4.1. Chemistry
All melting points were measured using a SMP3 melting point apparatus. IR spectra were recorded on an FTIR plus 460 or pyeunicam SP-1000 spectrophotometer using KBr pellets. The 1H and 13C NMR spectra were done in the Center of Drug Discovery Research and Development at Ain Shams University, and recorded on a Bruker Avance (III)-400 Spectrometer (400 and 100 MHz, respectively) in DMSOd6 as a solvent using Si(CH3)4 as an internal standard and chemical shifts are reported as δ ppm units. Progress of the reactions was monitored by thin-layer chromatography (TLC) using aluminum sheets coated with silica gel F254 (Merck), and UV lamp.
General procedures for preparation compounds (4a-f)
A mixture of 2-(benzo[d]thiazol-2-yl)acetohydrazide 2 (0.08 mole) and pyridine (10 mL) were stirred for 15 min. Benzoyl chloride derivatives 3a-f (0.16 mole) were added gradually to the reaction mixture in ice bath and stirred for 15 min. The reaction mixture was left at room temperature for 3 h. After the completion of the reaction, the solution was poured onto ice water and neutralized with HCl. The solid formed was filtered off and dried to produce a solid product. The solid product formed was washed using suitable solvent.
N '-(2-(Benzo[ d ]thiazol-2-yl)acetyl)benzohydrazide (4a)
White solid, yield 85%, m.p: 213–214 oC; IR (KBr, cm− 1): υ 3284 (NH), 2974 (CH-Ar), 1696, 1662 (2CO); 1H NMR (400 MHz, DMSO-d6): δ 4.23 (s, 2H, CH2), 7.43 (t, J = 7.2 Hz, 1H, benzothiazole-H), 7.49–7.53 (m, 3H, Ar-H), 7.58 (t, J = 8.4 Hz, 1H, benzothiazole-H), 7.91 (d, J = 7.2 Hz, 2H, Ar-H), 7.99 (d, J = 9.6 Hz, 1H, benzothiazole-H), 8.09 (d, J = 9.2 Hz, 1H, benzothiazole-H), 10.48 (s, 1H, NH), 10.55 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ 39.4 (CH2), 122.5, 122.8, 125.5, 126.5, 127.9, 128.9, 129.0, 132.4, 132.8, 136.9, 152.7, 165.0 (Ar-C), 165.9, 167.1 (2CO); Anal. calcd for C16H13N3O2S (311.36): C% 61.72; H% 4.21; N% 13.50; Found: C% 61.70; H% 4.24; N% 13.55.
N '-(2-(Benzo[ d ]thiazol-2-yl)acetyl)-4-chlorobenzohydrazide (4b)
White solid, yield 80%, m.p: 225–226 oC; IR (KBr, cm− 1): υ 3264 (NH), 3033 (CH-Ar), 1683, 1655 (2CO); 1H NMR (400 MHz, DMSO-d6): δ 4.23 (s, 2H, CH2), 7.44 (t, J = 7.8 Hz, 1H, benzothiazole-H), 7.51 (t, J = 6.6 Hz, 1H, benzothiazole-H), 7.58 (d, J = 10 Hz, 2H, Ar-H), 7.90 (d, J = 7.2 Hz, 2H, Ar-H), 7.98 (d, J = 8.4 Hz, 1H, benzothiazole-H), 8.09 (d, J = 10.8 Hz, 1H, benzothiazole-H), 10.60 (s, 2H, NH); Anal. calcd for C16H12ClN3O2S (345.80): C% 55.57; H% 3.50; N% 12.15; Found: C% 55.60; H% 3.48; N% 12.13.
N' -(2-(Benzo[ d ]thiazol-2-yl)acetyl)-4-bromobenzohydrazide (4c)
White solid, yield 80%, m.p: 238–239 oC; IR (KBr, cm− 1): υ 3265 (NH), 3033 (CH-Ar), 1683, 1656 (2CO); 1H NMR (400 MHz, DMSO-d6): δ 4.21 (s, 2H, CH2), 7.44 (t, J = 7.2 Hz, 1H, benzothiazole-H), 7.51 (t, J = 7.4 Hz, 1H, benzothiazole-H), 7.73 (d, J = 8.4 Hz, 2H, Ar-H), 7.83 (d, J = 8.4 Hz, 2H, Ar-H), 7.97 (d, J = 8 Hz, 1H, benzothiazole-H), 8.09 (d, J = 7.2 Hz, 1H, benzothiazole-H), 10.49 (s, 1H, NH), 10.63 (s, 1H, NH); Anal. calcd for C16H12BrN3O2S (390.25): C% 49.24; H% 3.10; N% 10.77; Found: C% 49.20; H% 3.13; N% 10.79.
N' -(2-(Benzo[ d ]thiazol-2-yl)acetyl)-4-methylbenzohydrazide (4d)
White solid, yield 83%, m.p: 193–195 oC; IR (KBr, cm− 1): υ 3190 (NH), 3027 (CH-Ar), 1669, 1602 (2CO); 1H NMR (400MHz, DMSO-d6): δ 2.36 (s, 3H, CH3), 4.21 (s, 2H, CH2), 7.30 (d, J = 8.0 Hz, 2H, Ar-H), 7.43 (t, J = 6.0 Hz, 1H, benzothiazole-H), 7.51 (t, J = 8.0 Hz, 1H, benzothiazole-H), 7.80 (d, J = 8.0 Hz, 2H, Ar-H), 7.98 (d, J = 8.0 Hz, 1H, benzothiazole-H), 8.08 (d, J = 8.0 Hz, 1H, benzothiazole-H), 10.45 (s, 1H, NH), 10.46 (s, 1H, NH); 13C NMR (100MHz, DMSO-d6): δ 21.4 (CH3), 39.4 (CH2), 122.4, 122.7, 125.5, 126.5, 127.9, 129.5, 129.8, 135.7, 142.5, 152.6, 165.0 (13C, Ar-C), 165.9, 167.1 (2CO); Anal. calcd for C17H15N3O2S (325.38): C% 62.75; H% 4.65; N% 12.91; Found: C% 62.78; H% 4.67; N% 12.89.
N' -(2-(Benzo[ d ]thiazol-2-yl)acetyl)-3-methoxybenzohydrazide (4e)
White solid, yield 70%, m.p: 171–172 oC; IR (KBr, cm− 1): υ 3272 (NH), 3027 (CH-Ar), 1693, 1661 (2CO); 1H NMR (400MHz, DMSO-d6): δ 3.81 (s, 3H, OCH3), 4.20 (s, 2H, CH2), 7.40 (d, J = 8.8 Hz, 1H, Ar-H), 7.39–7.53 (m, 5H, 3Ar-H & 2benzothiazole-H), 7.98 (d, J = 8.8 Hz, 1H, benzothiazole-H), 8.09 (d, J = 10.8 Hz, 1H, benzothiazole-H), 10.46 (s, 1H, NH), 10.51 (s, 1H, NH); Anal. calcd for C17H15N3O3S (341.38): C% 59.81; H% 4.43; N% 12.31; Found: C% 59.84; H% 4.40; N% 12.34.
N '-(2-(Benzo[ d ]thiazol-2-yl)acetyl)-2-nitrobenzohydrazide (4f)
Yellowish white solid, yield 68%, m.p: 178–179 oC; IR (KBr, cm− 1): υ 3175 (NH), 3034 (CH-Ar), 1602 (CO); 1H NMR (400MHz, DMSO-d6): δ 4.21 (s, 2H, CH2), 7.43 (t, J = 8.2 Hz, 1H, benzothiazole-H), 7.51 (t, J = 8.8 Hz, 1H, benzothiazole-H), 7.68–8.12 (m, 6H, 4Ar-H & 2benzothiazole-H), 10.75 (s, 1H, NH), 10.79 (s, 1H, NH); Anal. calcd for C16H12N4O4S (356.36): C% 53.93; H% 3.39; N% 15.72; Found: C% 53.95; H% 3.35; N% 15.70.
General procedures for preparation compounds (7a-g)
A mixture of N'-(2-(benzo[d]thiazol-2-yl)acetyl)benzohydrazide derivatives 4a,d (0.01 mole) and benzaldehyde derivatives 5a-d (0.01 mole) were stirred at room temperature in ethanol containing a catalytic amount of piperidine (3 drops) for 5 h. After the completion of the reaction, the solution was poured onto ice water. The solid formed was filtered, dried, and washed using suitable solvent.
( E )- N '-(2-(Benzo[ d ]thiazol-2-yl)-3-phenylacryloyl)benzohydrazide (7a)
Yellowish white solid, yield 75%, m.p: 216–217 oC; IR (KBr, cm− 1): υ 3267 (NH), 2993 (CH-Ar), 1641 (CO); 1H NMR (400MHz, DMSO-d6): δ 7.45–7.58 (m, 7H, 6 Ar-H & 1benzothiazole-H), 7.62 (t, J = 6.6 Hz, 1H, benzothiazole-H), 7.75 (s, 1H, CH), 7.97–8.04 (m, 5H, 4Ar-H & 1benzothiazole-H), 8.15 (d, J = 8.4 Hz, 1H, benzothiazole-H), 10.73 (s, 1H, NH), 10.89 (s, 1H, NH); Anal. calcd for C23H17N3O2S (399.46): C% 69.15; H% 4.29; N% 10.52; Found: C% 69.19; H% 4.28; N% 10.50.
( E )- N '-(2-(Benzo[ d ]thiazol-2-yl)-3-(4-chlorophenyl)acryloyl)benzohydrazide (7b)
Yellowish white solid, yield 75%, m.p: 232–233 oC; IR (KBr, cm− 1): υ 3268 (NH), 2923 (CH-Ar), 1692, 1644 (2CO); 1H NMR (400MHz, DMSO-d6): δ 7.47–7.64 (m, 7H, 5Ar-H & 2benzothiazole-H), 7.75 (s, 1H, CH), 7.98–8.03 (m, 5H, 4Ar-H & 1benzothiazole-H), 8.16 (d, J = 9.2 Hz, 1H, benzothiazole-H), 10.71 (s, 1H, NH); 13C NMR (400MHz, DMSO-d6): δ 122.6, 123.2, 126.4, 127.2, 128.1, 128.9, 129.1, 130.9, 132.4, 132.5, 132.8, 132.8, 134.5, 134.8, 134.9, 153.4, 165.5 (Ar-C), 166.2, 166.4 (2CO); Anal. calcd for C23H16ClN3O2S (433.91): C% 63.66; H% 3.72; N% 9.68; Found: C% 63.69; H% 3.70; N% 9.72.
( E )- N '-(2-(Benzo[ d ]thiazol-2-yl)-3-( p -tolyl)acryloyl)benzohydrazide (7c)
Yellowish white solid, yield 73%, m.p: 232–233 oC; IR (KBr, cm− 1): υ 3269 (NH), 2921 (CH-Ar), 1686, 1643 (2CO); 1H NMR (400MHz, DMSO-d6): δ 2.37 (s, 3H, CH3), 7.27 (d, J = 6.4 Hz, 2H, Ar-H), 7.47 (t, J = 7.6 Hz, 1H, benzothiazole-H), 7.53–7.57 (m, 3H, Ar-H), 7.62 (t, J = 7.0 Hz, 1H, benzothiazole-H), 7.70 (s, 1H, CH), 7.88 (d, J = 7.6 Hz, 2H, Ar-H), 7.99–8.02 (m, 3H, 2Ar-H & benzothiazole-H), 8.14 (d, J = 8.0 Hz, 1H, benzothiazole-H), 10.72 (s, 1H, NH), 10.82 (s, 1H, NH); Anal. calcd for C24H19N3O2S (413.50): C% 69.71; H% 4.63; N% 10.16; Found: C% 69.74; H% 4.60; N% 10.15.
( E )- N '-(2-(Benzo[ d ]thiazol-2-yl)-3-(4-methoxyphenyl)acryloyl)benzohydrazide (7d)
Yellow solid, yield 73%, m.p: 215–217 oC; IR (KBr, cm− 1): υ 3270 (NH), 2924 (CH-Ar), 1685, 1645 (CO); 1H NMR (400MHz, DMSO-d6): δ 3.82 (s, 3H, OCH3), 7.00 (d, J = 7.6 Hz, 2H, Ar-H), 7.46 (t, J = 8.0 Hz, 1H, benzothiazole-H), 7.52–7.57 (m, 3H, Ar-H), 7.62 (t, J = 7.6 Hz, 1H, benzothiazole-H), 7.67 (s, 1H, CH), 7.95–8.01 (m, 5H, 4Ar-H & 1benzothiazole-H), 8.12 (d, J = 8 Hz, 1H, benzothiazole-H), 10.70 (s, 1H, NH), 10.81 (s, 1H, NH); 13C NMR (400MHz, DMSO-d6):δ 55.8 (OCH3), 114.6, 122.5, 122.9, 125.8, 126.4, 127.0, 127.8, 128.2, 128.9, 132.3, 132.9, 133.0, 134.7, 135.8, 153.6, 161.1, 165.9 (Ar-C), 166.3, 166.9 (2CO); Anal. calcd for C24H19N3O3S (429.11): C% 67.12; H% 4.46; N% 9.78; Found: C% 67.16; H% 4.49; N% 9.74.
( E )- N' -(2-(Benzo[ d ]thiazol-2-yl)-3-phenylacryloyl)-4-methylbenzohydrazide (7e)
White solid, yield 65%, m.p: 200–203 oC; IR (KBr, cm− 1): υ 3265 (NH), 2971 (CH-Ar), 1684, 1641 (2CO); 1H NMR (400MHz, DMSO-d6): δ 2.40 (s, 3H, CH3), 7.35 (d, J = 8.0 Hz, 2H, Ar-H), 7.44–7.50 (m, 4H, Ar-H & benzothiazole-H), 7.56 (t, J = 7.2 Hz, 1H, benzothiazole-H), 7.74 (s, 1H, CH), 7.90 (d, J = 7.6 Hz, 2H, Ar-H), 7.97–7.99 (m, 2H, Ar-H), 8.02 (d, J = 8.0 Hz, 1H, benzothiazole-H), 8.15 (d, J = 8.4, 1H, benzothiazole-H), 10.71 (s, 2H, NH); Anal. calcd for C24H19N3O2S (413.49): C% 69.71; H% 4.63; N% 10.16; Found: C% 69.75; H% 4.65; N% 10.13.
( E )- N '-(2-(Benzo[ d ]thiazol-2-yl)-3-(4-chlorophenyl)acryloyl)-4-methylbenzohydrazide (7f)
White solid, yield 75%, m.p: 223–224 oC; IR (KBr, cm− 1): υ 3269 (NH), 2923 (CH-Ar), 1686,1645 (CO); 1H NMR (400MHz, DMSO-d6): δ 2.40 (s, 3H, CH3), 7.35 (d, J = 8.0 Hz, 2H, Ar-H), 7.47–7.50 (m, 3H, 2Ar-H & 1benzothiazole-H), 7.56 (t, J = 7.8 Hz, 1H, benzothiazole-H), 7.75 (s, 1H, CH), 7.90 (d, J = 8.4 Hz, 2H, Ar-H), 8.00-8.04 (m, 3H, 2Ar-H & 1benzothiazole-H), 8.15 (d, J = 8.4 Hz, 1H, benzothiazole-H), 10.73 (s, 2H, NH); Anal. calcd for C24H18ClN3O2S (447.94): C% 64.35; H% 4.05; N% 9.38; Found: C% 64.34; H% 4.06; N% 9.36.
( E )- N' -(2-(Benzo[ d ]thiazol-2-yl)-3-(4-methoxyphenyl)acryloyl)-4-methylbenzohydrazide (7g)
Off white solid, yield 75%, m.p: 241–243 oC; IR (KBr, cm− 1): υ 3278 (NH), 2953 (CH-Ar), 1681, 1636 (2CO); 1H NMR (400MHz, DMSO-d6): δ 2.39 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 6.99 (d, J = 9.2 Hz, 2H, Ar-H), 7.35 (d, J = 13.6 Hz, 2H, Ar-H), 7.45 (t, J = 11.6 Hz, 1H, benzothiazole-H), 7.54 (t, J = 9.8 Hz, 1H, benzothiazole-H), 7.69 (s, 1H, CH), 7.93 (d, J = 11.6 Hz, 2H, Ar-H), 7.97–8.02 (m, 3H, 2Ar-H & benzothiazole-H), 8.12 (d, J = 9.0 Hz, 1H, benzothiazole-H), 10.64 (s, 1H, NH), 10.77 (s, 1H, NH); Anal. calcd for C25H21N3O3S (443.52): C% 67.70; H% 4.77; N% 9.47; Found: C% 67.73; H% 4.75; N% 9.44.
General procedures for preparation of compounds (10a-d)
A mixture of N'-(2-(benzo[d]thiazol-2-yl)acetyl)benzohydrazide derivatives 4a,d (0.01 mole) and 2-(ethoxymethylene)malononitrile 8a or (E)-ethyl 2-cyano-3-ethoxyacrylate 8b (0.017 mole) were refluxed in ethanol (30 ml) containing sodium ethoxide (0.01 mole) for 5 hours. The formed precipitate was filtered then washed using suitable solvent after drying.
N -(6-Amino-3-(benzo[ d ]thiazol-2-yl)-5-cyano-2-oxopyridin-1(2 H )-yl)benzamide (10a)
Orange solid, yield 70%, m.p: over 350 oC; IR (KBr, cm− 1): υ 3430 (NH, NH2), 2924 (CH-Ar), 2216 (CN), 1631 (CO); 1H NMR (400MHz, DMSO-d6): δ 7.30 (t, J = 9.8 Hz, 1H, benzothiazole-H), 7.45–7.56 (m, 4H, 3Ar-H & 1benzothiazole-H), 7.89 (d, J = 9.2 Hz, 1H, benzothiazole-H), 8.04 (d, J = 9.6 Hz, 1H, benzothiazole-H), 8.23 (d, J = 6.0 Hz, 2H, Ar-H), 8.73 (s, 1H, pyridone-H); 13C NMR (400MHz, DMSO-d6): δ 118.6 (CN), 76.7, 103.9, 121.2, 122.0, 123.6, 126.1, 127.2, 129.2, 130.2, 131.4, 135.0, 136.8, 152.4, 153.7, 156.4 (Ar-C), 162.1, 164.1 (2CO); Anal. calcd for C20H13N5O2S (387.41): C% 62.00; H% 3.38; N% 18.08; Found: C% 62.02; H% 3.40; N% 18.06.
Ethyl 2-amino-1-benzamido-5-(benzo[ d ]thiazol-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (10b)
Orange solid, yield 65%, m.p: over 350 oC; IR (KBr, cm− 1): υ 3433 (NH, NH2), 2925 (CH-Ar), 1685, 1614 (2CO); 1H NMR (400MHz, DMSO-d6): δ 1.16 (t, J = 9.0 Hz, 3H, CH3), 3.97 (q, J = 7.6 Hz, 2H, CH2), 7.25 (t, J = 8.8 Hz, 1H, benzothiazole-H), 7.41 (t, J = 9.2 Hz, 1H, benzothiazole-H), 7.45–7.54 (m, 3H, Ar-H), 7.87 (d, J = 8.8 Hz, 1H, benzothiazole-H), 7.98 (d, J = 9.2 Hz, 1H, benzothiazole-H), 8.22 (d, J = 9.2 Hz, 2H, Ar-H), 9.10 (s, 1H, pyridone-H); Anal. calcd for C22H18N4O4S (434.47): C% 60.82; H% 4.18; N% 12.90; Found: C% 60.83; H% 4.20; N% 12.91.
N -(6-Amino-3-(benzo[ d ]thiazol-2-yl)-5-cyano-2-oxopyridin-1(2 H )-yl)-4-methylbenzamide (10c)
Orange solid, yield 70%, m.p: over 350 oC; IR (KBr, cm− 1): υ 3423 (NH, NH2), 3057 (CH-Ar), 2223 (CN), 1643 (2CO); 1H NMR (400MHz, DMSO-d6): δ 2.43 (s, 3H, CH3), 7.34 (t, J = 8.8 Hz, 1H, benzothiazole-H), 7.40 (d, J = 7.6 Hz, 2H, Ar-H), 7.48 (t, J = 7.8 Hz, 1H, benzothiazole-H), 7.92–7.97 (m, 3H, 2Ar-H & 1benzothiazole-H), 8.04 (d, J = 8.0 Hz, 1H, benzothiazole-H), 8.67 (s, 1H, pyridone-H), 8.71 (s, 2H, NH2), 11.27 (s, 1H, NH); Anal.calcd for C21H15N5O2S (401.44): C% 62.83; H% 3.77; N% 17.45; Found: C% 62.85; H% 3.79; N% 17.42.
Ethyl 2-amino-5-(benzo[ d ]thiazol-2-yl)-1-(4-methylbenzamido)-6-oxo-1,6-dihydropyridine-3-carboxylate (10d)
Orange solid, yield 65%, m.p: over 350 oC; IR (KBr, cm− 1): υ 3433 (NH, NH2), 2920 (CH-Ar), 1685, 1614 (2CO); 1H NMR (400MHz, DMSO-d6): δ 1.39 (t, J = 7.4 Hz, 3H, CH3), 2.44 (s, 3H, CH3), 4.38 (q, J = 7.0 Hz, 2H, CH2), 7.34 (t, J = 8.8 Hz, 1H, benzothiazole-H), 7.42 (d, J = 12.0 Hz, 2H, Ar-H), 7.48 (t, J = 8.8 Hz, 1H, benzothiazole-H), 7.95-8.00 (m, 3H, 2Ar-H & 1benzothiazole-H), 8.04 (d, J = 8.0 Hz, 1H, benzothiazole-H), 8.86 (s, 2H, NH2), 9.12 (s, 1H, pyridone-H), 11.05 (s, 1H, NH); Anal. calcd for C23H20N4O4S (448.49): C% 61.59; H% 4.49; N% 12.49; Found: C% 61.61; H% 4.47; N% 12.47.
General procedures for preparation of compounds (14a-d)
A mixture of N'-(2-(benzo[d]thiazol-2-yl)acetyl)benzohydrazide derivatives 4a,d (0.01 mole) and (Z)-2-cyano-3-(dimethylamino)-N-arylacrylamide derivatives 13a-c (0.01 mole) were refluxed in dioxane containing equimolar of KOH (0.01 mole) for 7 hours. The precipitate formed was filtered then after drying it was washed using a suitable solvent.