M.S.A. Elsayed et al. / European Journal of Medicinal Chemistry 61 (2013) 122e131
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6.1.5.1. 1-{3-[(2,4-Dichlorophenyl)amino]-1,1-dioxidobenzo[d]iso-
thiazol-5-yl}-3-phenylurea (9a). The product was separated as
yellowish white powder (0.1 g, 72%); m.p 221e222 ꢀC; 1H NMR
7.36e7.27 (m, 3H, ArH), 7.26e7.18 (m, 3H, ArH), 6.73e6.66 (m, 3H,
ArH); 13C NMR (126 MHz)
160.2, 152.7, 142.3, 140.1, 139.01, 132.6,
131.6, 131.2, 130.86, 128.5, 128.3, 124.93, 120.56, 119.47, 115.17; HR-
MS (ESI): m/z Calculated for (C20H14ClN3O4S) [M ꢁ H]ꢁ 426.0312,
found 426.0317.
d
(500 MHz): 1H NMR (500 MHz, DMSO-d6)
d 9.45 (s, 1H, NH), 8.65 (s,
1H, NH), 8.40(s,1H, NH), 8.22(d, J¼ 9.0Hz,1H, ArH), 7.62(d, J¼ 2.5Hz,
1H, ArH), 7.47 (m, 3H, ArH), 7.39 (dd, J ¼ 9.0, J ¼ 2.5 Hz,1H, ArH), 7.35e
7.25 (m, 4H, ArH), 7.01 (t, J ¼ 7.4 Hz, 1H, ArH); 13C NMR (126 MHz)
6.1.7.4. 1-(4-Bromophenyl)-3-{4-[(1,1-dioxidobenzo[d]isothiazol-3-
d
152.3, 152, 139.4, 139.2, 135.2, 128.9 (2C), 128.5, 127.6, 126.0, 122.5,
yl)oxy]phenylurea (12d). The product was separated as white
122.2, 122.0, 118.3, 118.23 (3C); HR-MS (ESI): m/z Calculated for
(C20H14Cl2N4O3S) [M ꢁ H]ꢁ 459.0082, found 459.0089.
powder (0.14 g, 79%); m.p ¼ 224e226 ꢀC; 1H NMR (500 MHz)
d 9.21
(s,1H, NH), 8.78 (s,1H, NH), 8.45 (s,1H, NH), 7.55e7.46 (m, 3H, ArH),
7.38e7.31 (m, 3H, ArH), 7.26e7.18 (m, 3H, ArH), 6.78e6.64 (m, 3H,
6.1.5.2. 1-(4-Chlorophenyl)-3-{3-[(2,4-dichlorophenyl)amino]-1,1-
dioxidobenzo[d]isothiazol-5-yl}urea (9b). The product wasseparated
as white powder (0.12 g, 80%); m.p 254e256 ꢀC; 1H NMR (500 MHz)
ArH); 13C NMR (126 MHz, DMSO)
d 159.7, 152.7, 152.5, 139.6, 139.1,
131.6, 131.4,131.3, 131.0, 120.1, 119.8,119.5, 115.1, 113.0,112.4; HR-MS
(ESI): m/z Calculated for (C20H14BrN3O4S) [M ꢁ H]ꢁ 469.9812, found
469.9815.
d
9.57 (s, 1H, NH), 8.86 (s,1H, NH), 8.41 (s, 1H, NH), 8.19 (d, J ¼ 9.0 Hz,
1H, ArH), 7.61 (d, J ¼ 2.5 Hz,1H, ArH), 7.52e7.47 (m, 4H, ArH), 7.38 (dd,
J ¼ 9.0, J ¼ 2.5 Hz, 1H, ArH), 7.37e7.35 (m, 1H), 7.34 (t, J ¼ 2.1 Hz, 1H,
6.1.8. General procedure for preparation of compounds 14aec
Compound 4b (0.1 g, 0.5 mmol) was dissolved in 1,4-dioxane
5 mL and a solution of the appropriate amine (13aee) 0.5 mmol
in 5 mL 1,4-dioxane was added drop wise while stirring to the
previous solution. The mixture was heated under reflux for 3 h and
cooled. The resulted solid was filtered washed with 10 mL 1,4-
dioxane twice and washed with 5 mL diethyl ether and dried to
give compounds (14aed) in a pure form.
ArH), 7.33e7.31 (m,1H, ArH); 13C NMR (126 MHz)
d 152.3,151.9,138.5,
138.2, 135.0, 128.7, 128.6, 128.5, 128.5, 127.6, 126.2, 125.8, 125.4, 122.7,
122.1, 119.7, 119.7, 119.7; HR-MS (ESI): m/z Calculated for
(C20H13Cl3N4O3S) [M þ H]þ 494.9848, found 494.9850.
6.1.6. 3-(4-Aminophenoxy)benzo[d]isothiazole 1,1-dioxide (11)
To a solution of (10) (1 g, 3.2 mmol) in ethanol (30 mL), Tin II
chloride (3.12 g, 16.4 mmol) was added. The reaction mixture was
stirred at reflux for 16 h then cooled to room temperature. The reac-
tion mixture was basified to pH 8 with aq. NaHCO3 then extracted
with ethyl acetate (3 ꢂ 10 mL). The organic extracts were combined,
dried over MgSO4, filtered and concentrated under reduced pressure
to give (x) as yellow powder (0.6 g, 68.4%) [39]. 1H NMR (500 MHz)
6.1.8.1. 1-{4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)amino]phenyl}-3-
phenylurea (14a). The product was separated as buff powder
(0.18 g, 94%); m.p >300 ꢀC; 1H NMR (500 MHz)
d 10.90 (s, 1H, NH),
8.98 (s, 1H, NH), 8.85 (s, 1H, NH), 8.52 (d, J ¼ 7.4 Hz, 1H, ArH), 8.11e
8.01 (m, 1H, ArH), 7.97e7.85 (m, 2H, ArH), 7.84e7.75 (m, 2H, ArH),
7.66e7.53 (m, 2H, ArH), 7.48 (t, J ¼ 8.4 Hz, 2H, ArH), 7.35e7.22 (m,
d
8.27e8.14 (m, 1H), 8.05 (d, J ¼ 7.6 Hz,1H), 8.02e7.82 (m, 3H), 6.73e
6.65 (m, 2H), 6.51e6.41 (m, 3H), 4.59 (s, 2H, NH2); HR-MS (ESI): m/z
Calculated for (C13H10N2O3S) [M ꢁ H]ꢁ 273.0332, found 273.0338.
2H, ArH), 6.98 (t, J ¼ 7.3 Hz, 1H, ArH); 13C NMR (126 MHz)
d 156.3,
152.5, 140.8, 139.6, 137.4, 133.5, 133.2, 131.3, 128.7, 128.3, 125.1,
123.4, 122.7, 121.87, 121.3, 118.8; HR-MS (ESI): m/z Calculated for
(C20H16N4O3S) [M ꢁ H]ꢁ 391.0862, found 391.0869.
6.1.7. General procedure for preparation of compounds 12aed
Compound 11, 0.1 g (0.36 mmol) was taken in DCM (10 mL) and
the solution was cooled in ice bath. Solution of excess phenyl-
isocyanate derivative (0.5 mmol) in DCM (5 mL) was added drop
wise to the previous solution while stirring. The mixture was stir-
red at room temperature overnight and then the solid formed was
collected washed with 10 mL DCM and recrystallized from absolute
Ethanol to afford the urea derivative in a pure form.
6.1.8.2. 1-{4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)amino]phenyl}-3-
(4-methoxyphenyl)urea (14b). The product was separated as
brownish white powder (0.2 g, 94%); m.p >300 ꢀC; 1H NMR
(500 MHz) d 11.13 (s, 1H, NH), 10.18 (s, 1H, NH), 8.90 (s, 1H, NH), 8.60
(d, J ¼ 7.5 Hz, 1H, ArH), 8.03e8.14 (m, 3H, ArH), 7.99e7.85 (m, 2H,
ArH), 7.77e7.82 (m, 1H, ArH), 7.70 (d, J ¼ 8.7 Hz, 2H, ArH), 6.95 (d,
J ¼ 8.6 Hz, 2H, ArH), 6.88 (d, J ¼ 8.7 Hz, 1H, ArH), 3.76 (s, 3H, OCH3);
6.1.7.1. 1-{4-[(1,1-Dioxidobenzo[d]isothiazol-3-yl)oxy]phenyl}-3-
13C NMR (126 MHz)
d 164.3, 156.9, 155.5, 140.5, 140.1, 132.1, 131.6,
phenylurea (12a). The product was separated as white powder
128.5, 128.1, 123.8, 122.7, 122.0, 121.3, 119.9, 118.1, 113.7, 55.1; HR-MS
(ESI): m/z Calculated for (C21H18N4O4S) [M ꢁ H]ꢁ 421.0972, found
421.0967.
(0.1 g, 71%); m.p ¼ 179e180 ꢀC; 1H NMR (500 MHz)
d 8.79 (s, 1H,
NH), 8.64 (s, 1H, NH), 8.25 (d, J ¼ 8 Hz, 1H, ArH), 8.00e7.92 (m, 3H,
ArH), 7.5e7.35 (m, 4H, ArH), 7.32 (m, 2H, ArH), 7.10e6.9 (m, 3H,
ArH); FT-IR (ύmax, cmꢁ1): 3015 (CH aromatic), 2950 (CH aliphatic),
1785 (C]O), 1370, 1180 (SO2); HR-MS (ESI): m/z Calculated for
(C20H15N3O4S) [M ꢁ H]ꢁ 392.0702, found 392.0706.
6.1.8.3. 1-(3-Bromophenyl)-3-{4-[(1,1-dioxidobenzo[d]isothiazol-3-
yl)amino]phenyl}urea (14c). The product was separated as yellow
powder (0.21 g, 91%); m.p >300 ꢀC; 1H NMR (500 MHz)
d 10.88 (s,
1H, NH), 9.00 (s, 2H, NH), 8.50 (d, J ¼ 7.5 Hz, 1H, ArH), 8.11e8.04 (m,
1H, ArH), 7.95e7.86 (m, 3H, ArH), 7.83e7.77 (m, 2H, ArH), 7.59 (d,
J ¼ 8.8 Hz, 2H, ArH), 7.36e7.31 (m, 1H, ArH), 7.25 (t, J ¼ 8.0 Hz, 1H,
6.1.7.2. 1-(2-Chlorophenyl)-3-{4-[(1,1-dioxidobenzo[d]isothiazol-3-
yl)oxy]phenyl}urea (12b). The product was separated as white
powder (0.12 g, 78%); m.p ¼ 224e226 ꢀC; 1H NMR (500 MHz)
d
9.2 (s,
ArH), 7.18e7.13 (m, 1H, ArH); 13C NMR (126 MHz)
d 156.3, 152.3,
1H, NH), 8.82 (s,1H, NH), 8.51 (s,1H, NH), 7.56e7.45 (m, 3H, ArH), 7.52e
141.3, 140.8, 137.1, 133.6, 133.2, 131.6, 130.7, 128.3, 124.3, 123.5, 122.7,
121.7, 121.4, 120.4, 118.6, 117.0; HR-MS (ESI): m/z Calculated for
(C20H15BrN4O3S) [M ꢁ H]ꢁ 468.9972, found 468.9964.
7.33 (m, 3H, ArH), 7.33e7.21 (m, 3H, ArH), 6.75e6.62 (m, 3H, ArH); 13C
NMR (126 MHz)
d 152.6, 152.4, 139.0, 130.8, 129.3, 129.1, 128.5, 124.8,
120.5,119.4,118.5,118.3,117.9,117.5,116.5,116.3,115.16; HR-MS (ESI): m/
z Calculated for (C20H14ClN3O4S) [M ꢁ H]ꢁ 426.0312, found 426.0310.
6.2. Antiproliferative activity
6.1.7.3. 1-(4-Chlorophenyl)-3-{4-[(1,1-dioxidobenzo[d]isothiazol-3-
The antiproliferative activity of the synthesized compounds was
performed among the National Cancer Institute anticancer
screening program (National Cancer Institute Bethesda, Maryland,
USA). The procedure of assay has been discussed in the literature
yl)oxy]phenylurea (12c). The product was separated as white
powder (0.11 g, 76%); m.p ¼ 235e236 ꢀC; 1H NMR (500 MHz)
d 9.09
(s,1H, NH), 8.76 (s,1H, NH), 8.43 (s,1H, NH), 7.52e7.43 (m, 3H, ArH),