General procedure for the preparation of coumarin-indole derivatives 4a–m
A mixture of 4-hydroxycoumarin 1 (1.0 mmol), benzaldehyde derivatives 2a-m (1.0 mmol), and 1H-indole 3 (1.0 mmol) was heated at 50 °C for 24 h in solvent free condition. After that, the mixture was washed with petroleum ether and the obtained participate was purified using recrystallization from ethyl acetate to obtain pure products 4a–m.
3-((1H-indol-3-yl)(phenyl)methyl)-4-hydroxy-2H-chromen-2-one (4a)
Isolated yield: 87%, mp: 231-233 °C; IR (KBr) 3518, 1740, 1401, 1271, 1142 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 11.65 (s, 1H), 10.95 (s, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.61 (td, J = 7.9, 7.2, 1.5 Hz, 1H), 7.43 – 7.31 (m, 6H), 7.27 (t, J = 7.3 Hz, 2H), 7.22 – 7.12 (m, 2H), 7.12 – 7.02 (m, 1H), 6.98 – 6.89 (m, 1H), 6.15 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 162.24, 160.76, 152.65, 143.18, 136.46, 132.34, 128.63, 128.19, 127.77, 126.15, 124.81, 124.26, 123.92, 121.28, 118.93, 118.78, 116.75, 116.66, 114.64, 111.93, 109.00, 37.56 ppm. Anal. calcd. For C24H17NO3: C, 78.46; H, 4.66; N, 3.81. Found: C, 78.65; H, 4.81; N, 3.62.
3-((1H-indol-3-yl)(p-tolyl)methyl)-4-hydroxy-2H-chromen-2-one (4b)
Isolated yield: 79%, mp: 269-271 °C; IR (KBr) 3397, 1737, 1387, 1284, 1122 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 2H), 7.89 (d, J = 7.9 Hz, 2H), 7.63 – 7.52 (m, 2H), 7.42 – 7.24 (m, 4H), 7.02 (s, 5H), 6.31 (s, 1H), 2.23 (s, 3H). 13C NMR (125 MHz, dmso) δ 165.63, 165.26, 152.63, 137.14, 134.87, 132.31, 129.11, 128.73, 128.52, 127.06, 124.32, 124.18, 123.89, 121.11, 118.36, 118.30, 116.39, 116.31, 114.23, 111.86, 104.69, 36.06, 20.97 ppm. Anal. calcd. For C25H19NO3: C, 78.72; H, 5.02; N, 3.67. Found: C, 78.95; H, 5.19; N, 3.37.
3-((1H-indol-3-yl)(4-methoxyphenyl)methyl)-4-hydroxy-2H-chromen-2-one (4c)
Isolated yield: 85%, mp: 246-248 °C; IR (KBr) 3406, 1736, 1387, 1243, 1123 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 11.86 (s, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.65 – 7.55 (m, 2H), 7.44 – 7.23 (m, 5H), 7.05 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 7.2 Hz, 2H), 6.29 (s, 1H), 3.69 (s, 3H). 13C NMR (125 MHz, dmso) δ 165.40, 165.25, 157.79, 152.60, 133.13, 132.37, 131.73, 128.21, 124.35, 124.30, 124.23, 123.63, 121.52, 118.22, 118.11, 116.80, 116.42, 114.89, 113.95, 111.99, 104.86, 55.40, 35.69 ppm. Anal. calcd. For C25H19NO4: C, 75.55; H, 4.82; N, 3.52. Found: C, 75.83; H, 5.03; N, 3.29.
3-((1H-indol-3-yl)(3-phenoxyphenyl)methyl)-4-hydroxy-2H-chromen-2-one (4d)
Isolated yield: 83%, mp: 183-185 °C; IR (KBr) 3489, 1729, 1401, 1231, 1112 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 2H), 7.88 (dd, J = 7.9, 1.6 Hz, 2H), 7.61 – 7.52 (m, 2H), 7.26 (dq, J = 37.6, 8.2 Hz, 9H), 6.94 (dq, J = 32.0, 6.5, 5.7 Hz, 3H), 6.82 (s, 1H), 6.75 (dd, J = 8.0, 2.2 Hz, 1H), 6.31 (s, 1H). 13C NMR (125 MHz, dmso) δ 166.45, 165.08, 157.21, 156.53, 152.73, 143.55, 136.25, 132.12, 130.25, 130.19, 129.92, 127.25, 124.41, 123.96, 123.92, 123.32, 122.48, 121.27, 118.84, 118.38, 117.96, 116.27, 116.19, 114.08, 111.91, 109.99, 104.18, 36.49 ppm. Anal. calcd. For C30H21NO4: C, 78.42; H, 4.61; N, 3.05. Found: C, 78.25; H, 4.36; N, 3.24.
4-hydroxy-3-((3-hydroxyphenyl)(1H-indol-3-yl)methyl)-2H-chromen-2-one (4e)
Isolated yield: 80%, mp: 200-202 °C; IR (KBr) 3509, 1735, 1399, 1226, 1110 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 3H), 7.90 (dd, J = 8.0, 1.8 Hz, 2H), 7.68 – 7.53 (m, 2H), 7.41 – 7.26 (m, 4H), 7.00 (t, J = 7.5 Hz, 1H), 6.61 – 6.45 (m, 3H), 6.28 (s, 1H). 13C NMR (125 MHz, dmso) δ 165.73, 165.26, 157.67, 152.62, 141.85, 136.51, 132.35, 129.42, 126.68, 124.37, 124.21, 123.98, 121.22, 118.37, 118.34, 117.85, 116.42, 116.39, 114.03, 113.05, 109.95, 104.55, 36.28 ppm. Anal. calcd. For C24H17NO4: C, 75.19; H, 4.47; N, 3.65. Found: C, 74.93; H, 4.69; N, 3.81.
4-Hydroxy-3-((4-hydroxyphenyl)(1H-indol-3-yl)methyl)-2H-chromen-2-one (4f)
Isolated yield: 86%, mp: 286-288 °C; IR (KBr) 3513, 1732, 1378, 1241, 1089 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 3H), 7.82 (dd, J = 7.9, 1.6 Hz, 2H), 7.50 (ddd, J = 8.6, 7.2, 1.7 Hz, 2H), 7.30 – 7.14 (m, 5H), 7.08 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 8.6 Hz, 2H), 6.17 (s, 1H). 13C NMR (75 MHz, DMSO) δ 168.00, 165.01, 155.08, 152.94, 140.00, 132.78, 131.21, 128.00, 124.55, 124.36, 123.68, 123.25, 121.45, 118.39, 118.27, 117.06, 116.85, 114.95, 114.70, 112.02, 104.28, 35.79 ppm. Anal. calcd. For C24H17NO4: C, 75.19; H, 4.47; N, 3.65. Found: C, 75.38; H, 4.57; N, 3.39.
3-((3-Fluorophenyl)(1H-indol-3-yl)methyl)-4-hydroxy-2H-chromen-2-one (4g)
Isolated yield: 87%, mp: 222-224 °C; IR (KBr) 3494, 1730, 1410, 1259, 1126 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 11.78 (s, 1H), 11.00 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.63 (ddd, J = 8.6, 7.1, 1.5 Hz, 1H), 7.45 – 7.30 (m, 5H), 7.22 – 7.14 (m, 2H), 7.12 – 6.84 (m, 4H), 6.15 (s, 1H). 13C NMR (75 MHz, DMSO) δ 164.07 (1JCF=240 Hz), 162.26, 161.02, 152.69, 146.51, 136.45 (3JCF=6.75 Hz), 132.45, 130.01 (3JCF=8.25 Hz), 127.59, 124.86, 124.68 (4JCF=2.25 Hz), 124.29, 123.99, 121.39, 118.92, 118.87, 116.85, 116.71, 115.49 (2JCF=21.75 Hz), 113.95, 113.07 (2JCF=21 Hz), 112.01, 108.57, 37.30 ppm. Anal. calcd. For C24H16FNO3: C, 74.80; H, 4.18; N, 3.63. Found: C, 75.05; H, 3.96; N, 3.77.
3-((4-Fluorophenyl)(1H-indol-3-yl)methyl)-4-hydroxy-2H-chromen-2-one (4h)
Isolated yield: 85%, mp: 243-245 °C; IR (KBr) 3490, 1736, 1392, 1237, 1073, 912 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 10.92 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.45 – 7.18 (m, 6H), 7.11 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 10.3, 7.8 Hz, 3H), 6.90 (t, J = 7.5 Hz, 1H), 6.10 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 162.18, 161.93 (1JCF=240 Hz), 160.78, 152.64, 139.22 (4JCF=2.5 Hz), 136.49, 132.34, 130.43 (3JCF=7.5 Hz), 127.56, 124.72, 124.23, 123.93, 121.30, 118.89, 118.81, 116.70, 116.64, 114.82 (2JCF=20 Hz), 114.51, 111.93, 108.82, 36.94 ppm. Anal. calcd. For C24H16FNO3: C, 74.80; H, 4.18; N, 3.63. Found: C, 74.62; H, 4.41; N, 3.36.
3-((3-Chlorophenyl)(1H-indol-3-yl)methyl)-4-hydroxy-2H-chromen-2-one (4i)
Isolated yield: 80%, mp: 205-207 °C; IR (KBr) 3513, 1728, 1354, 1270, 1118 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 11.00 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.84 (dd, J = 7.8, 1.4 Hz, 1H), 7.75 – 7.53 (m, 2H), 7.45 – 7.32 (m, 6H), 7.20 (d, J = 2.1 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.15 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 162.29, 161.15, 152.71, 136.46, 133.13, 132.90, 132.43, 130.02, 128.37, 127.56, 127.38, 126.15, 124.88, 124.36, 123.67, 121.43, 118.95, 118.88, 116.75, 116.70, 113.81, 112.03, 108.47, 37.27 ppm. Anal. calcd. For C24H16ClNO3: C, 71.73; H, 4.01; N, 3.49. Found: C, 71.98; H, 4.16; N, 3.27.
3-((4-chlorophenyl)(1H-indol-3-yl)methyl)-4-hydroxy-2H-chromen-2-one (4j)
Isolated yield: 82%, mp: 235-237 °C; IR (KBr) 3482, 1663, 1727, 1411, 1240, 1100 cm-1; 1H NMR (499 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.95 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.61 (td, J = 7.6, 7.0, 1.5 Hz, 1H), 7.41 – 7.22 (m, 8H), 7.14 (s, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.09 (s, 1H). 13C NMR (126 MHz, dmso) δ 162.26, 161.67, 152.58, 140.06, 136.57, 133.36, 132.16, 130.86, 127.22, 125.50, 124.69, 124.49, 123.89, 121.31, 118.69, 118.59, 116.72, 116.61, 114.32, 111.78, 104.82, 35.77 ppm. Anal. calcd. For C24H16ClNO3: C, 71.73; H, 4.01; N, 3.49. Found: C, 71.56; H, 3.87; N, 3.70.
3-((3-Bromophenyl)(1H-indol-3-yl)methyl)-4-hydroxy-2H-chromen-2-one (4k)
Isolated yield: 86%, mp: 212-214°C; IR (KBr) 3505, 1737, 1412, 1272, 1010 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.95 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.40 – 7.26 (m, 7H), 7.20 (t, J = 7.9 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.09 (s, 1H). 13C NMR (125 MHz, dmso) δ 162.21, 161.01, 152.66, 146.24, 136.41, 132.46, 131.15, 130.36, 129.03, 127.74, 127.49, 124.82, 124.29, 123.97, 121.58, 121.39, 118.91, 118.81, 116.70, 116.66, 113.71, 111.99, 108.47, 37.21 ppm. Anal. calcd. For C24H16BrNO3: C, 64.59; H, 3.61; N, 3.14. Found: C, 64.79; H, 3.44; N, 3.32.
3-((1H-indol-3-yl)(2-nitrophenyl)methyl)-4-hydroxy-2H-chromen-2-one (4l)
Isolated yield: 84%, mp: 240-242 °C; IR (KBr) 3488, 1726, 1551, 1357, 1239, 1101 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 2H), 7.84 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.59 – 7.46 (m, 4H), 7.40 (d, J = 7.8 Hz, 3H), 7.34 – 7.19 (m, 5H), 6.52 (s, 1H). 13C NMR (125 MHz, dmso) δ 166.02, 163.74, 152.76, 149.92, 135.27, 132.32, 132.03, 130.28, 128.97, 127.42, 126.36, 124.42, 124.26, 123.93, 123.85, 121.70, 118.69, 118.52, 116.43, 116.30, 114.87, 112.00, 103.65, 34.67 ppm. Anal. calcd. For C24H16N2O5: C, 69.90; H, 3.91; N, 6.79. Found: C, 70.17; H, 4.16; N, 6.96.
3-((1H-indol-3-yl)(3-nitrophenyl)methyl)-4-hydroxy-2H-chromen-2-one (4m)
Isolated yield: 84%, mp: 198-200 °C; IR (KBr) 3521, 1729, 1557, 1353, 1150 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 8.2 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.62 – 7.41 (m, 5H), 7.29 (d, J = 8.2 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 6.35 (s, 1H). 13C NMR (125 MHz, dmso) δ 167.93, 164.75, 152.96, 148.21, 145.28, 137.29, 134.30, 131.82, 129.85, 127.77, 124.58, 124.35, 123.63, 121.53, 120.86, 119.80, 118.91, 118.82, 116.12, 116.03, 114.68, 112.13, 103.22, 36.71 ppm. Anal. calcd. For C24H16N2O5: C, 69.90; H, 3.91; N, 6.79. Found: C, 70.11; H, 4.08; N, 6.58.
In vitro α‐glucosidase inhibition assay and kinetic study
The α‐glucosidase inhibition assays of the coumarin-indole derivatives 4a–m and kinetic study of the most potent compound 4d were performed into yeast α‐glucosidase (Saccharomyces cerevisiae, EC 3.2.1.20, 20 U/mg) according to the literature [27].
Docking study
Docking study of the most potent compounds 4a-d in the modeled α-glucosidase active site was performed according to our previously described method [27].
In silico druglikeness/ADME/T studies
In silico druglikeness/ADME/T prediction of the most potent compounds 4a-d, 4g, and 4m were performed using the preADMET online server [28].