Chemistry
Melting points (uncorrected) were determined in open capillary on a Gallen Kamp melting point apparatus (Sanyo Gallen Kamp, UK). Precoated silica gel plates (Kieselgel 0.25 mm, 60 F254, Merck, Germany) were used for thin layer chromatography. A developing solvent system of chloroform/methanol (8:2) was used and the spots were detected by ultraviolet light. IR spectra (KBr disc) were recorded using an FT-IR spectrophotometer (Perkin Elmer, USA). 1H-NMR spectra were scanned on an NMR spectrophotometer (Bruker AXS Inc., Switzerland), operating at 500 MHz for 1H- and 125.76 MHz for 13C. Chemical shifts are expressed in δ-values (ppm) relative to TMS as an internal standard, using DMSO-d
6
as a solvent. Elemental analyses were done on a model 2400 CHNSO analyser (Perkin Elmer, USA). All the values were within ±0.4 % of the theoretical values. All reagents used were of AR grads.
(E)-1-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-(dimethylam-ino)prop-2-en-1-one (4)
1-(4-(7-chloroquinoline-4-ylamino)phenyl)ethanone 2 (2.97 g, 0.01 mol) and dimethylformamide-dimethylacetal (1.19 g, 0.01 mol) was added into dry xylene (30 mL). Reaction was refluxed for 10 h, and the solid product recrystallized from ethanol to give 4.
Yield, 89 %; m.p.268.1 °C. IR: 3100 (arom.), 2966, 2856 (aliph.), 1696 (CO), 1618 (CN), 776 (CCl).). 1HNMR: 2.4 [s, 3H, N(CH3)2], 3.6 [s, 1H, N-CH3], 5.4, 6.5 [2d, 2H, CH = CH quinoline, J = 7.1, 7.3 Hz], 6.1,7.4 [2d, 2H, CH = CH, J = 7.5, 7.4 Hz], 6.9–7.6 [m, 3H, Ar–H]. 13CNMR: 36.3, 44.5 (2), 91.5, 114.6, 115.3, 116.9, 121.4 (2), 131.7, 132.8 (2), 133.0, 135.9, 136.6, 141.4, 146.2, 152.5, 161.4, 166.4, 191.3. MS m/z (%): 365 (M+) (2.84), 74 (100). Anal.Calcd. For C21H20ClN3O (365.86): C, 68.94; H, 5.51; N, 11.49. Found: C, 68.66; H, 5.22; N, 11.74.
Synthesis of sulfonamide derivatives 5–21
4-(7-chloro-1-methylquinolin-4-(1H)-ylideneamino) phenyl-3-(dimethylamino)-prop-2-en-1-one 4 (3.65 g, 0.01 mol) and sulfa-drugs (0.012 mol) was added into ethanol (10 mL) and acetic acid (5 mL). The mixture was refluxed for 18 h. The solid product formed was recrystallized from dioxane to give 5–21.
4-(E)-3-(4-(E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino) phenyl)-3-oxoprop-1-en-ylamino)benzenesulfonamide (5)
Yield, 88 %; m.p. 299.0 °C. IR: 3381, 3209 (NH2, NH), 3078 (arom.), 2937, 2869 (aliph.), 1635 (CO), 1593 (CN), 1373, 1182 (SO2), 867 (CCl). 1HNMR: 3.6 [s, 3H, N-CH3], 6.2, 7.3 [2d, 2H, 2CH quinoline, J = 7.2 Hz], 6.1, 7.6 [2d, 2H, CH = CH, J = 7.4 Hz], 7.7–8.6 [m, 13H, Ar–H + SO2NH2], 12.0 [s, 1H, NH]. 13CNMR: 40.5, 95.1, 99.8, 104.9 (2), 112.5, 115.4, 116.2, 119.5 (2), 125.8 (2), 127.9, 128.2 (2), 133.8, 137.6, 138.4, 143.1, 144.6, 146.7, 152.5, 172.5, 189.3. MS m/z (%): 492 (M+) (4.72), 91 (100). Anal. Calcd. For C25H21ClN4O3S (492.98): C, 60.91; H, 4. 29; N, 11.36. Found: C, 61.19; H, 4.52; N, 11.01.
N-(4-(E)-3-(4-(E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)phenylsulfonyl)acetamide(6)
Yield, 76 %; m.p. 310.0 °C. IR: 3367 (NH), 3066 (arom.), 2939, 2877 (aliph.), 1724, 1635 (2CO), 1593 (CN), 1369,1184 (SO2), 833 (CCl). 1HNMR: 2.0 [s, 3H, COCH3], 3.5 [s, 3H, N-CH3], 6.3, 7.3 [2d, 2H, 2CH quinoline, J = 7.4 Hz], 6.6, 7.6 [2d, 2H, CH = CH, J = 7.6 Hz], 7.7–8.6 [m, 12H, Ar–H + SO2NH], 12.0 [s, 1H, NH]. 13CNMR: 23.6, 40.5, 97.8, 101.3, 112.7(2), 115.1, 116.0, 119.5, 120.2 (2), 125.9 (2), 128.1, 129.5 (2), 130.2, 134.6, 142.8 (2), 144.5, 146.9, 150.0, 152.4, 163.1, 186.7, 189.6. MS m/z (%): 535 (M+) (9.36), 74 (100). Anal. Calcd. For C27H23ClN4O4S (535.01): C, 60.61; H, 4.33; N, 10.47. Found: C, 60.29; H, 4.59; N, 10.19.
N-carbamimidoyl-4-(E)-3-(4-(E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)- phenyl)-3-oxoprop-1-enylamino)benzenesulfonamide (7)
Yield, 81 %; m.p. 146.6 °C. IR: 3431, 3336, 3209 (NH2, NH), 3100 (arom.), 2957, 2858 (aliph.), 1635 (CO), 1593 (CN), 1373, 1178 (SO2), 827 (CCl). 1HNMR: 3.4 [s, 3H, NCH3], 6.2, 7.6 [2d, 2H, 2CH quinoline, J = 7.3 Hz], 6.1, 7.4 [2d, 2H, CH = CH, J = 7.4 Hz], 7.7–8.6 [m, 13H, Ar–H + NH2], 9.4 [s, 1H, NH imino], 10.3, 12.0 [2s, 2H, NH + SO2NH]. 13CNMR: 40.5, 94.9, 99.4, 112.8 (2), 115.2, 116.1, 119.5, 120.2 (2), 125.8 (2), 127.8, 129.5 (2), 131.2, 133.8, 134.6, 138.0, 142.9, 144.8, 145.1, 158.2, 158.5, 172.8, 189.2. MS m/z (%): 535 (M+) (7.74), 76 (100). Anal. Calcd. For C26H23ClN6O3S (535.02): C, 58.37; H, 4. 33; N, 15.71. Found: C, 58.55; H, 4.09; N, 15.47.
4-(E)-3-(4-(E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino) phenyl)-3-oxoprop-1-en-ylamino)-N-(3-methylisoxazol-5-yl)benzenesulfonamide (8)
Yield, 86 %; m.p. 192.5 °C. IR: 3446, 3215 (NH), 3088 (arom.), 2970, 2883 (aliph.), 1635 (CO), 1616 (CN), 1369,1159 (SO2), 821 (CCl). 1HNMR: 2.3 [s, 3H, CH3], 3.4 [s, 3H, NCH3], 6.1, 7.3 [2d, 2H, 2CH quinoline, J = 7.7 Hz], 6.6, 7.6 [2d, 2H, CH = CH, J = 7.4 Hz], 6.7 [s, 1H, CH isoxazole], 7.7–8.5 [m, 12H, Ar–H + SO2NH], 12.0 [s,1H, NH]. 13CNMR: 12.4, 40.5, 95.5, 100.4, 104.7, 113.0 (2), 115.5, 116.3, 119.5, 120.1 (2), 125.8, 129.2 (2), 132.9 (2), 133.7, 134.6, 142.8, 144.9, 145.2, 146.8, 147.4, 153.7, 154.3, 158.5, 170.5, 186.9. MS m/z (%): 574 (M+) (1.62), 58 (100). Anal. Calcd. For C29H24ClN5O4S (574.05): C, 60.68; H, 4. 21; N, 12.20. Found: C, 60.39; H, 4.54; N, 12.49.
4-(E)-3-(4-(E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino) phenyl)-3-oxoprop-1-en-ylamino)-N- (3,4-dimethylisoxazol-5-yl)benzenesulfonamide (9)
Yield, 77 %; m.p. 212.1 °C. IR: 3381, 3230 (NH), 3099 (arom.), 2926, 2819, 2763 (aliph.), 1635 (CO), 1589 (CN), 1373, 1180 (SO2), 810 (CCl). H1 NMR: 1.9, 2.6 [2s, 6H, 2CH3], 3.4 [s, 3H, NCH3], 6.2, 7.3 [2d, 2H, 2CH quinoline, J = 7.6 Hz], 6.6, 7.5 [2d, 2H, CH = CH, J = 7.5 Hz], 7.6–8.6 [m, 11H, Ar–H], 10.4, 12.0 [2s,2H, NH +SO2NH]. 13CNMR: 6.4, 10.8, 40.5, 95.5, 100.3, 102.9, 104.4 (2), 115.5, 116.4, 119.2, 120.7 (2), 126.1, 127.3 (2), 129.5 (2), 133.6, 134.1, 135.2, 142.9, 144.4, 145.4, 147.7, 157.4, 157.9, 161.5, 172.5, 189.3. MS m/z (%): 588 (M+) (11.22), 55 (100). Anal. Calcd. For C30H26ClN5O4S (588.08): C, 61.27; H, 4. 46; N, 11.91. Found: C, 61.01; H, 4.17; N, 11.64.
4-(E)-3-(4-(E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino) phenyl)-3-oxoprop-1-en-ylamino)-N-(1-phenyl-1H-pyrazol-5-yl)benzenesulfonamide (10)
Yield, 80 %; m.p. 94.3 °C. IR: 3417, 3230 (NH), 3064 (arom.), 2966, 2827 (aliph.), 1635 (CO), 1591 (CN), 1373, 1180 (SO2), 763 (CCl). 1HNMR: 3.4 [s, 3H, NCH3], 6.2, 7.5 [2d, 2H, 2CH quinoline, J = 7.5 Hz], 6.5, 7.2 [2d, 2H, CH = CH, J = 7.7 Hz], 7.8–8.6 [m, 18H, Ar–H], 10.2, 12.0 [2s, 2H, NH +SO2NH]. 13CNMR: 40.5, 97.3, 100.0, 103.5, 111.6 (2), 113.0, 116.2, 118.6, 123.7 (2), 124.7 (2), 125.1, 129.0 (2), 129.1, 129.2 (2), 129.3 (2), 129.4, 129.5, 135.1, 136.2, 137.7, 138.9, 140.2, 142.7, 144.3, 146.1, 156.8, 172.4, 186.8. MS m/z (%): 635 (M+) (4.43), 103 (100). Anal. Calcd. For C34H27ClN6O3S (635.13): C, 64.30; H, 4. 28; N, 13.23. Found: C, 64.56; H, 4.52; N, 13.49.
4-(E)-3-(4-(E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino) phenyl)-3-oxoprop-1-en-ylamino)-N-(thiazol-2-yl) benzenesulfonamide (11)
Yield, 69 %; m.p. 172.7 °C. IR: 3341, 3219 (NH), 3101 (arom.), 2937, 2869 (aliph.), 1635 (CO), 1589 (CN), 1373, 1180 (SO2), 773 (CCl). 1HNMR): 3.4 [s, 3H, N-CH3], 5.8, 7.6 [2d, 2H, 2CH quinoline, J = 7.0 Hz], 6.2, 7.2 [2d, 2H, CH = CH, J = 7.3 Hz], 6.6, 6.8 [2d, 2CH thiazole, J = 7.9 Hz], 7.7–8.6 [m, 11H, Ar–H], 10.2, 12.0 [2s, 2H, NH + SO2NH]. 13CNMR: 40.5, 95.1, 99.8, 108.5, 112.9(2), 115.3, 116.2, 119.5, 120.1 (2), 125.9, 128.3 (2), 129.5 (2), 133.0, 134.6, 135.7, 136.9, 143.0, 144.6, 145.1, 146.9, 152.6, 168.4, 172.5, 186.6. MS m/z (%): 576 (M+) (8.99), 101 (100). Anal. Calcd. For C28H22ClN5O3S2 (576.09): C, 58.38; H, 3.85; N, 12.16. Found: C, 58.23; H, 4.11; N, 12.46.
4-(E)-3-(4-(E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino) phenyl)-3-oxoprop-1-en-ylamino)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (12)
Yield, 82 %; m.p. 304.3 °C. IR: 3246, 3115 (NH), 3088 (arom.), 2937, 2859 (aliph.), 1635 (CO), 1589 (CN), 1383, 1182 (SO2), 769 (CCl). 1HNMR: 2.4 [s, 3H, CH3 thiadiazole], 3.4 [s, 3H, N-CH3], 6.2, 7.6 [2d, 2H, 2CH quinoline, J = 7.6 Hz], 6.6, 7.2 [2d, 2H, CH = CH, J = 7.8 Hz], 7.7–8.5 [m, 11H, Ar–H], 10.3, 12.0 [2s, 2H, NH + SO2NH]. 13CNMR: 16.4, 40.5, 95.2, 99.9, 115.4 (2), 116.3, 120.2, 120.4, 125.2 (2), 127.9, 128.2 (2), 129.5 (2), 133.1, 134.8, 135.3, 143.0, 143.8, 144.6, 144.8, 152.1, 154.7, 168.3, 172.4, 189.3. MS m/z (%): 591 (M+) (25.7), 178 (100). Anal. Calcd. For C28H23ClN6O3S2 (591.10): C, 56.89; H, 3.92; N, 14.22. Found: C, 56.59; H, 3.68; N, 14.49.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(pyridin-2-yl)benzenesulfonamide (13)
Yield, 91 %; m.p. 177.1 °C. IR: 3323, 3219 (NH), 3080 (arom.), 2939, 2849 (aliph.), 1654 (CO), 1596 (CN), 1375, 1178 (SO2), 773 (CCl). 1HNMR: 3.4 [s, 3H, NCH3], 6.2, 7.6 [2d, 2H, 2CH quinoline, J = 7.6 Hz], 6.6, 7.3 [2d, 2H, CH = CH, J = 7.1 Hz], 7.7–8.6 [m, 15H, Ar–H],10.3, 12.0 [2s, 2H, NH +SO2NH]. 13CNMR: 40.5, 95.3, 100.0, 104.9, 112.9 (2), 113.7, 115.3, 116.4, 119.5, 120.2 (2), 128.2, 129.5 (2), 132.9 (2), 133.7, 134.4, 135.7, 140.3, 142.9, 143.9, 144.6, 145.2, 146.7, 152.4, 153.4, 172.5, 186.6. MS m/z (%): 570 (M+) (18.2), 79 (100). Anal. Calcd. For C30H24ClN5O3S (570.06): C, 63.21; H, 4. 24; N, 12. 29. Found: C, 63.47; H, 4.52; N, 12.55.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(pyrimidin-2-yl)benzenesulfonamide (14)
Yield, 65 %; m.p. 212.9 °C. IR: 3367, 3179 (NH), 3078 (arom.), 2937, 2870 (aliph.), 1635 (CO), 1577 (CN), 1375,1178 (SO2), 883 (CCl). 1HNMR: 3.4 [s, 3H, N-CH3], 6.2, 7.3 [2d, 2H, 2CH quinoline, J = 7.4 Hz], 6.6, 7.6 [2d, 2H, CH = CH, J = 7.5 Hz], 7.0–8.6 [m, 15H, Ar–H + SO2NH], 12.0 [s, 1H, NH]. 13CNMR: 40.5, 95.5, 100.3, 112.6 (2), 115.9, 116.0, 119.5, 120.2 (2), 125.8, 128.1 (2), 130.3 (2), 132.9, 133.7, 134.3, 134.6, 142.8, 144.3, 145.2, 146.9, 157.6 (2), 157.7, 158.6, 172.5, 186.6. MS m/z (%): 571 (M+) (33.2), 158 (100). Anal. Calcd. For C29H23ClN6O3S (571.05): C, 60.99; H, 4. 06; N, 14.72. Found: C, 61.28; H, 4.32; N, 14.47.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(4-methylpyrimidin-2-yl)benzenesulfonamide (15)
Yield, 78 %; m.p. 274.8 °C. IR: 3366, 3259 (NH), 3076 (arom.), 2962, 2870 (aliph.), 1635 (CO), 1562 (CN), 1373, 1182 (SO2), 773 (CCl). 1HNMR: 2.3 [s, 3H, CH3], 3.4 [s, 3H, NCH3], 6.2, 7.6 [2d, 2H, 2CH quinoline, J = 7.3 Hz], 6.6, 7.3 [2d, 2H, CH = CH, J = 7.4 Hz], 7.5–8.5 [m, 13H, Ar–H], 10.3, 12.0 [2s, 2H, NH + SO2NH]. 13CNMR: 23.7, 40.5, 95.4, 100.2, 104.9, 112.4 (2), 114.9, 115.2, 115.8, 119.6 (2), 128.2, 129.5 (2), 130.5 (2), 132.9, 134.4, 134.6, 142.8, 144.3, 145.3, 146.7, 152.4, 157.4, 158.0, 168.6, 172.5, 186.6. MS m/z (%): 585 (M+) (9.36), 172 (100). Anal.Calcd. For C30H25ClN6O3S (585.08): C, 61.59; H, 4.31; N, 14.36. Found: C, 61.29; H, 4.59; N, 14.09.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (16)
Yield, 91 %; m.p. 97.9 °C. IR: 3354, 3239 (NH), 3055 (arom.), 2947, 2861 (aliph.), 1635 (CO), 1593 (CN), 1371, 1180 (SO2), 864 (CCl). 1HNMR: 2.2 [s, 6H, 2CH3], 3.4 [s, 3H, NCH3], 5.8, 7.2 [2d, 2H, 2CH quinoline, J = 7.3 Hz], 6.6, 7.7 [2d, 2H, CH = CH, J = 7.5 Hz], 7.8–8.5 [m, 13H, Ar–H + SO2NH], 12.0 [s, 1H, NH]. 13CNMR: 23.4 (2), 40.2, 95.3, 100.1, 104.7, 112.3 (2), 113.8, 114.6, 115.4, 120.6 (2), 125.7, 129.4 (2), 130.8 (2), 132.9, 133.7, 134.8, 144.8, 145.0, 146.9, 157.1, 167.7, 167.8 (2), 172.7, 189.3. MS m/z (%): 599 (M+) (2.71), 109 (100). Anal. Calcd. For C31H27ClN6O3S (599.10): C, 62.15; H, 4. 54; N, 14.03. Found: C, 62.36; H, 4.19; N, 14.29.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide (17)
Yield, 84 %; m.p. 264.5 °C. IR: 3396, 3221 (NH), 3101 (arom.), 2979, 2865 (aliph.), 1637 (CO), 1593 (CN), 1371, 1178 (SO2), 862 (CCl). 1HNMR: 3.4 [s, 3H, NCH3], 3.9 [s, 3H, OCH3], 5.9, 7.4 [2d, 2H, 2CH pyrimidine, J = 7.1 Hz], 6.2, 7.3 [2d, 2H, 2CH quinoline, J = 7.8 Hz], 6.6, 7.6 [2d, 2H, CH = CH, J = 7.4 Hz], 7.7–8.6 [m, 11H, Ar–H], 10.3, 12.0 [2s, 2H, NH + SO2NH]. 13CNMR: 40.5, 56.7, 95.4, 100.2, 105.0 (2), 112.6, 115.1, 116.0, 119.6 (2), 125.8, 128.2 (2), 129.8 (2), 130.1, 133.7, 134.6, 142.8, 144.2, 144.9, 145.3, 149.9, 151.7, 152.4, 153.3, 172.5, 186.6, 186.9. MS m/z (%): 601 (M+) (11.87), 74 (100). Anal. Calcd. For C30H25ClN6O4S (601.08): C, 59.95; H, 4.19; N, 13.98. Found: C, 60.23; H, 3.81; N, 13.69.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(2,6-dimethoxypyrimidin-4-yl)benzenesulfonamide (18)
Yield, 87 %; m.p. 232.6 °C. IR: 3387, 3201 (NH), 3097 (arom.), 2980, 2839 (aliph.), 1635 (CO), 1589 (CN), 1352, 1178 (SO2), 771 (CCl). 1HNMR: 3.4 [s, 3H, N-CH3], 3.7 [s, 6H, 2OCH3], 5.9 [s, 1H, CH pyrimidine], 6.2, 7.3 [2d, 2H, 2CH quinoline, J = 7.5 Hz], 6.6, 7.2 [2d, 2H, CH = CH, J = 7.8 Hz], 7.4–8.5 [m, 11H, Ar–H], 10.3, 12.0 [2s, 2H, NH + SO2NH]. 13CNMR: 40.5, 54.1, 54.9, 85.1, 95.6, 100.4, 104.9 (2), 115.4, 116.2, 119.5, 120.2 (2), 128.1, 129.8 (2), 132.7 (2), 132.9, 133.7, 134.6, 142.7, 144.2, 144.9, 145.2, 152.3, 160.8, 161.0, 164.7, 172.0, 186.6. MS m/z (%): 631 (M+) (34.47), 154 (100). Anal. Calcd. For C31H27ClN6O5S (631.10): C, 59.00; H, 4.31; N, 13.32. Found: C, 58.76; H, 4.62; N, 13.03.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(5,6-dimethoxypyrimidin-4-yl)benzenesulfonamide (19)
Yield, 83 %; m.p. 110.5 °C. IR: 3365, 3230 (NH), 3095 (arom.), 2941, 2863 (aliph.), 1635 (CO), 1577 (CN), 1375, 1159 (SO2), 773 (CCl). 1HNMR: 3.4 [s, 3H, N-CH3], 3.6, 3.8 [2s, 6H, 2OCH3], 6.2, 7.2 [2d, 2H, 2CH quinoline, J = 7.6 Hz], 6.6, 7.6 [2d, 2H, CH = CH, J = 7.7 Hz], 7.7–8.4 [m, 11H, Ar–H], 8.5 [s, 1H, CH pyrimidine], 10.3, 12.0 [2s, 2H, NH + SO2NH]. 13CNMR: 40.5, 54.2, 56.5, 95.3, 100.1, 112.6 (2), 115.8, 119.4, 120.8 (2), 127.9, 129.5 (2), 130.2, 133.0 (2), 133.8, 134.7, 142.9, 144.7, 145.1, 146.9, 149.8, 150.9, 152.0, 154.3, 161.7, 172.5, 186.6. MS m/z (%): 631 (M+) (22.13), 189 (100). Anal. Calcd. For C31H27ClN6O5S (631.10): C, 59.00; H, 4.31; N, 13.32. Found: C, 59.31; H, 4.04; N, 13.10.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(1H-indazol-6-yl)benzenesulfonamide (20)
Yield, 89 %; m.p. 100.1 °C. IR: 3374, 3231 (NH), 3086 (arom.), 2978, 2848 (aliph.), 1635 (CO), 1589 (CN), 1363, 1151 (SO2), 819 (CCl). 1HNMR: 3.4 [s, 3H, N-CH3], 5.8, 6.6 [2d, 2H, 2CH quinoline, J = 7.2 Hz], 6.2, 6.8 [2d, 2H, CH = CH, J = 7.5 Hz], 7.0–8.5 [m, 16H, Ar–H + SO2NH], 10.8, 12.0 [2s, 2H, 2NH]. 13CNMR: 40.5, 91.1, 95.5, 100.4, 113.0, 115.1 (2), 115.4, 116.3, 119.5, 119.6, 119.8, 120.0, 120.6, 125.8, 129.0 (2), 129.8 (2), 132.1, 132.8, 133.5, 137.3, 140.7, 143.6, 144.3, 145.3, 146.8, 147.0, 154.3, 173.4, 189.8. MS m/z (%): 609 (M+) (51.63), 117 (100). Anal. Calcd. For C32H25ClN6O3S (609.10): C, 63.10; H, 4.14; N, 13.80. Found: C, 62.76; H, 4.40; N, 14.18.
4-((E)-3-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)-3-oxoprop-1-enylamino)-N-(quinoxalin-2-yl)benzenesulfonamide (21)
Yield, 66 %; m.p. 209.9 °C. IR: 3334, 3212 (NH), 3064 (arom.), 2981, 2863 (aliph.), 1635 (CO), 1591 (CN), 1375, 1178 (SO2), 767 (CCl). 1HNMR: 3.4 [s, 3H, NCH3], 6.2, 7.3 [2d, 2H, 2CH quinoline, J = 7.0 Hz], 6.6, 7.2 [2d, 2H, CH = CH, J = 7.3 Hz], 7.5–8.6 [m, 16H, Ar–H], 10.3, 12.0 [2s, 2H, NH + SO2NH]. 13CNMR: 40.5, 95.5, 100.3, 112.7 (2), 115.1, 116.0, 119.5,120.2 (2), 125.1, 126.3, 127.2, 127.3, 129.1, 130.1 (2), 131.1 (2), 132.8, 133.0, 133.8, 134.7, 138.0, 138.1, 139.2, 140.3, 142.7, 144.3, 149.7, 152.1, 169.6, 186.7. MS m/z (%): 621 (M+) (10.76), 177 (100). Anal. Calcd. For C33H25ClN6O3S (621.11): C, 63.81; H, 4.06; N, 13.53. Found: C, 63.49; H, 4.34; N, 13.23.
(E)-3-(4-(4-aminophenylsulfonyl)phenylamino)-1-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)prop-2-en-1-one (22)
Compound 4 (3.65gm, 0.01 mol) and dapson (2.48 g, 0.01 mol) was added into ethanol (10 mL) and acetic acid (5 mL). The reaction was refluxed for 9 h and the solid obtained while hot was recrystallized from dioxane to give 22.
Yield, 69 %; m.p. 95.2 °C. IR: 3446, 3348, 3213 (NH2, NH), 3100 (arom.), 2956, 2838 (aliph.), 1635 (CO), 1591 (CN), 1369, 1180 (SO2), 821 (CCl). 1HNMR: 3.4 [s, 3H, NCH3], 5.9 [s, 2H, NH2], 6.1, 7.4 [2d, 2H, 2CH quinoline, J = 7.8 Hz], 6.5, 6.6 [2d, 2H, CH = CH, J = 7.9 Hz], 7.5–8.6 [m, 15H, Ar–H], 12.0 [s, 1H, NH]. 13CNMR: 40.5, 95.5, 100.3, 113.3 (2), 113.4, 115.8 (2), 116.6, 119.3, 125.8 (2), 128.9 (4), 129.6 (2), 132.9 (3), 133.7, 135.9, 142.8, 144.2, 145.2, 146.9, 152.4, 154.3, 172.5, 186.6. MS m/z (%): 569 (M+) (19.87), 90 (100). Anal. Calcd. For C31H25ClN4O3S (569.07): C, 65.43; H, 4.43; N, 9.85. Found: C, 65.13; H, 4.71; N, 9.57.
(2E,2′E)-3,3′-(4,4′-sulfonylbis(4,1-phenylene)bis(azanediyl))bis(1-(4-((E)-7-chloro-1-methylquinolin-4(1H)-ylideneamino)phenyl)prop-2-en-1-one) (23)
Compound 4 (7.30 gm, 0.02 mol) and Dapson (2.48 g, 0.01 mol) was added into ethanol (20 mL) containing acetic acid (10 mL). Reaction was refluxed for 12 h and the solid obtained while hot was recrystallized from acetic acid to give 23.
Yield, 60 %; m.p. 186.9 °C. IR: 3143 (NH), 3078 (arom.), 2964, 2842 (aliph.), 1635 (CO), 1570 (CN), 1375, 1180 (SO2), 819 (CCl). 1HNMR: 3.4 [s, 6H, 2N-CH3], 6.2, 7.3 [2d, 4H, 4CH quinoline, J = 7.7 Hz], 6.6, 7.2 [2d, 4H, 2CH = CH, J = 7.8 Hz], 7.4–8.5 [m, 22H, Ar–H], 9.3, 12.0 [2s, 2H, 2NH]. 13CNMR: 40.5 (2), 95.8 (2), 100.7 (2), 104.9 (2), 113.4 (4), 115.8 (2), 116.7 (2), 119.6 (4), 125.8 (4), 129.7 (4), 132.8 (4), 133.6 (2), 134.6 (2), 142.6 (2), 144.0 (2), 145.9 (2), 146.7 (2), 152.3 (2), 172.5 (2), 186.7. MS m/z (%): 889 (M+) (6.48), 272 (100). Anal. Calcd. For C50H38Cl2N6O4S (889.85): C, 67.49; H, 4.30; N, 9.44. Found: C, 67.83; H, 4.66; N, 9.12.
Anticancer screening
The cytotoxic activity in vitro of the novel synthesized compounds was measured using the sulforhodamine B stain (SRB) assay and the method of Skehan et al. [29]. The in vitro anticancer screening was done at pharmacognosy Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Cells were plated in 96-multiwell plate (104 cells/well) for 24 h before treatment with the compound(s) to allow attachment of cell to the wall of the plate. Test compounds were dissolved in dimethylsulfoxide. Different concentrations of the compound under test (10, 25, 50, and 100 μΜ) were added to the cell monolayer. Triplicate wells were prepared for each individual concentration. Monolayer cells were incubated with the compound(s) for 48 h at 37 °C and in an atmosphere of 5 % CO2. After 48 h, cells were fixed, washed and stained for 30 min with 0.4 % (Wt/vol) SRB dissolved in 1 % acetic acid. Excess unbound dye was removed by four washes with 1 % acetic acid and attached stain was recovered with Trise-EDTA buffer. Color intensity was measured using an enzyme-linked immunosorbent assay ELISA reader. Optical density was read at 510 nm. The relation between the surviving fraction and drug concentration was plotted to get the survival curve after the specified time The molar concentration required for 50 % inhibition of cell viability (IC
50
) was calculated and compared to the reference drug 2′,7′-dichlorofluorescein (DCF). The results are given in Table 1.
Molecular docking
“All the molecular modeling studies were carried out on an Intel Pentium 1.6 GHz processor, 512 MB memory with Windows XP operating system using Molecular Operating Environment (MOE, 10.2008) software. All the minimizations were performed with MOE until a RMSD gradient of 0.05 kcal mol−1 Å−1 with MMFF94X force field and the partial charges were automatically calculated. The protein data bank file (PDB: 3S2A) was selected for this purpose. The file contains PI3K enzyme co-crystallized with a quinoline ligand obtained from protein data bank. The enzyme was prepared for docking studies where: (i) Ligand molecule was removed from the enzyme active site. (ii) Hydrogen atoms were added to the structure with their standard geometry. (iii) MOE Alpha Site Finder was used for the active sites search in the enzyme structure and dummy atoms were created from the obtained alpha spheres. (iv) The obtained model was then used in predicting the ligand enzymes interactions at the active site”.