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D. H. Hua et al. / Bioorg. Med. Chem. 11 (2003) 4357–4361
2,20-Bis-(4-methoxycarbonylphenoxy)ethyl ether (9). By
a procedure similar to that above, 2.00 g (7.8 mmol) of
2,20-di(bromoethyl) ether, 2.68 g (17.6 mmol) of 4, 11.0 g
(79.6 mmol) of K2CO3, and 15 mL of acetone gave
2.47 g (85% yield) of 911 as a white solidꢁ after crystal-
water, dried under vacuum, and crystallized from etha-
nol to give 0.22 g (79% yield) of 6:12 mp 283–286 ꢁC; 1H
NMR (DMSO-d6) d 7.86 (d, J=8.4 Hz, 4H, Ar), 6.99
(d, J=8.4 Hz, 4H, Ar), 4.06 (t, J=7 Hz, 4H, OCH2),
1.79 (pent, J=7 Hz, 4H, CH2), 1.56 (pent, J=7 Hz, 2H,
CH2); 13C NMR (DMSO-d6) d 164.0, 160.8, 124.7,
122.8, 114.0, 67.5, 28.2, 22.0.
1
lization from ethyl acetate. Mp 120–123 C; H NMR
(CDCl3) d 7.97 (d, J=8.5 Hz, 4H, Ar), 6.92 (d,
J=8.5 Hz, 4H, Ar), 4.21 (t, J=5 Hz, 4H, CH2), 3.95 (t,
J=5 Hz, 4H, CH2), 3.88 (s, 6H, OCH3); 13C NMR
(CDCl3) d 166.7, 162.4, 131.5, 122.8, 114.1, 69.7, 67.5,
51.8.
trans-1,4-Bis-[4-(hydroxycarbonyl)phenoxy]-2-butene (8).
A mixture of 0.10 g (0.28 mmol) of ester 7, 3.0 mL of
ethanol, and 2.0 mL (12 mmol) of 6 N NaOH was trea-
ted similarly to that described above for the preparation
ꢁ
1
1,5-Bis-[4-(hydroxyaminocarbonyl)phenoxy]pentane (1).
To a mixture of 0.9 g (2.4 mmol) of ester 5 in 24 mL of
.
0.5 M solution of NH2OH HCl (12 mmol) was added
of 6 to give 67 mg (74% yield) of 8:13 mp >290 C; H
NMR (DMSO-d6) d 7.88 (d, J=9 Hz, 4H, Ar), 7.03 (d,
J=9 Hz, 4H, Ar), 6.09 (bs, 2H, ¼CH), 4.69 (bs, 4H,
CH2O); 13C NMR (DMSO-d6) d 166.9, 161.7, 131.3,
128.2, 123.2, 114.5, 67.4.
4.8 mL (28.8 mmol) of 6 M aqueous NaOH solution.
The mixture was refluxed for 5 min, then cooled to
room temperature, and 28.8 mL (28.8 mmol) of 1 N HCl
was added. The precipitated solids, was collected by fil-
tration and dried thoroughly under vacuum, to weight
2,20-Bis-[(4-hydroxycarbonyl)phenoxy]ethyl ether (10). A
mixture of 0.15 g (0.40 mmol) of 9, 5.0 mL of ethanol,
and 2.7 mL (16.2 mmol) of 6 N NaOH was treated
similarly to that described above for the preparation of
6 to give 0.115 g (83% yield) of 10:12a,14 mp 308–310 ꢁC;
1H NMR (DMSO-d6) d 7.86 (d, J=7.5 Hz, 4H, Ar),
7.00 (d, J=7.5 Hz, 4H, Ar), 4.18 (t, J=3.5 Hz, 4H,
OCH2), 3.83 (t, J=3.5 Hz, 4H, OCH2); 13C NMR
(DMSO-d6) d 166.9, 162.0, 131.3, 123.0, 114.3, 68.9,
67.4.
1
0.74 g (82% crude yield). H NMR spectrum indicated
the presence of 1 and a small amount of biscarboxylic
acid 6. Recrystallization from DMSO–water (10:1) three
times gave 1,4d 0.51 g (57% yield): mp 200–202 ꢁC (lit.4d
202–203 ꢁC); 1H NMR (DMSO-d6) d 7.69 (d, J=8.8 Hz,
4H, Ar), 6.96 (d, J=8.8 Hz, 4H, Ar), 4.03 (t, J=6.4 Hz,
4H, OCH2), 1.78 (m, 4H, CH2), 1.55 (m, 2H, CH2); 13C
NMR (DMSO-d6) d 165.6, 156.7, 131.2, 128.5, 114.1,
67.6, 28.1, 22.0.
1,5-Bis-[4-(hydroxy-sodio-aminocarbonyl)phenoxy]pentane
(11). To a solution of 0.10 g (0.27 mmol) of 1 in 1 mL of
water was added 21.4 mg (0.53 mmol) of NaOH. The
solution was concentrated to dryness to give 0.112 g
(100% yield) of sodium salt 11. Compound 11 is soluble
trans-1,4-Bis[4-(hydroxyaminocarbonyl)phenoxy]-2-butene
(2). A mixture of 0.45 g (1.26 mmol) of ester 7, 12 mL of
.
0.5 M solution of NH2OH HCl (6 mmol), and 1.0 mL
(6 mmol) of 6 M aqueous NaOH was treated similarly to
that described above for the preparation of 1. Three
crystallizations of the crude product from DMSO–water
1
in water and H NMR is similar to that of 1.
(10:1) gave 2, 0.18 g (40% yield): mp 205–210 ꢁC; H
2,20-Bis-[(4-hydroxy-sodio-aminocarbonyl)phenoxy]ethyl
ether (12). By a procedure similar to that above descri-
bed for the preparation of 11, 0.10 g of 3 gave 0.112 g
(100% yield) of 12. Compound 12 is soluble in water
1
NMR (DMSO-d6) d 7.70 (d, J=8.8 Hz, 4H, Ar), 6.99
(d, J=8.8 Hz, 4H, Ar), 6.07 (bs, 2H, ¼CH), 4.62 (bs,
4H, OCH2); 13C NMR (DMSO-d6) d 166.9, 160.4,
131.3, 128.6, 125.2, 114.3, 67.3. HRMScalcd for
C18H18N2O6Na: 381.1063, found 381.1064.
1
and the H NMR spectrum is similar to that of 3.
Inhibition of the growth of P. falciparum. A reported
method16 for the inhibition of the growth of P. falci-
parum was followed. The incubation period of the
parasites was 66 h and the starting parasitemia was
0.2% with a 1% hematocrit. The medium used was
RPMI-1640 culture medium with no folate or p-amino-
benzoic acid and 10% normal heat-inactivated human
plasma, and P. falciparum D6 and W2 clones were used.
D6 is a clone from the Sierra I/UNC isolates and is
susceptible to chloroquine and pyrimethamine but has
reduced susceptibilities to mefloquine and halofantrine.
W2 is a clone of the Indochina I isolate and is resistant
to chloroquine and pyrimethamine but susceptible to
mefloquine. Compounds were dissolved in DMSO,
diluted 400-fold with complete culture media, and then
diluted 2-fold, 11 times, to give a concentration range of
1048-fold by a Biomek 1000 or 2000 liquid handling
system into 96-well microtiter plates. The diluted com-
pounds were transferred (25 mL) to test plates, 200 mL of
parasitized erythrocytes (0.2% parasitemia and 1%
hematocrit) was added, and was incubated at 37 ꢁC in a
2,20-Bis-[(4-hydroxyaminocarbonyl)phenoxy]ethyl ether
(3). A mixture of 1.0 g (2.67 mmol) of ester 9, 27 mL of
.
0.5 M solution of NH2OH HCl (13.5 mmol), and 5.3 mL
(32 mmol) of 6 M aqueous NaOH was treated similarly
to that described above for the preparation of 1. Two
crystallizations of the crude product from DMSO–water
(10:1) gave 2, 0.804 g (80% yield): mp 220–226 ꢁC; H
1
NMR (DMSO-d6) d 7.68 (d, J=8 Hz, 4H, Ar), 6.97 (d,
J=8 Hz, 4H, Ar), 4.17 (t, J=4 Hz, 4H, OCH2), 3.80 (t,
J=4 Hz, 4H, OCH2); 13C NMR (DMSO-d6) d 164.2,
160.8, 128.8, 125.1, 114.2, 69.0, 67.5. HRMScalcd for
C18H20N2O7Na: 399.1168, found 399.1155.
1,5-Bis-[4-(hydroxycarbonyl)phenoxy]pentane (6). To a
solution of 0.30 g (0.81 mmol) of ester 5 in 20 mL of
ethanol, 1.6 mL of 6 M aqueous NaOH was added and
the solution was stirred under reflux for 10 min. After
being cooled to room temperature, the solution was
acidified with 1 N HCl to pH 1, and the precipitated
white solids were collected by filtration, washed with