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L. Nagarapu et al. / European Journal of Medicinal Chemistry 45 (2010) 4720e4725
d
1.40 (t, J ¼ 7.08 Hz, 3H, CH3), 4.36 (q, J ¼ 7.08 Hz, 2H, OCH2CH3),
4.5.4. 1-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]-3-m-tolyl-1H-
7.32 (s, 1H, AreH), 7.69 (t, J ¼ 6.51 Hz,1H, AreH), 8.15 (d, J ¼ 7.36 Hz,
1H, AreH), 8.24 (d, J ¼ 7.36 Hz, 1H, AreH), 8.66 (s, 1H, AreH), ESI-
MS: m/z ¼ 262 [MþH]þ.
pyrazole-5-carboxylic acid (3d)
Brown solid in a yield of 76%, mp 150 ꢀC, IR (KBr, v cmꢁ1): 3441
(OeH, NeH), 2925 (AreH), 1634 (C]O), 1H NMR (300 MHz, DMSO-
d6):
d
2.78 (s, 1H, OH), 2.39 (s, 3H, CH3), 4.24 (d, J ¼ 4.91 Hz, 2H,
4.4.7. Ethyl 3-(2-nitrophenyl)-1H-pyrazole-5-carboxylate (1g)
Yellow solid in a yield of 98%, mp 106 ꢀC, IR (KBr, cmꢁ1): 3276
(NeH), 2992 (AreH), 1705 (C]O), 1H NMR (400 MHz, DMSO-d6):
CH2), 4.53e4.63 (m, 1H, CH), 4.92e4.99 (m, 2H, CH2), 6.58 (d,
J ¼ 7.74 Hz, 1H, AreH), 7.01e7.15 (m, 3H, AreH), 7.18e7.31 (m, 3H,
AreH), 7.40 (d, J ¼ 8.12 Hz, 1H, AreH), 7.55 (d, J ¼ 7.74 Hz, 1H,
AreH), 7.60 (s, 1H, AreH), 7.82 (s, 1H, AreH), 8.35 (d, J ¼ 7.74 Hz, 1H,
d
1.41 (t, J ¼ 7.17 Hz, 3H, CH3), 4.36 (q, J ¼ 7.17 Hz, 2H, OCH2CH3), 6.88
(s, 1H, AreH), 7.50 (t, J ¼ 7.64 Hz, 1H, AreH), 7.62 (t, J ¼ 7.45 Hz, 1H,
AreH), 10.79 (s, 1H, NH), 13C NMR (DMSO-d6, 75 MHz)
d: 21.14,
AreH), 7.72 (d, J ¼ 7.17 Hz, 2H, AreH), ESI-MS: m/z ¼ 262 [MþH]þ
54.04, 68.94, 70.06,100.48, 104.14, 107.75, 110.43, 111.74, 118.81,
121.83, 122.50, 122.96, 124.71, 125.82, 126.60, 128.67, 132.45, 136.26,
137.98, 139.02, 141.24, 149.08, 154.93, 161.27; ESI-MS: m/z ¼ 464
[MþNa]þ
4.5. General procedure for the synthesis 1-[3-(9H-carbazol-4-
yloxy)-2-hydroxypropyl]-3-aryl-1H-pyrazole-5-carboxylic acid
(3aeg)
4.5.5. 1-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]-
A mixture of 5-(4-methoxyphenyl)-2H-pyrazole-3-carboxylic
acid ethyl ester 1a (103 mg, 0.42 mmol), 4-oxiranylmethoxy-9H-
carbazole (2, 100 mg, 0.42 mmol), potassium carbonate (116 mg,
0.82) and tetrabutylammonium iodide (2 mg) were heated in
acetonitrile (10 mL) at 80 ꢀC for 32 h under nitrogen atmosphere.
The reaction mass were extracted with ethyl acetate. The organic
layer dried over sodium sulphate and concentrated crude product
obtained was purified by column chromatography over silica gel to
give following compounds.
3-(4-nitrophenyl)-1H-pyrazole-5-carboxylic acid (3e)
Yellow solid in a yield of 75%, mp 145 ꢀC, IR (KBr, v cmꢁ1): 3407
(OeH, NeH), 2928(AreH), 1707 (C]O), 1H NMR (400 MHz, DMSO-
d6): d2.79 (s, 1H, OH), 4.16 (dd, 2H, CH2), 4.45 (m, 1H, CH), 4.93 (dd,
2H, CH2), 6.56 (d, J ¼ 8.0 Hz, 1H, AreH), 7.02 (d, J ¼ 8.05 Hz, 1H,
AreH), 7.12 (m, 2H, AreH), 7.19 (t, J ¼ 8.05, 1H, AreH), 7.25 (t,
J ¼ 8.05 Hz, 1H, AreH), 7.37 (d, J ¼ 8.05 Hz, 1H, AreH), 7.92
(d, J ¼ 8.79 Hz, 2H, AreH), 8.14 d, J ¼ 8.79 Hz, 2H, AreH), 8.31 (d,
J ¼ 8.05 Hz, 1H, AreH), 10.79 (s, 1H, NH), 13C NMR (DMSO-d6,
75 MHz) d: 54.12, 69.38, 70.04, 100.42, 104.00, 107.53, 110.36, 11.65,
4.5.1. 1-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]-3-
118.69, 121.73, 122.73, 124.07, 124.56, 125.78, 126.46, 138.97, 139.60,
141.15, 142.04, 146.18, 146.32, 154.85, 162.56, ESI-MS: m/z ¼ 495
[M þ þNa]þ.
(4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (3a)
Brown solid in a yield of 67%, mp 140e142 ꢀC, IR (KBr, v cmꢁ1):
3400 (OeH, NeH), 2931 (AreH), 1713 (C]O), 1H NMR (400 MHz,
DMSO-d6):
d
2.74 s, 1H, OH), 3.81 (s, 3H, OCH3), 4.16e4.26 (m, 2H,
4.5.6. 1-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]-
CH2), 4.49e4.58 (m, 1H, CH), 4.79e4.99 (m, 2H, CH2), 6.62 (d,
J ¼ 8.05 Hz,1H, AreH), 6.93 (d, J ¼ 8.95 Hz, 2H, AreH), 7.04e7.15 (m,
3H, AreH), 7.21e7.35 (m, 2H, AreH), 7.42 (d, J ¼ 7.16 Hz, 1H, AreH),
7.73 (d, J ¼ 8.95 Hz, 2H, AreH), 8.35 (d, J ¼ 8.05 Hz, 1H, AreH), 11.10
3-(3-nitrophenyl)-1H-pyrazole-5-carboxylic acid (3f)
Pale yellow solid in a yield of 73%, mp 138 ꢀC, IR (KBr, v cmꢁ1):
3048 (OeH, NeH), 2928 (AreH), 1712 (C]O); 1H NMR (400 MHz,
DMSO-d6):
d
2.81 (s, 1H, OH); 4.28 (d, J ¼ 4.72 Hz, 2H, CH2), 5.04 (d,
(s, 1H, NH), 13C NMR (DMSO-d6, 75 MHz)
d
: 53.79, 55.03, 68.67,
J ¼ 5.85 Hz, 2H, CH2), 4.62 (m, 1H, CH), 6.59 (d, J ¼ 7.93 Hz, 1H,
AreH), 7.03 (d, J ¼ 7.93 Hz, 1H, AreH), 7.12 (t, J ¼ 7.46 Hz,1H, AreH),
7.24 (m, 3H, AreH), 7.38 (d, J ¼ 8.12 Hz, 1H, AreH), 7.57 (t,
J ¼ 7.83 Hz, 2H, AreH), 8.12 (d, J ¼ 7.93 Hz, 1H, AreH), 8.34 (d,
J ¼ 7.74 Hz, 1H, AreH), 8.61 (s, 1H, AreH), 10.47 (s, 1H, NH), 13C NMR
70.01, 100.28, 103.91, 107.17, 110.19, 111.56, 114.01, 118.57, 121.61,
122.75, 124.47, 125.02, 126.37, 135.33, 138.84, 141.05, 148.80, 154.76,
158.97,160.86, ESI-MS: m/z ¼ 458 [MþH]þ.
4.5.2. 1-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]-3-
(DMSO-d6, 75 MHz) d: 54.28, 68.77, 70.02, 100.30, 103.97, 108.34,
(3-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (3b)
110.25, 111.58, 118.59, 119.17, 121.65, 122.32, 122.79, 124.50, 126.40,
130.37, 131.50, 134.19, 137.05, 138.88, 141.08, 146.69, 148.26, 154.74,
160.99, ESI-MS: m/z ¼ 495 [MþNa].
Brown solid in a yield of 90%, mp 142 ꢀC, IR (KBr, v cmꢁ1): 3407
(OeH, NeH), 2932 (AreH), 1668 (C]O), 1H NMR (300 MHz, DMSO-
d6):
d
2.79 (s,1H, OH), 3.79 (s, 3H, OCH3), 4.24 (d, J ¼ 5.09 Hz, 2H, CH2),
4.56 (m, 1H, CH), 4.99 (m, 2H, CH2), 6.59 (d, J ¼ 7.93 Hz, 1H, AreH),
6.79 (d, J ¼ 7.55 Hz, 1H, AreH), 7.07 (m, 3H, AreH), 7.24 (m, 2H,
AreH), 7.42 (d, J ¼ 7.16 Hz,1H, AreH), 7.32 (t, J ¼ 6.98 Hz, 2H, AreH),
7.40 (d, J ¼ 7.93 Hz,1H, AreH), 7.82 (s,1H, AreH), 8.36 (d, J ¼ 7.74 Hz,
1H, AreH), 10.79 (s, 1H, NH), ESI-MS: m/z ¼ 480[MþNa]þ.
4.5.7. 1-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]-
3-(3-nitrophenyl)-1H-pyrazole-5-carboxylic acid (3g)
Pale yellow solid in a yield of 76%, mp 139 ꢀC, IR (KBr, v cmꢁ1):
3416 (OeH, NeH), 2928 (AreH), 1704 (C]O), 1H NMR (400 MHz,
DMSO-d6):
d
2.80 (s, 1H, OH), 4.22 (d, J ¼ 5.09 Hz, 2H, CH2), 4.56 (m,
1H, CH), 4.97 (d, J ¼ 5.66 Hz, 2H, CH2), 6.60 (d, J ¼ 7.74 Hz, 1H,
AreH), 6.96 (s, 1H, AreH), 7.04 (d, J ¼ 8.12 Hz, 1H, AreH), 7.12 (t,
J ¼ 7.17 Hz, 1H, AreH), 7.19e7.31 (m, 2H, AreH), 7.39 (d, J ¼ 7.93 Hz,
1H, AreH), 7.49 (t, J ¼ 7.64 Hz, 1H, AreH), 7.72(t, J ¼ 7.74 Hz, 2H,
AreH), 8.32 (d, J ¼ 7.74 Hz, 1H, AreH), 10.69 (s, 1H, NH), 13C NMR
4.5.3. 1-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]-3-p-tolyl-1H-
pyrazole-5-carboxylic acid (3c)
Light brown solid in a yield of 78%, mp 154 ꢀC, IR (KBr, v cmꢁ1):
3410 (OeH, NeH), 2926 (AreH), 1709 (C]O), 1H NMR (500 MHz,
DMSO-d6):
d
2.73 (s, 1H, OH), 2.29 (s, 3H, CH3), 4.14e4.23 (m, 2H,
(DMSO-d6, 75 MHz) d: 54.16, 68.83, 69.99, 100.53, 104.14, 109.58,
CH2), 4.46e4.55 (m, 1H, CH), 4.83e4.99 (m, 2H, CH2), 6.51 (d,
J ¼ 9.25 Hz,1H, AreH), 6.97 (d, J ¼ 8.22 Hz,1H, AreH), 6.99e7.14 (m,
3H, AreH), 7.21(t, J ¼ 8.22 Hz, 1H, AreH), 7.32 (d, J ¼ 8.22 Hz, 2H,
AreH), 7.58 (d, J ¼ 8.22 Hz, 2H, AreH), 7.62 (s, 1H, AreH), 8.29 (d,
J ¼ 8 Hz, 1H, AreH), 10.55 (s, 1H, NH), 13C NMR (DMSO-d6, 75 MHz)
110.39, 111.71, 118.83, 121.80, 122.94, 123.74, 124.71, 125.38, 126.60,
129.40, 130.38, 132.36, 136.49, 138.99, 141.21, 144.76, 148.62, 154.85,
160.90, ESI-MS: m/z ¼ 495 [MþNa]þ.
4.6. In vitro cytotoxic activity evaluation by SRB assay
d
: 20.82, 53.87, 69.18, 70.07, 100.35, 104.02, 106.67, 110.34, 111.65,
118.66, 121.74, 122.82. 124.56, 125.06, 126.46, 129.25, 130.06, 136.93,
138.47, 138.96, 141.15, 148.65, 154.85, 162.06, ESI-MS: m/z ¼ 464
[MþNa]þ.
The newly obtained derivatives were evaluated for cytotoxic
activity to cancer cell lines by using the sulforhodamine B (assay)
method [8,9]. The cells were grown in minimal essential medium