPT 135 δ CH (121.3, 120.4, 112.7, 112.4, 99.4, 93.8),
CH2 (69.4, 34.9), CH3 (56.4); HRMS calcd for C21H17NO10,
444.0852; found, 444.0977 (M+ + 1); calcd for C21H17NO10Na,
466.0750; found, 466.0766 (M + Na); HPLC (C8 column).
Ethyl ({4-[2-({5-Hydroxy-2-[(4-methoxybenzylamino)carbon-
yl]-4-oxo-4H-chromen-7-yl}oxy)ethyl]phenyl}amino)(oxo)-
acetate (29a): Compound 29a was prepared by following general
procedure I, giving a yellow solid (48 mg, 41%). 1H NMR (DMSO)
δ 12.4 (s, 1H), 10.72 (s, NH), 9.51 (t, NH), 7.67 (d, 2H, J ) 8.0
Hz), 7.29 (d, 2H, J ) 8.4 Hz), 7.25 (d, 2H, J ) 8.4 Hz), 6.88 (d,
2H, J ) 8.4 Hz), 6.75 (s, 1H), 6.61 (s, 1H), 6.37 (d, 1H, J ) 1.6
Hz), 4.40 (d, 2H, J ) 2.4 Hz), 4.28 (m, 4H), 3.70 (s, 3H), 3.01 (t,
2H), 1.29 (t, 3H); 13C NMR (DMSO) δ 182.4, 165.2, 161.6, 161.1,
158.9, 158.7, 157.2, 156.5, 155.8, 136.3, 134.7, 130.7, 129.7, 129.4,
120.9, 114.2, 109.8, 106.1, 99.2, 93.8, 69.4, 62.8, 55.5, 42.6, 34.4,
14.3; HRMS calcd for C30H28N2O9, 561.1795; found, 561.1860 (M
+ 1); calcd for C30H28N2O9Na, 583.1693; found, 583.1713 (M +
Na).
Ethyl ({2-Cyano-4-[2-({5-hydroxy-2-[(4-methoxybenzylami-
no)carbonyl]-4-oxo-4H-chromen-7-yl}oxy)ethyl]phenyl}amino)-
(oxo)acetate (29b): Compound 29b was prepared by following
general procedure I, giving a yellow solid (85 mg, 38%). 1H NMR
(DMSO) δ 12.4 (br, 1H), 10.9 (s, 1H), 9.52 (s, 1H), 7.84 (s, 1H),
7.68 (d, 1H, J ) 8.0 Hz), 7.52 (d, 1H, J ) 8.0 Hz), 7.25 (d, 2H,
J ) 8.0 Hz), 6.88 (d, 2H, J ) 8.8 Hz), 6.75 (s, 1H), 6.63 (s, 1H),
6.41 (s, 1H), 4.40 (d, 2H, J ) 5.2 Hz), 4.32 (m, 4H), 3.69 (s, 3H),
3.10 (t, 2H), 1.30 (t, 3H); 13C NMR (DMSO) δ 182.4, 165.1, 161.6,
160.4, 158.9, 158.8, 157.2, 156.6, 156.4, 137.8, 137.4, 135.1, 133.8,
130.7, 129.4, 126.6, 116.9, 114.2, 109.8, 108.9, 106.2, 99.2, 94.0,
68.8, 63.1, 42.6, 33.8, 14.2; DEPT 135 δ CH (135.1, 133.8, 129.4,
126.6, 114.2, 109.8, 99.2, 94.0), CH2 (68.8, 63.2, 42.6, 33.8), CH3
(55.5, 14.2); HRMS calcd for C31H27N3O9, 586.1747; found,
586.1794 (M+ + 1); calcd for C31H27N3O9Na, 608.1645; found,
608.1622 (M + Na).
1
procedure I. H NMR (CDCl3) δ 12.2 (s, 1H), 8.89 (s, 1H), 7.61
(d, 2H, J ) 8.4 Hz), 7.29 (d, 2H, J ) 8.0 Hz), 6.96 (s, 1H), 6.50
(d, 1H, J ) 2.0 Hz), 6.36 (d, 1H, J ) 2.0 Hz), 4.45 (m, 4H), 4.21
(t, 2H), 3.10 (t, 2H), 1.42 (m, 6H); 13C NMR (CDCl3) δ 182.1,
165.4, 162.0, 160.9, 159.9, 157.5, 153.8, 152.4, 135.0, 134.8, 129.7,
120.0, 113.6, 106.8, 99.3, 93.5, 69.1, 63.7, 63.0, 34.8, 14.0, 13.9;
LC-MS (M - 1) 470.42.
Ethyl 7-[2-(3-Cyano-4-{[ethoxy(oxo)acetyl]amino}phenyl)-
ethoxy]-5-hydroxy-4-oxo-4H-chromene-2-carboxylate (28b): DIAD
(43 µL, 0.22 mmol) was added to a mixture of compound 20b (50
mg, 0.19mmol), triphenylphosphine (57 mg, 0.22 mmol), and
compound 11 (55 mg, 0.22 mmol) in CH2Cl2 at 0 °C. After the
reaction was completed, a yellow solid (65 mg, 69%) was obtained
1
as described in general procedure I. H NMR (CDCl3) δ 12.2 (br,
1H), 9.39 (s, 1H), 8.42 (d, 1H, J ) 8.0 Hz), 7.58 (m, 2H), 6.97 (s,
1H), 6.50 (d, 1H, J ) 2.0 Hz), 6.35 (d, 1H, J ) 2.0 Hz), 4.45 (m,
4H), 4.25 (t, 2H), 3.14 (t, 2H), 1.45 (t, 6H); 13C NMR (CDCl3) δ
182.1, 165.0, 162.1, 159.8, 159.7, 157.7, 154.2, 152.5, 137.7, 135.6,
134.9, 132.6, 121.1, 115.4, 113.6, 106.9, 103.2, 99.2, 93.5, 68.3,
64.1, 63.0, 34.4, 34.0, 14.0, 13.9; LC-MS (M - 1) 493.00.
Ethyl 7-[2-(3-Methoxy-4-{[ethoxy(oxo)acetyl]amino}phenyl)-
ethoxy]-5-hydroxy-4-oxo-4H-chromene-2-carboxylate (28c): DIAD
(43 µL, 0.22 mmol) was added to a mixture of compound 20c (50
mg, 0.18mmol), triphenylphosphine (57 mg, 0.22 mmol), and
compound 11 (55 mg, 0.22 mmol) in CH2Cl2 at 0 °C. After the
reaction was completed, a yellow solid (42 mg, 45%) was obtained
1
as described in general procedure I. H NMR (CDCl3) δ 12.2 (s,
1H), 9.45 (s, 1H), 8.36 (d, 1H, J ) 8.0 Hz), 6.98 (s, 1H), 6.91 (d,
1H, J ) 8.4 Hz), 6.85 (s, 1H), 6.52 (d, 1H, J ) 2.0 Hz), 6.38 (d,
1H, J ) 2.0 Hz), 4.44 (m, 4H), 4.24 (t, 2H), 3.94 (s, 3H), 3.10 (t,
2H), 1.43 (m, 6H); 13C NMR (CDCl3) δ 182.1, 165.4, 162.0, 160.8,
159.9, 157.5, 153.6, 152.4, 148.5, 134.9, 124.8, 121.3, 119.9, 113.6,
106.8, 99.3, 93.4, 69.2, 63.5, 63.0, 55.8, 35.3, 14.0, 13.9; LC-MS
(M - H) 500.31; HRMS calcd for C25H25NO10, 500.1512; found,
500.1522 (M+ + 1).
Ethyl ({2-Methoxy-4-[2-({5-hydroxy-2-[(4-methoxybenzyl-
amino)carbonyl]-4-oxo-4H-chromen-7-yl}oxy)ethyl]phenyl}-
amino)(oxo)acetate (29c): Compound 29c was prepared by
following general procedure I, giving a yellow solid (80 mg, 68%).
1H NMR (DMSO) δ 12.4 (br, 1H), 9.59 (s, NH), 9.56 (t, NH),
7.89 (d, 1H, J ) 8.0 Hz), 7.26 (d, 2H, J ) 8.0 Hz), 7.07 (s, 1H),
6.88 (m, 3H,), 6.68 (s, 1H), 6.57 (s, 1H), 6.38 (s, 1H), 4.39 (d,
2H), 4.28 (m, 4H), 3.85 (s, 3H), 3.70 (s, 3H), 3.02 (t, 2H), 1.28 (t,
3H); 13C NMR (DMSO) δ 182.4, 165.2, 161.6, 160.9, 158.9, 158.7,
157.2, 156.5, 154.9, 149.9, 136.2, 130.7, 129.4, 124.3, 121.3, 121.2,
114.2, 112.5, 109.8, 106.1, 99.2, 93.8, 69.4, 63.1, 56.4, 55.5, 42.6,
34.9, 14.2; HRMS calcd for C31H30N2O10, 591.1900; found,
591.1982 (M + 1); HRMS calcd for C31H30N2O10Na, 613.1798;
found, 613.1786 (M + Na).
7-(2-{4-[(Carboxycarbonyl)amino]phenyl}ethoxy)-5-hydroxy-
4-oxo-4H-chromene-2-carboxylic Acid (2): LiOH (1 N, 0.32
mmol) was added to a solution of compound 28a (75 mg, 0.16
mmol) in THF/H2O (2 mL/1 mL). The reaction was performed as
described in general procedure II to give a yellow solid (50 mg,
1
68%). H NMR (DMSO) δ 12.35 (br, OH), 10.59 (br, NH), 7.66
(br, 2H), 7.24 (br, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 6.25 (br, 1H),
4.20 (br, 2H), 2.95 (br, 2H); 13C NMR (DMSO) δ 182.6, 165.3,
162.7, 161.4, 161.3, 157.6, 155.3, 136.5, 134.5, 129.6, 120.7, 112.2,
106.2, 99.2, 93.6, 69.4, 34.4; HRMS calcd for C20H15NO9,
414.0747; found, 414.0826 (M + 1); HPLC (C8 column).
({4-[2-({5-Hydroxy-2-[(4-methoxybenzylamino)carbonyl]-4-
oxo-4H-chromen-7-yl}oxy)ethyl]phenyl}amino)(oxo)acetic Acid
(5): By following general procedure II, compound 5 was prepared,
giving a yellow solid (12 mg, 46%). 1H NMR (DMSO) δ 12.4 (s,
OH), 10.6 (br, 1H), 9.54 (t, NH), 7.68 (d, 1H), 7.31 (s, 1H), 7.28
(d, 2H, J ) 8.8 Hz), 6.91 (d, 2H, J ) 8.8 Hz), 6.79 (s, 1H), 6.67
(s, 1H), 6.44 (s, 1H), 4.43 (d, 2H, J ) 5.6 Hz), 4.29 (t, 2H), 3.73
(s, 3H), 3.03 (t, 2H); 13C NMR (DMSO) δ 182.4, 165.3, 161.6,
158.9, 158.8, 157.5,157.2, 156.6, 134.5, 130.8, 129.6, 129.4, 120.8,
114.2, 109.8, 106.2, 99.3, 93.9, 69.5, 55.5, 42.6, 34.4; HRMS calcd
for C28H24N2O9, 533.1482; found, 533.1548 (M+ + 1); HPLC (C8
column).
({2-Cyano-4-[2-({5-hydroxy-2-[(4-methoxybenzylamino)car-
bonyl]-4-oxo-4H-chromen-7-yl}oxy)ethyl]phenyl}amino)(oxo)-
acetic Acid (6): By following general procedure II, compound 6
was prepared, giving a yellow solid (29 mg, 62%). 1H NMR
(DMSO) δ 12.4 (s, OH), 10.9 (br, 1H), 9.52 (t, 1H), 7.84 (s, 1H),
7.69 (d, 1H, J ) 8.0 Hz), 7.65 (d, 1H, J ) 8.0 Hz), 7.28 (d, 2H,
J ) 8.8 Hz), 6.88 (d, 2H, J ) 8.8 Hz), 6.79 (s, 1H), 6.68 (d, 1H,
J ) 2.0 Hz), 6.46 (s, 1H, J ) 2.0 Hz), 4.43 (d, 2H, J ) 6.0 Hz),
4.35 (t, 2H), 3.12 (t, 2H); 13C NMR (DMSO) δ 182.5, 165.2, 161.6,
7-(2-{4-[(Carboxycarbonyl)amino]-3-cyanophenyl}ethoxy)-5-
hydroxy-4-oxo-4H-2-carboxylic Acid (3): By following procedure
1
II, compound 3 was prepared as a yellow solid (27 mg, 77%). H
NMR (DMSO) δ 12.6 (s, 1H), 10.7 (br, 1H), 7.87 (s, 1H) 7.64 (m,
2H), 6.76 (s, 1H), 6.61 (s, 1H), 6.32 (s, 1H), 4.36 (t, 2H), 3.10 (t,
2H); 13C NMR (DMSO) δ 182.5, 165.3, 161.8, 161.5, 161.2, 157.6,
154.3, 137.6, 137.4, 135.1, 133.7, 126.1, 116.9, 112.7, 108.4, 106.3,
99.3, 93.8, 68.7, 33.8; LC-MS (M + Na) 459.20; HRMS calcd for
C21H14N2O9, 439.0699; found, 439.0763 (M+ + 1); HPLC (C8
column).
7-(2-{4-[(Carboxycarbonyl)amino]-3-methoxyphenyl}ethoxy)-
5-hydroxy-4-oxo-4H-2-carboxylic Acid (4): By following proce-
dure II, compound 4 was prepared as a yellow solid (29 mg, 77%).
1H NMR (DMSO) δ 12.40 (br, OH), 9.55 (br, NH), 7.95 (br, 1H),
7.01 (br, 1H), 6.90 (br, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 6.39 (s,
1H), 4.31 (br, 2H), 3.86 (s, 3H), 3.01 (br, 2H); 13C NMR (DMSO)