Design, synthesis, molecular docking, and in vitro antidiabetic activity of novel PPARc agonist
J = 7.3 Hz 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.57–7.55 (dd,
J = 1.2, 6.5 Hz, 1H), 7.41–7.30 (m, 3H), 7.18 (t,
J = 3.2 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.96 (t,
J = 3.6 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 4.27 (t,
J = 6.5 Hz, 2H), 3.40 (t, J = 6.5 Hz, 2H) ppm; 13C NMR
(CDCl3, 100 MHz): d = 159.59, 157.80, 153.78, 148.76,
139.76, 132.63, 132.41, 130.45, 129.28, 126.98, 125.94,
125.79, 124.76, 124.29, 124.08, 122.30, 121.19, 119.49,
112.81, 112.12, 69.12, 29.89 ppm; IR (KBr): m = 3102,
3024, 2926, 2874, 2740, 2500, 1726, 1594, 1502, 1302,
1253, 1152 cm-1; MS (ESI): m/z = 405.07 [M??1].
After the completion of reaction, as indicated by TLC
(dichloromethane/methanol, 9:1), the reaction mass was
cooled at 10 °C, filtered, and washed with methanol. The
product was re-crystallized from methanol to get the titled
compounds.
4-[[o-[(3R)-3-Hydroxy-3-phenylpropoxy]phenyl]methyl-
idene]-5-thia-2,7-diazatricyclo[6.4.0.02,6]dodeca-1,(8),6,9,11-
tetraen-3-one (28a, C25H20N2O3S) Light-yellow solid;
yield 0.36 g (35%); m.p.: 126–128 °C; Rf = 0.55
(dichloromethane/methanol, 9:1); 1H NMR (DMSO-d6,
400 MHz): d = 8.39 (s, 1H), 7.98–7.95 (m, 1H), 7.63 (d,
J = 7.2 Hz, 1H), 7.57–7.55 (m, 1H), 7.49–7.45 (m, 1H),
7.40–7.30 (m, 6H), 7.22 (t, J = 7.2 Hz, 1H), 7.13–7.08 (m,
2H), 5.39 (d, J = 4.3 Hz, 1H, –OH), 4.90–4.85 (m, 1H),
4.32–4.26 (m, 1H), 4.16–4.11 (m, 1H), 2.19-2.14 (m, 2H)
ppm; 13C NMR (DMSO-d6, 100 MHz): d = 158.99,
157.70, 153.11, 148.24, 145.44, 135.17, 132.82, 131.11,
130.01, 128.70, 127.92, 126.68, 125.53, 125.45, 124.16,
123.77, 121.28, 120.72, 119.04, 112.44, 112.20, 105.0,
69.16, 65.41, 38.53 ppm; IR (KBr): m = 3355, 3064, 3003,
3030, 2934, 1724, 1501, 1380, 1251, 1152 cm-1; MS
(ESI): m/z = 429.16 [M??1].
4-[[m-[2-Thienyl)ethoxy]phenyl]methylidene]-5-thia-2,7-di-
azatricyclo[6.4.0.02.6]dodeca-1(8),6,9,11-tetraene-3-one
(27b, C22H16N2O2S2) The title compound was synthesized
from 0.24 g compound 26b (1.0 mmol) and 0.20 g com-
pound 7 (1.0 mmol) according to the general procedure
described above. Light-yellow solid; yield 0.24 g (58%);
m.p.: 138–140 °C; Rf = 0.79 (ethyl acetate/hexane, 3:7);
1H NMR (CDCl3, 400 MHz): d = 7.99–7.95 (m, 2H), 7.64
(d, J = 7.6 Hz, 1H), 7.40–7.25 (m, 3H), 7.19–7.15 (m, 2H),
7.09–7.08 (m, 1H), 6.99–6.93 (m, 3H), 4.22 (t, J = 6.6 Hz,
2H), 3.33 (t, J = 6.6 Hz, 2H) ppm; 13C NMR (CDCl3,
100 MHz): d = 159.38, 159.20, 153.37, 148.80, 139.99,
136.69, 134.13, 130.42, 130.36, 126.91, 125.95, 125.68,
125.33, 124.26, 124.18, 123.01, 119.64, 117.53, 116.11,
112.84, 68.66, 29.93 ppm; IR (KBr): m = 3058, 3017,
2954, 2880, 2756, 2534, 1728, 1610, 1503, 1379, 1274,
1172 cm-1; MS (ESI): m/z = 405.10 [M??1].
4-[[m-[(3R)-3-Hydroxy-3-phenylpropoxy]phenyl]methyl-
idene]-5-thia-2,7-diazatricyclo[6.4.0.02,6]dodeca-1,(8),6,9,11-
tetraen-3-one (28b, C25H20N2O3S) Light-yellow solid;
yield 0.34 g (33%); m.p.: 132–134 °C; Rf = 0.62
(dichloromethane/methanol, 9:1); 1H NMR (DMSO-d6,
400 MHz): d = 8.03 (s, 1H), 7.95–7.93 (dd, J = 1.4,
5.6 Hz, 1H), 7.64–7.62 (dd, J = 1.2, 5.8 Hz, 1H), 7.43 (t,
J = 8.0 Hz,1H), 7.40–7.31 (m, 6H), 7.25–7.21 (m, 2H),
7.19 (d, J = 1.9 Hz, 1H), 7.05–7.02 (dd, J = 2.2, 5.9 Hz,
1H), 5.34 (d, J = 4.4 Hz, 1H, –OH), 4.85–4.80 (m, 1H),
4.24–4.16 (m, 1H), 4.07–4.02 (m, 1H), 2.12–2.07 (m, 2H)
ppm; 13C NMR (DMSO-d6, 100 MHz): d = 159.08,
158.74, 152.90, 148.27, 145.58, 136.14, 133.74, 130.24,
129.99, 127.89, 126.67, 125.59, 125.51, 124.86, 123.87,
122.15, 119.13, 117.35, 115.71, 112.22, 69.07, 64.80,
38.48 ppm; IR (KBr): m = 3277, 3062, 2957, 2879, 1728,
1606, 1510, 1376, 1256, 1149 cm-1; MS (ESI): m/
z = 429.16 [M??1].
4-[[p-[2-Thienyl)ethoxy]phenyl]methylidene]-5-thia-2,7-di-
azatricyclo[6.4.0.02.6]dodeca-1(8),6,9,11-tetraene-3-one
(27c, C22H16N2O2S2) The title compound was synthesized
from 0.24 g compound 26c (1.0 mmol) and 0.20 g com-
pound 7 (1.0 mmol) according to the general procedure
described above. Light-yellow solid; yield 0.26 g (63%);
m.p.: 218–220 °C; Rf = 0.82 (ethyl acetate/hexane, 3:7);
1H NMR (CDCl3, 400 MHz): d = 8.09 (s, 1H), 7.98–7.96
(m, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.70 (d, J = 7.0 Hz,
2H), 7.43–7.36 (m, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.0–6.97
(m, 2H), 4.32 (t, J = 6.6 Hz, 2H), 3.29 (t, J = 6.6 Hz, 2H)
ppm; 13C NMR (CDCl3, 100 MHz): d = 159.38, 159.20,
153.37, 148.80, 139.99, 136.69, 134.13, 130.42, 130.36,
126.91, 125.95, 125.68, 125.33, 124.26, 124.18, 123.01,
119.64, 117.53, 116.11, 112.84, 68.66, 29.93 ppm; IR
(KBr): m = 3073, 3106, 2943, 2883, 1713, 1594,1378,
1260, 1153 cm-1; MS (ESI): m/z = 405.10 [M??1].
4-[[p-[(3R)-3-Hydroxy-3-phenylpropoxy]phenyl]methyl-
idene]-5-thia-2,7-diazatricyclo[6.4.0.02,6]dodeca-1,(8),6,9,11-
tetraen-3-one (28c, C25H20N2O3S) Light-yellow solid;
yield 0.43 g (41%); m.p.: 182–184 °C; Rf = 0.75
(dichloromethane/methanol, 9:1); 1H NMR (DMSO-d6,
400 MHz): d = 2.10–2.05 (m, 2H), 4.10–4.05 (m, 1H),
4.27–4.21 (m, 1H), 4.81–4.77 (m, 1H), 5.36 (d, J = 4.5 Hz,
1H, –OH) 7.12–7.10 (d, J = 8.8 Hz, 2H), 7.25–7.21 (m,
1H), 7.41–7.30 (m, 6H), 7.69–7.64 (m, 1H), 7.97–7.95 (dd,
J = 1.3, 5.4 Hz, 1H), 8.05 (s, 1H) ppm; 13C NMR (DMSO-
d6, 100 MHz): d = 161.0, 159.17, 148.28, 145.60, 136.23,
General procedure for the synthesis
of compounds 28a–28c
A mixture of 0.64 g of compounds 15a–15c (2.50 mmol)
and 0.48 g compound 7 (2.50 mmol) was refluxed for 8 h
in methanol in the presence of 1–2 drops of pyrrolidine.
123