430
R. Raj et al. / European Journal of Medicinal Chemistry 84 (2014) 425e432
Table 3
colored solid precipitated out in reaction mixture. This crude
product was filtered and purified by recrystallization in
CHCl3:Hexane (9:1) to afford pure compound 7.
Cytotoxicity and selective index of conjugates 10ae10c.
Compound Cytotoxicitya
IC50 standard error (
72 6.22
P. falciparum
SIc
m
M) W2 (CQ-R) strainb IC50 (nM)
3.3.1. 1-(7-Chloro-quinolin-4-yl)-3-(2-oxo-4-styryl-1-p-tolyl-
azetidin-3-yl)-thiourea (7a)
10a
10b
10c
39.84
42.54
57.21
1807
2139
>1747
91 8.12
>100
Yellow Solid; Yield: 89%; m.p. 151e152 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
(ppm): 2.23 (s, 3H, eCH3); 5.01 (t, J ¼ 5.7 Hz, 1H, H3); 5.90
a
CQ-R: Chloroquine resistant strain.
Cytotoxicity against HeLa cell line.
SI: Selective index is ratio of IC50 of HeLa cell line to that of W2-resistant strain.
(s, 1H, H4); 6.24 (dd, J ¼ 6.9, 16.2 Hz, 1H, H2); 6.68 (d, J ¼ 15.9 Hz, 1H,
H1); 6.94 (d, J ¼ 8.1 Hz, 2H, ArH); 7.07e7.33 (m, 10H, eNH-
exchangeable with D2O þ H6 þ H8 þ 7ArH); 7.68 (d, J ¼ 9.0 Hz, 1H,
H7); 7.82 (s, 1H, eNH-exchangeable with D2O); 7.94 (s, 1H, H9); 8.56
b
c
3.2.2. 3-Isobutyl-5-(3-phenyl-allylidene)-2-thioxo-imidazolidin-4-
one (3b)
(d, J ¼ 4.2 Hz, 1H, H5); 13C NMR (75 MHz, DMSO-d6):
ppm ¼ 20.9,
d
60.0, 63.7, 100.1, 117.3, 121.6, 122.0, 123.0, 123.7, 124.9, 126.7, 128.2,
128.7, 128.9, 129.6, 134.2, 134.7, 135.5, 136.2, 149.1, 150.8, 152.3,
163.3, 174.9; HRMS Calculated for C28H23ClN4OS [MþH]þ 499.1281
found 499.1288; Anal. Calcd (%) for: C, 67.39; H, 4.65; N, 11.23,
found: C, 67.45; H, 4.54; N, 11.32.
Yellow Solid; Yield: 84%; m.p. >220 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
(ppm): 1.03 (d, J ¼ 7.5 Hz, 6H, 2ꢁeCH3), 2.52 (m, 1H, eCH),
3.28 (m, 2H, eNeCH2), 6.50 (d, J ¼ 11.7 Hz, 1H, H3), 7.06 (dd, J ¼ 11.7,
15.3 Hz, 1H, H2), 7.18 (d, J ¼ 15.3 Hz, 1H, H1), 7.32e7.50 (m, 5H, ArH),
12.61 (s, 1H, eNH-exchangeable with D2O); 13C NMR (75 MHz,
DMSO-d6):
d
ppm ¼ 19.3, 33.6, 42.7, 115.3, 121.6, 125.8, 127.4, 128.9,
3.3.2. 1-(7-Chloro-quinolin-4-yl)-3-(1-cyclohexyl-2-oxo-4-styryl-
azetidin-3-yl)-thiourea (7b)
129.3, 134.6, 142.1, 166.4, 178.1; HRMS Calculated for C16H18N2OS
[MþH]þ 287.1140 found 287.1135; Anal. Calcd (%) for: C, 67.10; H,
6.33; N, 9.78 found: C, 67.22; H, 6.43; N, 9.64.
Yellow Solid; Yield: 92%; m.p. 164e165 ꢀC. 1H NMR (300 MHz,
CDCl3)
d (ppm): 1.05e1.87 (m, 10H, cyclohexyl-H); 3.30e3.38 (m,
1H, Cyclohexyl-H); 4.61 (dd, J ¼ 4.5, 8.1 Hz, 1H, H3); 5.70 (s, 1H, H4);
6.10 (dd, J ¼ 8.1, 15.9 Hz, 1H, H2); 6.71 (d, J ¼ 15.9 Hz, 1H, H1);
7.17e7.36 (m, 7H, eNH-exchangeable with D2O þ H8 þ 5ArH); 7.67
(d, J ¼ 4.5 Hz, 1H, H6); 7.74 (d, J ¼ 9.0 Hz, 1H, H7); 8.02 (d, J ¼ 1.8 Hz,
1H, H9); 8.13 (s, 1H, eNH-exchangeable with D2O); 8.67 (d,
3.2.3. 5-(3-Phenyl-allylidene)-2-thioxo-3-p-tolyl-imidazolidin-4-
one (3c)
Yellow Solid; Yield: 88%; m.p. >220 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
(ppm): 2.35 (s, 3H, CH3), 6.56 (d, J ¼ 11.7 Hz, 1H, H3), 7.04
(dd, J ¼ 11.7, 15.0 Hz, 1H, H2), 7.14 (d, J ¼ 15.0 Hz, 1H, H1), 7.26e7.80
J ¼ 4.2 Hz, 1H, H5); 13C NMR (75 MHz, DMSO-d6):
d
ppm ¼ 23.6,
(m, 9H, ArH), 12.58 (s, 1H, eNH-exchangeable with D2O); 13C NMR
25.2, 29.1, 30.3, 37.7, 50.9, 57.9, 61.9, 100.5, 114.1, 120.4, 122.6, 123.8,
125.3, 125.4, 126.7, 127.3, 129.4, 133.5, 134.9, 147.9, 150.0, 151.8,
163.9, 175.2; HRMS Calculated for C27H27ClN4OS [MþH]þ 491.1594
found 491.1585; Anal. Calcd (%) for: C, 66.04; H, 5.54; N, 11.41,
found: C, 66.16; H, 5.48; N, 11.49.
(75 MHz, DMSO-d6):
d
ppm ¼ 20.5, 112.6, 113.9, 114.4, 120.7, 125.7,
125.8, 127.2, 127.6, 128.5, 129.1, 134.6, 138.4, 164.3, 175.3; HRMS
Calculated for C19H16N2OS [MþH]þ 321.0983 found 321.0990; Anal.
Calcd (%) for: C, 71.22; H, 5.03; N, 8.74 found: C, 71.13; H, 5.10; N,
8.66.
3.3.3. 1-[1-(4-Chloro-phenyl)-2-oxo-4-styryl-azetidin-3-yl]-3-(7-
chloro-quinolin-4-yl)-thiourea (7c)
3.2.4. 3-Cyclohexyl-5-(3-phenyl-allylidene)-2-thioxo-imidazolidin-
4-one (3d)
Yellow Solid; Yield: 85%; m.p. 188e189 ꢀC. 1H NMR (300 MHz,
Yellow Solid; Yield: 90%; m.p. >220 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
(ppm): 4.75 (dd, J ¼ 4.8, 7.8 Hz, 1H, H3); 5.80 (s, 1H, H4);
CDCl3)
d (ppm): 1.19e2.39 (m, 10H, cyclohexyl-H), 4.51e4.62 (m,
6.22 (dd, J ¼ 7.8, 15.9 Hz, 1H, H2); 6.70 (d, J ¼ 15.9 Hz, 1H, H1); 6.99
(d, J ¼ 8.1 Hz, 2H, ArH); 7.05e7.35 (m, 10H, eNH-exchangeable with
D2O þ H6 þ H8 þ 7ArH); 7.76 (d, J ¼ 9.0 Hz, 1H, H7); 7.92 (s, 1H,
eNH-exchangeable with D2O); 7.96 (s, 1H, H9); 8.63 (d, J ¼ 4.2 Hz,
1H, cyclohexyl-H), 6.52 (d, J ¼ 11.7 Hz, 1H, H3), 7.02 (dd, J ¼ 11.7,
15.0 Hz, 1H, H2), 7.16 (d, J ¼ 15.0 Hz, 1H, H1), 7.30e7.75 (m, 5H, ArH),
12.62 (s, 1H, eNH-exchangeable with D2O); 13C NMR (75 MHz,
DMSO-d6):
d
ppm ¼ 24.7, 25.9, 28.7, 56.6, 115.4, 121.5, 125.8, 127.51,
1H, H5); 13C NMR (75 MHz, DMSO-d6):
d
ppm ¼ 59.8, 62.4, 100.3,
128.9, 129.5, 134.7, 142.0, 166.5, 178.2; HRMS Calculated for
C
18H20N2OS [MþH]þ 313.1296 found 313.1291; Anal. Calcd (%) for:
116.6, 121.7, 122.1, 122.8, 123.5, 124.6, 126.7, 128.4, 128.7, 128.9,
129.6, 130.1, 134.4, 135.5, 136.3, 149.7, 150.3, 152.4, 163.6, 175.0;
HRMS Calculated for C27H20Cl2N4OS [MþH]þ 519.0735 found
519.0742; Anal. Calcd (%) for: C, 62.43; H, 3.88; N, 10.79, found: C,
62.33; H, 3.80; N, 10.73.
C, 69.20; H, 6.45; N, 8.97 found: C, 69.27; H, 6.55; N, 8.90.
3.2.5. 3-(4-Fluoro-phenyl)-5-(3-phenyl-allylidene)-2-thioxo-
imidazolidin-4-one (3e)
Yellow Solid; Yield: 87%; m.p. >220 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
(ppm): 6.55 (d, J ¼ 12.0 Hz, 1H, H3), 7.05 (d, J ¼ 15.0 Hz, 1H,
3.3.4. 1-(7-Chloro-quinolin-4-yl)-3-[1-(4-fluoro-phenyl)-2-oxo-4-
styryl-azetidin-3-yl]-thiourea (7d)
H1), 7.22e7.69 (m, 10H, H2 þ ArH), 12.50 (s, 1H, eNH-exchangeable
with D2O); 13C NMR (75 MHz, DMSO-d6):
d
ppm ¼ 112.5, 113.9,
Yellow Solid; Yield: 93%; m.p. 156e157 ꢀC. 1H NMR (300 MHz,
(ppm): 4.90 (dd, J ¼ 5.1, 7.8 Hz, 1H, H3); 5.76 (s, 1H, H4);
114.2, 120.8, 125.6, 125.9, 127.2, 127.4, 128.9, 129.0, 134.8, 138.6,
161.3, 174.5; HRMS Calculated for C18H13N2OFS [MþH]þ 325.0733
found 325.0742; Anal. Calcd (%) for: C, 66.65; H, 4.04; N, 8.64 found:
C, 66.71; H, 4.16; N, 8.50.
CDCl3)
d
6.25 (dd, J ¼ 7.8, 15.9 Hz, 1H, H2); 6.76 (d, J ¼ 15.9 Hz, 1H, H1); 7.04
(d, J ¼ 8.1 Hz, 2H, ArH); 7.09e7.36 (m, 10H, eNH-exchangeable with
D2O þ H6 þ H8 þ 7ArH); 7.72 (d, J ¼ 9.0 Hz, 1H, H7); 7.91 (s, 1H,
eNH-exchangeable with D2O); 7.98 (s, 1H, H9); 8.61 (d, J ¼ 4.2 Hz,
3.3. General procedure for the synthesis of thiourea tethered 7-
1H, H5); 13C NMR (75 MHz, DMSO-d6):
d
ppm ¼ 59.6, 62.7, 100.4,
chloroquinoline-
b-lactam conjugates (7ae7f)
117.3, 121.5, 122.1, 122.9, 123.6, 124.7, 126.8, 128.3, 128.5, 128.8,
129.0, 129.6, 134.8, 135.5, 136.3, 149.6, 151.0, 152.2, 163.5, 175.1;
HRMS Calculated for C27H20ClFN4OS [MþH]þ 503.1030 found
503.1040; Anal. Calcd (%) for: C, 64.47; H, 4.01; N, 11.14, found: C,
64.56; H, 4.06; N, 11.06.
To a stirred solution of compound 5 (1 mmol) in dry acetone, 3-
amino-2-azetidinone 6 (1 mmol) was added. The reaction mixture
was stirred at room temperature for 10 min, after which a yellow