Design, synthesis and antiproliferative activities of diaryl urea derivatives bearing N-acylhydrazone moiety

Article abstract of DOI:10.1016/j.cclet.2012.06.009

A new series of diaryl urea derivatives bearing N-acylhydrazone moiety were designed and synthesized. All the target compounds were evaluated for their antiproliferative activities against human leukemia cell line (HL-60), human lung adenocarcinoma epithelial cell line (A549) and human breast cancer cell line (MDA-MB-231) in vitro by standard MTT assay. The pharmacological results indicated that some compounds exhibited promising antitumor activities. Compound 1j showed the most potent antiproliferative activity against the tested three cell lines with IC₅₀ values of 0.13 μmol/L, 0.7 μmol/L and 0.5 μmol/L, respectively.

Full text of DOI:10.1016/j.cclet.2012.06.009

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 915–918
www.elsevier.com/locate/cclet
Design, synthesis and antiproliferative activities of diaryl urea
derivatives bearing N-acylhydrazone moiety
Bei Zhang a, Yan Fang Zhao a, Xin Zhai a, Wei Jie Fan a, Jun Ling Ren a,
Chun Fu Wu b, Ping Gong a,
*
a Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering,
Shenyang Pharmaceutical University, Shenyang 110016, China
b School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
Received 17 April 2012
Available online 4 July 2012
Abstract
A new series of diaryl urea derivatives bearing N-acylhydrazone moiety were designed and synthesized. All the target compounds
were evaluated for their antiproliferative activities against human leukemia cell line (HL-60), human lung adenocarcinoma epithelial
cell line (A549) and human breast cancer cell line (MDA-MB-231) in vitro by standard MTT assay. The pharmacological results
indicated that some compounds exhibited promising antitumor activities. Compound 1j showed the most potent antiproliferative
activity against the tested three cell lines with IC50 values of 0.13 mmol/L, 0.7 mmol/L and 0.5 mmol/L, respectively.
# 2012 Ping Gong. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Diaryl ureas; N-acylhydrazone; Antiproliferative activities
In recent years, medicinal chemists paid much attention to the design and discovery of multi-targeted anti-cancer
drugs, with an aim of enhancing the efficacy and safety relative to drugs that modulate only a single target [1–4].
Sorafenib (Fig. 1), the first bioavailable multiple kinase inhibitor, is reported to have a reasonable enzyme potency
against both Raf and VEGF and PDGF receptor tyrosine kinases [5] and pathway inhibition in cells (IC50 values of 40–
1200 nmol/L depending on the cell line) [6,7]. PAC-1 (Fig. 1) is the first small molecular procaspase-3 activator [8],
which induces apoptotic death in tumor cell lines and retards tumor growth in vivo [9].
Inspired by the structures of sorafenib and PAC-1, we retained the pharmacophoric domains (diaryl urea from
sorafenib and N-acylhydrazone from PAC-1) and fused them through a thiazole ring as the linker. Thus we designed
and synthesized a series of diaryl urea derivatives bearing N-acylhydrazone moiety (Fig. 1). Various ureido-linked
phenyl (Ar1) and hydrazone-linked phenyl (Ar2) groups were introduced to explore the influence of electronic and
steric effects on the antitumor activity (structure 1). Since the PAC-1 derivatives without the hydroxyl group displayed
no anti-cancer activity in vitro [9], 2-hydroxy substitution was retained for the phenyl ring Ar2. Furthermore, an
imidazolindione fragment was inserted between the hydrazone and Ar2 to investigate the influence of the alteration of
the hydrazone scaffold on the antiproliferative activity (structure 2).
* Corresponding author.
E-mail address: gongpinggp@126.com (P. Gong).
1001-8417/$ – see front matter # 2012 Ping Gong. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.009

[(Fig._1)TD$FIG]
916
B. Zhang et al. / Chinese Chemical Letters 23 (2012) 915–918
Fig. 1. Structures of sorafenib, PAC-1 and target compounds.
A general synthesis of target compounds is described in Scheme 1. The commercially available 4-aminobezo-nitrile
reacted with triphosgene in dioxane to obtain 4-isocyanatobenzonitrile 3. Subsequent treatment of 3 with different
substituted anilines afforded diaryl ureas 4a–f, which were then turned into thioamides 5a–f under the condition of
magnesium chloride and sodium bisulfide in N,N-dimethylformamide. Cyclization of 5a–f with 1,3-dichloroacetone in
tetrahydrofuran readily afforded thiozoles 6a–f, which was subjected to a three-step nucleophilic substitution reaction to
obtain acylhydrazines 9a–f. Finally, target compounds 1a–k and 2a–g were prepared via condensation of 9a–f with
various benzaldehydes, benzyloxybenzaldehydes 10a–d and imidazolindiones 12a–c, respectively. 10a–d were readily
prepared according to the reported procedure [10] and 12a–c were obtained from the condensation reactions of N,N-
dimethylformamide dimethyl acetal (DMF-DMA) with intermediates 11a–c which were synthesized according to the
reported procedure [11]. All the structures of target compounds were confirmed by MS and 1H NMR [12].
All the target compounds were evaluated for their antiproliferative activities against human leukemia cell line
(HL-60), human lung adenocarcinoma epithelial cell line (A549) and human breast cancer cell line (MDA-MB-231)
with sorafenib and PAC-1 as the positive controls. As listed in Table 1, most of the target compounds exhibited
moderate to strong activities to the tested cell lines. Compound 1j showed the most potent antiproliferative activity
[(Scheme_1)TD$FIG]
Scheme 1. Synthesis of target compounds. Reactions and conditions: (a) triphosgene, dioxane, 80 8C, 24 h, 84%; (b) Ar1NH2, THF, r.t., 1 h; (c)
MgCl2, NaSH, DMF, overnight; (d) 1,3-dichloroacetone, THF, 50 8C, 7 h; (e) piperazine, ethanol, r.t., 2 h; (f) ethyl chloroacetate, K2CO3, NaI,
ethanol, 50 8C, 2 h; (g) 80% hydrazine hydrate, ethanol, 50 8C, 48 h; (h) Ar2CHO or 10a–d, ethanol; then HCl–ethanol; (i) 12a–c, ethanol; then HCl–
ethanol; (j) DMF-DMA, CH3CN, r.f., 4 h.

B. Zhang et al. / Chinese Chemical Letters 23 (2012) 915–918
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Table 1
Structures and antiproliferative activities of compounds 1a–k and 2a–g against HL-60, A549 and MDA-MB-231 cell lines.
Compd.
Ar1
Ar2
IC50 (mmol/L)
HL-60
A549
MDA-MB-231
1a
1b
3-F-C6H4
5-Br-2-OH-C6H3
7.1
6.2
1.1
9.9
6
2.3
1.9
NA
2.0
4.4
0.7
NA
1.1
0.8
0.7
0.9
18
1.4
1.1
23
3-F-C6H4
3,4-F-2-OH-C6H2
2-OH-3,5-t-butyl-C6H2
2-OH-C6H4
1c
1d
3-F-C6H4
2-Cl-4-CF3-C6H3
3-Cl-C6H4
3-Cl-C6H4
3-Cl-C6H4
3-F-C6H4
1.4
1.6
1.0
NA
1.0
0.8
0.5
0.7
93
1e
5-Cl-2-OH-C6H3
1f
1g
2-OH-3,5-t-butyl-C6H2
2-OH-4-CH3-C6H3
2-OH-4-(C6H5-CH2O)-C6H3
2-OH-4-(4-Cl-C6H4-CH2O)-C6H3
2-OH-4-(2,4-Cl-C6H3-CH2O)-C6H3
2-OH-4-(3-F-C6H4-CH2O)-C6H3
4-CH3-C6H4
2.7
1.2
1.1
2.8
0.13
1.6
32
1h
1i
3-F-C6H4
1j
1k
3-F-C6H4
3-F-C6H4
2a
2b
3-F-C6H4
3-F-C6H4
4-Cl-C6H4
22
12
31
2c
2d
3-Cl-C6H4
3-OCH3-C6H4
2-Cl-4-CF3-C6H3
3,5-CF3-C6H3
3,4-F-C6H3
4-CH3-C6H4
24
73
14
4-CF3-C6H4
NA
30
NA
NA
12
NA
NA
31
2e
4-CF3-C6H4
2f
2g
4-CF3-C6H4
12
4-CF3-C6H4
6.2
ND
9.1
3.5
2.6
5.6
3.0
5.4
4.1
Sorafenib
PAC-1
NA, no activity; ND, not determined.
against HL-60, A549 and MDA-MB-231 cell lines with IC50 values of 0.13 mmol/L, 0.7 mmol/L and 0.5 mmol/L,
which were 3.7- to 70-fold higher than sorafenib and PAC-1.
The phenylhydrazones 1a–k were more potent than the imidazolidinylhydrazones 2a–f with the exception of
compound 2g, which suggested that the directly linked phenyl group Ar2 to the hydrazone is essential for the activity.
As for substituents on the hydrazone-linked phenyl ring Ar2, compounds 1a, 1b, 1e and 1c with bromo, fluoro, chloro
and tert-butyl groups, respectively, showed comparable inhibitory activities against the three cell lines to compound
1d with only ortho-hydroxyl group. It suggested that the electronic effects of substituents on Ar2 make few
contributions to the activity. Interestingly, compounds 1h–k with the benzyloxy group at the para-position of Ar2
displayed a remarkable enhanced activity against the three tested cell lines. These investigations prompt us to carry on
further studies on their mechanisms of action.
Acknowledgments
This work was supported by the National High Technology Research and Development Program (‘‘863’’ Program)
of China (No. 2012AA020305), National Natural Science Foundation of China (No. 21002065) and Shenyang Science
and Technology Plan Projects (No. F11-151-9-00).
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[10] B.R. Bhattarai, B. Kafle, J.S. Hwang, et al. Bioorg. Med. Chem. Lett. 20 (2010) 6758.
[11] X.Y. He, P. Zhou, J. Qiu, et al. Bioorg. Med. Chem. 19 (2011) 6726.
[12] 1a: mp: 199–201 8C. ESI-MS m/z: 666.3 (M+H)+. HRMS-ESI: calcd. for C30H30BrFN7O3S (M+H)+ 666.1293, found 666.1303. IR (KBr,
cmÀ1): 3398.5, 1669.1, 1600.1, 1544.0, 1457.5, 1313.5, 1207.8, 1144.0, 1003.4, 970.5, 838.3. 1H NMR (300 MHz, DMSO-d6) d: 11.13 (s, 1H),
10.49 (s, 1H), 9.51 (s, 1H), 9.48 (s, 1H), 8.46 (s, 1H), 7.90–7.88 (m, 3H), 7.73 (s, 1H), 7.61 (d, 3H, J = 7.1 Hz), 7.51 (d, 2H, J = 11.9 Hz), 7.43–
7.35 (m, 1H), 7.32 (d, 1H, J = 7.1 Hz), 7.13 (d, 1H, J = 8.3 Hz), 6.90 (d, 1H, J = 8.3 Hz), 6.80 (t, 1H, J = 8.6 Hz), 4.51 (s, 1H), 3.77 (s, 2H), 2.73
(brs, 9H). 13C NMR (75 MHz, DMSO-d6) d: 164.48, 161.29, 156.82, 156.26, 152.84, 145.55, 142.17, 141.91, 134.04, 130.87, 130.74, 130.62,
127.58, 122.72, 121.76, 119.22, 118.60, 114.28, 111.21, 110.90, 108.83, 108.54, 105.38, 105.02, 83.71, 72.35, 51.47, 51.43. 1b: mp: 207–
210 8C. ESI-MS m/z: 624.3 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 11.50 (s, 1H), 9.04 (s, 1H), 8.98 (s, 1H), 8.47 (s, 1H), 7.85 (d, 2H,
J = 8.7 Hz), 7.62–7.57 (m, 3H), 7.50 (d, 2H, J = 12.0 Hz), 7.41 (s, 1H), 7.32 (q, 1H, J = 8.1 Hz), 7.14 (d, 1H, J = 8.1 Hz), 6.95 (dd, 1H,
J1 = 6.9 Hz, J2 = 12.0 Hz), 6.81 (t, 1H, J = 8.7 Hz), 3.66 (s, 1H), 3.64 (s, 1H), 3.32 (s, 1H), 3.10 (s, 1H), 2.53 (brs, 8H). 1c: mp: 215–217 8C.
ESI-MS m/z: 700.6 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 12.10 (s, 1H), 11.41 (s, 1H), 9.02 (s, 1H), 8.97 (s, 1H), 8.49 (s, 1H), 7.85 (d, 3H,
J = 8.7 Hz), 7.58 (d, 2H, J = 8.7 Hz), 7.50 (d, 1H, J = 11.9 Hz), 7.41 (s, 1H), 7.33–7.28 (m, 2H), 7.18 (d, 1H, J = 2.3 Hz), 7.14 (d, 1H,
J = 8.1 Hz), 6.82 (t, 1H, J = 8.4 Hz), 3.67 (s, 1H), 3.64 (s, 1H), 3.30 (s, 1H), 3.14 (s, 1H), 2.56 (brs, 8H), 1.39 (s, 9H), 1.27 (s, 9H). 1d: mp: 267–
269 8C. ESI-MS m/z: 672.3 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 11.96 (s, 1H), 10.57 (s, 1H), 10.15 (s, 1H), 9.00 (s, 1H), 8.61 (s, 1H),
8.37 (s, 1H), 7.96 (d, 1H, J = 1.6 Hz), 7.94 (d, 2H, J = 2.2 Hz), 7.75 (d, 1H, J = 9.2 Hz), 7.69 (d, 3H, J = 9.0 Hz), 7.39 (d, 1H, J = 8.3 Hz), 7.32–
7.23 (m, 1H), 6.96–6.84 (m, 2H), 4.59 (s, 2H), 4.50 (s, 2H), 3.84 (brs, 8H). 1e: mp: 234–235 8C. ESI-MS m/z: 637.8 (M+H)+. 1H NMR
(300 MHz, DMSO-d6) d: 11.12 (s, 1H), 10.48 (s, 1H), 9.66–9.60 (m, 2H), 7.92–7.87 (m, 3H), 7.72 (s, 2H), 7.64–7.60 (m, 3H), 7.32 (s, 1H), 7.30
(s, 2H), 7.04–7.01 (m, 1H), 6.95 (d, 1H, J = 8.8 Hz), 4.49 (s, 2H), 3.76 (brs, 2H), 3.25 (brs, 8H). 1f: mp: 240–242 8C. ESI-MS m/z: 716.5
(M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 12.10 (s, 1H), 11.43 (s, 1H), 9.07 (s, 1H), 8.98 (s, 1H), 8.49 (s, 1H), 7.86 (d, 2H, J = 8.6 Hz), 7.72
(s, 1H), 7.59 (d, 2H, J = 8.6 Hz), 7.43 (s, 1H), 7.31 (s, 1H), 7.30 (s, 2H), 7.18 (d, 1H, J = 2.2 Hz), 7.05–7.02 (m, 1H), 3.71 (s, 2H), 3.30 (s, 1H),
3.15 (s, 1H), 2.58 (brs, 8H), 1.39 (s, 9H), 1.27 (s, 9H). 1g: mp: 222–224 8C. ESI-MS m/z: 618.3 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d:
11.45 (s, 1H), 11.16 (s, 1H), 9.53 (s, 2H), 8.47 (s, 1H), 7.86 (d, 2H, J = 8.6 Hz), 7.72 (s, 1H), 7.59 (d, 2H, J = 8.6 Hz), 7.50 (s, 1H), 7.35 (s, 1H),
7.30 (d, 2H, J = 4.8 Hz), 7.04–7.00 (m, 1H), 6.74 (s, 1H), 6.71 (s, 1H), 3.78 (s, 2H), 3.30 (s, 1H), 3.16 (s, 1H), 2.62 (brs, 6H), 2.38 (s, 2H), 2.27
(s, 3H). 1h: mp: 207–209 8C. ESI-MS m/z: 694.0 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 11.76 (s, 1H), 10.21 (s, 1H), 9.55–9.47 (m, 2H),
8.40 (s, 1H), 8.25 (s, 1H), 7.91 (d, 2H, J = 8.6 Hz), 7.62 (d, 3H, J = 8.6 Hz), 7.52–7.30 (m, 8H), 7.13 (d, 1H, J = 9.3 Hz), 6.80 (t, 1H,
J = 8.7 Hz), 6.59 (d, 1H, J = 8.7 Hz), 6.54 (s, 1H), 5.12 (s, 1H), 5.09 (s, 1H), 4.42 (brs, 2H), 4.32 (s, 2H), 3.53 (brs, 8H). 1i: mp: 222–224 8C.
ESI-MS m/z: 728.3 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 11.80 (s, 1H), 10.23 (s, 1H), 9.67 (t, 2H, J = 12.2 Hz), 8.41 (s, 1H), 8.26 (s, 1H),
7.93–7.90 (m, 3H), 7.64 (t, 3H, J = 8.6 Hz), 7.52 (s, 1H), 7.46 (brs, 5H), 7.31 (q, 1H, J = 8.2 Hz), 7.13 (d, 1H, J = 8.0 Hz), 6.79 (t, 1H,
J = 8.6 Hz), 6.59–6.54 (m, 2H), 5.12 (s, 1H), 5.09 (s, 1H), 4.51 (s, 1H), 4.44 (s, 2H), 3.67 (s, 1H), 3.54 (brs, 8H). 1j: mp: 215–217 8C. ESI-MS
m/z: 762.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 11.79 (s, 1H), 10.25 (s, 1H), 9.60 (t, 2H, J = 12.8 Hz), 8.42 (s, 1H), 8.26 (s, 1H), 7.91 (d,
2H, J = 8.6 Hz), 7.90–7.59 (m, 4H), 7.52–7.44 (m, 3H), 7.31 (q, 1H, J = 7.2 Hz), 7.13 (d, 1H, J = 8.7 Hz), 6.78 (t, 1H, J = 8.9 Hz), 6.61–6.55
1
(m, 2H), 5.16 (s, 1H), 5.14 (s, 1H), 4.48 (s, 2H), 4.43 (s, 2H), 3.50 (brs, 8H). 1k: mp: 220–222 8C. ESI-MS m/z: 712.1 (M+H)+. H NMR
(300 MHz, DMSO-d6) d: 11.82 (s, 1H), 10.24 (s, 1H), 9.76 (s, 1H), 9.70 (d, 1H, J = 12.2 Hz), 8.42 (s, 1H), 8.26 (s, 1H), 7.92 (d, 3H,
J = 10.6 Hz), 7.63 (d, 3H, J = 8.7 Hz), 7.53–7.41 (m, 2H), 7.35–7.27 (m, 3H), 7.20–7.12 (m, 2H), 6.79 (t, 1H, J = 8.4 Hz), 6.61–6.55 (m, 3H),
5.15 (s, 1H), 5.12 (s, 1H), 4.53 (s, 1H), 4.46 (s, 2H), 3.73 (s, 1H), 3.59(brs, 8H). 2a: mp: 210–212 8C. ESI-MS m/z: 683.9 (M+H)+. HRMS-ESI:
calcd. for C34H35FN9O4S (M+H)+ 684.2511, found 684.2510. IR (KBr, cmÀ1): 3270.5, 1725.0, 1597.8, 1540.3, 1408.1, 1313.4, 1209.5,
1143.6, 1003.9, 969.7, 840.2. 1H NMR (300 MHz, DMSO-d6) d: 11.38 (s, 1H), 10.20 (s, 1H), 9.46–9.26 (m, 3H), 8.20 (s, 1H), 7.87 (d, 3H,
J = 8.4 Hz), 7.61 (d, 3H, J = 8.6 Hz), 7.51 (d, 2H, J = 12.0 Hz), 7.35–7.14 (m, 6H), 6.79 (t, 1H, J = 8.3 Hz), 3.94 (s, 2H), 3.17 (s, 2H), 2.86 (s,
4H), 2.69 (s, 4H), 2.33 (s, 3H). 13C NMR (75 MHz, DMSO-d6) d: 164.50, 161.27, 160.15, 156.54, 154.66, 152.74, 145.33, 142.92, 142.15,
142.01, 141.86, 130.87, 130.74, 129.84, 129.59, 127.47, 127.11, 126.98, 126.87, 126.77, 118.78, 114.47, 108.95, 108.64, 105.57, 105.22,
99.98, 83.27, 73.36, 51.87, 51.61, 21.16. 2b: mp: 233–235 8C. ESI-MS m/z: 704.3 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 10.58 (s, 1H),
9.88 (s, 1H), 9.65 (d, 2H, J = 12.8 Hz), 8.63 (d, 1H, J = 8.6 Hz), 7.91 (d, 3H, J = 8.0 Hz) 7.62 (d, 2H, J = 8.6 Hz), 7.52 (d, 3H, J = 8.5 Hz), 7.44
(d, 2H, J = 8.7 Hz), 7.31 (q, 1H, J = 7.9 Hz), 7.13 (d, 1H, J = 7.9 Hz), 6.78 (t, 1H, J = 8.5 Hz), 6.68 (d, 1H, J = 8.8 Hz), 4.47 (s, 2H), 3.68 (s,
2H), 3.46 (brs, 8H). 2c: mp: 230–231 8C. ESI-MS m/z: 700.3 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 12.06 (s, 1H), 10.57 (s, 1H), 9.77–
9.66 (m, 3H), 8.55 (d, 1H, J = 7.4 Hz), 7.92 (d, 4H, J = 8.0 Hz), 7.71 (s, 1H), 7.62 (d, 2H, J = 8.5 Hz), 7.30–7.24 (m, 6H), 7.03 (s, 1H), 6.63 (d,
1H, J = 8.4 Hz), 4.48 (s, 2H), 3.70 (s, 2H), 3.45 (s, 8H), 2.33 (s, 3H). 2d: mp: 199–200 8C. ESI-MS m/z: 749.9 (M+H)+. 1H NMR (300 MHz,
DMSO-d6) d: 10.17 (s, 1H), 9.32–9.26 (m, 1H), 9.00–8.71 (m, 1H), 8.02–7.87 (m, 5H), 7.70–7.59 (m, 5H), 7.37 (d, 3H, J = 8.8 Hz), 6.88 (d, 3H,
J = 8.8 Hz), 4.27 (s, 2H), 3.72 (s, 3H), 3.26 (brs, 10H). 2e: mp: 213–215 8C. ESI-MS m/z: 822.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d:
10.67 (s, 1H), 10.43 (s, 1H), 10.05 (s, 1H), 8.94 (s, 1H), 8.80 (d, 1H, J = 9.1 Hz), 8.63 (s, 1H), 7.95 (d, 2H, J = 8.5 Hz), 7.94 (s, 1H), 7.84 (d, 2H,
J = 8.6 Hz), 7.73 (d, 2H, J = 8.8 Hz), 7.69 (dd, 3H, J1 = 2.5 Hz, J2 = 8.6 Hz), 7.40 (d, 1H, J = 8.3 Hz), 6.73 (d, 1H, J = 9.1 Hz), 4.50 (s, 2H),
3.73 (s, 2H), 3.48–3.41 (m, 8H). 2f: mp: 194–196 8C. ESI-MS m/z: 856.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 10.35 (s, 1H), 10.15 (s,
1H), 9.83 (s, 1H), 9.77 (s, 1H), 8.53 (s, 1H), 8.14 (s, 2H), 7.94–7.83 (m, 5H), 7.70–7.64 (m, 7H), 6.72 (d, 1H, J = 9.3 Hz), 4.41 (s, 2H), 3.48–
3.41 (m, 2H), 3.24 (brs, 8H). 2g: mp: 211–213 8C. ESI-MS m/z: 756.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6) d: 10.91 (s, 1H), 10.40 (s, 1H),
10.29 (s, 1H), 10.11 (s, 1H), 8.91 (d, 1H, J = 8.6 Hz), 8.06 (d, 2H, J = 8.1 Hz), 7.85 (d, 2H, J = 8.5 Hz), 7.69 (d, 2H, J = 8.6 Hz), 7.65 (d, 3H,
J = 8.2 Hz), 7.38 (q, 1H, J = 9.6 Hz), 7.23–7.16 (m, 1H), 6.89–6.87 (m, 1H), 6.75 (d, 1H, J = 9.1 Hz), 4.14 (s, 2H), 4.03 (s, 1H), 3.42 (brs, 3H),
3.27 (brs, 2H), 3.05 (brs, 2H), 2.81 (brs, 2H).