Synthesis and bioactivities of novel pyrazole and triazole derivatives containing 5-phenyl-2-furan

Article abstract of DOI:10.1111/j.1747-0285.2011.01266.x

A series of novel pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized. Their toxicities were predicted using in silico assays and proven to be less toxic. The antitumor results showed that the activity

Full text of DOI:10.1111/j.1747-0285.2011.01266.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01266.x
Chem Biol Drug Des 2012; 79: 121–127
Research Article
Synthesis and Bioactivities of Novel Pyrazole and
Triazole Derivatives Containing 5-Phenyl-2-Furan
Zi-Ning Cui1,†, Yan-Xia Shi2,†
,
the compounds showed diverse and significant bioactivities such as
fungicidal, insecticidal, and antitumor activities.
Jing-Rong Cui3, Yun Ling1, Bao-Ju Li2 and
Xin-Ling Yang1,*
In continuation of our research on the synthesis of biological het-
erocyclic compounds, a series of novel pyrazole and triazole deriva-
tives containing 5-phenyl-2-furan moiety were synthesized (Scheme
1), and their antitumor and antifungal activities were evaluated.
1Department of Applied Chemistry, College of Science, China
Agricultural University, Key Laboratory of Pesticide Chemistry and
Application, Ministry of Agriculture, Beijing 100193, China
2Institute of Vegetables and Flowers, Chinese Academy of
Agricultural Sciences, Beijing 100081, China
Experimental
3State Key Laboratory of Natural and Biomimetic Drugs, Peking
University, Beijing 100191, China
*Corresponding author: Xin-Ling Yang, yangxl@cau.edu.cn
Both authors contributed equally to this paper.
Instruments
All the melting points were determined with a Cole-Parmer melting
point apparatus, while the thermometer was uncorrected. IR spectra
were recorded on a NEXUS-470 FTIR (Nicolet) spectrometer (Inter-
national Equipment Trading Ltd., Vernon Hills, IL, USA) with KBr pel-
lets. 1H NMR spectra were recorded with a Bruker DPX300
instrument (Bruker, Fallanden, Switzerland); while tetramethylsilane
was used as the internal standards. Analytical thin-layer chromatog-
raphy (TLC) was carried out on precoated plates (silica gel 60 F254),
and spots were visualized with ultraviolet (UV) light. Elemental
analysis, which was performed at the laboratories of the Institute
of Chemistry, Chinese Academy of Sciences, was carried out with a
Flash EA 1112 elemental analyzer.
A series of novel pyrazole and triazole derivatives
containing 5-phenyl-2-furan functionality were
designed and synthesized. Their toxicities were
predicted using in silico assays and proven to be
less toxic. The antitumor results showed that the
activity of compounds containing 1,3,4-triazole
(series II) was higher than that of pyrazole-
attached derivatives (series I). Among them, IIa
and IIg showed much higher activity against Bel-
7402 than doxorubicin. The fungicidal tests
showed that most title compounds II exhibited
great selectivity against Phytophthora capsici
in vivo.
Synthetic procedures
Key words: 5-phenyl-2-furan, antifungal activity, antitumor activity,
pyrazole and triazole derivatives, synthesis
General synthetic procedure for the key
intermediate 1
The key intermediate 1 was synthesized from substituted aniline by
Meerwein arylation reaction according to the reported procedure
(11,12).
Received 12 March 2011, revised 30 September 2011 and accepted 4
October 2011
Nitrogen-linked heterocyclic compounds received considerable
attention in recent several years because of their broad bioactivities
(1–3). It is well known that the study of pyrazole and triazole deriv-
atives is significant in medicinal and pesticidal chemistry. Some
pyrazole and triazole derivatives were shown to have antiviral (4),
antitumor (5), anti-inflammatory (6), antibacterial (7), herbicidal (8),
insecticidal (9), and fungicidal activities (10).
General synthetic procedure for the target
compounds I and II
A
mixture of 5-substituted phenyl-2-furancarboxylic acid 1
(0.05 mol) and thionyl chloride (0.15 mol) was refluxed in anhydrous
benzene for 3 h. The excess of thionyl chloride and the solvent was
distilled off, and the residue was dissolved in anhydrous dichlorom-
ethane. The solution of 5-phenyl-2-furancarbonyl chloride in anhy-
drous dichloromethane was added into pyrazole or 1, 2, 4-triazole.
The mixture was stirred and refluxed for 4 h. After cooling, the sol-
vent was evaporated off under reduced pressure, and the solid was
recrystallized from ethanol to obtain the target compounds I and II.
The furan ring is an electron-rich system, which can easily form the
intermolecular hydrogen bonds with different kinds of biological
enzymes. It has been reported that the compounds containing furan
showed broad-spectrum bioactivities. In our previous work, some
dibenzoylureas (11), semicarbazides (12), diacylhydrazines (13–15), a-
cylhydrazones (16), and carbamic acid esters (17) derivatives con-
taining 5-phenyl-2-furan moiety were designed and synthesized. All
N-5-(4¢-Chlorophenyl)-2-furoyl-1H-pyrazole (Ia): yellow solid, yield
83.5%, m.p. 174–175 ꢀC. IR (KBr) mmax: 3154.9, 3131.4, 1678.4,
121

Cui et al.
COOH
COOH
NaNO2
HCl
O
O
NH2
N2Cl
R1
R1
cat. CuCl2
acetone-H2O
R1
1
N
N
X
N
X
HN
COCl
O
SOCl2
O
O
1
R1
R1
X=C, Ia~Im
X=N, IIa~IIk
Scheme 1: The synthetic route of the title compounds I and II. R1 = Ia: 4-Cl; Ib: 2-NO2; Ic: 3-NO2; Id: 2-Cl; Ie: 3-Cl; If: 2-F; Ig: 3-F;
Ih: 4-F; Ii: 2.4-di-F; Ij: 2.6-di-F; Ik: H; Il: 4-CH3; Im: 4-OCH3; IIa: 4-Cl; IIb: 2-NO2; IIc: 2-Cl; IId: 3-Cl; IIe: 3-F; IIf: 4-F; IIg: 2.4-di-F; IIh:
2.6-di-F; IIi: H; IIj: 4-CH3; IIk: 4-OCH3.
1515.9, 1475.0, 1417.2, 1383.9, 1346.3, 1266.1, 1193.9, 1086.7,
1040.3, 1013.3 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 6.71 (dd,
J = 2.81, 1.52 Hz, 1H, PyH), 7.38 (d, J = 3.81 Hz, 1H, FuH), 7.59–
7.62 (m, 2H, ArH-Fu), 7.91–7.94 (m, 2H, ArH-Fu), 8.03 (d,
J = 1.52 Hz, 1H, PyH), 8.13 (d, J = 3.81 Hz, 1H, FuH), 8.60 (d,
J = 2.79 Hz, 1H, PyH). Anal. Calcd. (%) for C14H9ClN2O2: C, 61.66;
H, 3.33; N, 10.27. Found: C, 61.73; H, 3.52; N, 10.51.
1264.7, 1189.7, 1084.0, 1040.0, 1005.9 ⁄ cm. 1H NMR (300 MHz,
DMSO-d6) d: 6.72 (dd, J = 2.84, 1.52 Hz, 1H, PyH), 7.47 (d,
J = 3.82 Hz, 1H, FuH), 7.51–7.55 (m, 2H, ArH-Fu), 7.86–7.89 (m, 1H,
ArH-Fu), 7.96–7.97 (m,1H, ArH-Fu), 8.03 (d, J = 1.42 Hz, 1H, PyH),
8.13 (d, J = 3.80 Hz, 1H, FuH), 8.60 (d, J = 2.87Hz, 1H, PyH). Anal.
Calcd. (%) for C14H9ClN2O2: C, 61.66; H, 3.33; N, 10.27. Found: C,
61.48; H, 3.45; N, 10.12.
N-5-(2¢-Nitrophenyl)-2-furoyl-1H-pyrazole (Ib): yellow solid, yield
79.8%, m.p. 95–96 ꢀC. IR (KBr) mmax: 3162.4, 1697.2, 1524.9,
1511.5, 1473.3, 1418.2, 1386.2, 1365.4, 1345.1, 1251.6, 1191.4,
1084.7, 1056.7, 1033.6, 1002.8 ⁄ cm. 1H NMR (300 MHz, DMSO-d6)
d: 6.72 (dd, J = 2.84, 1.52 Hz, 1H, PyH), 7.22 (d, J = 3.79 Hz, 1H,
FuH), 7.73–7.78 (m, 1H, ArH-Fu), 7.83–7.89 (m, 1H, ArH-Fu), 7.97–
8.00 (m, 1H, ArH-Fu), 8.04–8.07 (m, 2H, ArH-Fu + PyH), 8.12 (d,
J = 3.80 Hz, 1H, FuH), 8.58 (d, J = 2.86 Hz, 1H, PyH). Anal. Calcd.
(%) for C14H9N3O4: C, 59.37; H, 3.20; N, 14.84. Found: C, 59.41; H,
3.31; N, 14.94.
N-5-(2¢-Fluorophenyl)-2-furoyl-1H-pyrazole (If): light yellow solid,
yield 85.9%, m.p. 114–115 ꢀC. IR (KBr) mmax: 3164.4, 1691.7,
1513.0, 1481.1, 1448.7, 1412.1, 1387.3, 1369.4, 1343.4, 1260.3,
1210.8, 1083.2, 1040.4 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 6.72
(dd, J = 2.86, 1.54 Hz, 1H, PyH), 7.18 (t, J = 3.66 Hz, 1H, FuH),
7.39–7.44 (m, 2H, ArH-Fu), 7.51–7.53 (m, 1H, ArH-Fu), 7.94–7.99 (m,
1H, ArH-Fu), 8.04 (dd, J = 1.51, 0.63 Hz, 1H, PyH), 8.16 (d,
J = 3.81 Hz, 1H, FuH), 8.61 (dd, J = 2 .86, 0.63 Hz, 1H, PyH). Anal.
Calcd. (%) for C14H9FN2O2: C, 65.62; H, 3.54; N, 10.93. Found: C,
65.98; H, 3.68; N, 11.24.
N-5-(3¢-Nitrophenyl)-2-furoyl-1H-pyrazole (Ic): yellow solid, yield
80.5%, m.p. 200–201 ꢀC. IR (KBr) mmax: 3163.9, 3102.7, 1683.7,
1532.4, 1511.6, 1467.1, 1418.7, 1394.8, 1348.9, 1262.6, 1192.4,
1088.1, 1038.7 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 6.73 (dd,
J = 2.83, 1.52 Hz, 1H, PyH), 7.62 (d, J = 3.82 Hz, 1H, FuH), 7.81–
7.86 (m, 1H, ArH-Fu), 8.04 (d, J = 1.14 Hz, 1H, PyH), 8.16 (d,
J = 3.83 Hz, 1H, FuH), 8.28–8.36 (m, 2H, ArH-Fu), 8.61–8.65 (m, 2H,
ArH-Fu + PyH). Anal. Calcd. (%) for C14H9N3O4: C, 59.37; H, 3.20; N,
14.84. Found: C, 59.27; H, 3.37; N, 14.86.
N-5-(3¢-Fluorophenyl)-2-furoyl-1H-pyrazole (Ig): light yellow solid,
yield 80.4%, m.p. 135–136 ꢀC. IR (KBr) mmax: 3135.3, 1690.3,
1592.7, 1515.1, 1478.4, 1434.3, 1417.6, 1396.5, 1349.6, 1264.8,
1185.7, 1088.5, 1035.6, 1001.9 ⁄ cm. 1H NMR (300 MHz, DMSO-d6)
d: 6.72 (dd, J = 2.86, 1.53 Hz, 1H, PyH), 7.31–7.32 (m, 1H, ArH-Fu),
7.44 (d, J = 3.80 Hz, 1H, FuH), 7.56–7.63 (m, 1H, ArH-Fu), 7.72–7.77
(m,2H, ArH-Fu), 8.03 (dd, J = 1.51, 0.61 Hz, 1H, PyH), 8.13 (d,
J = 3.81 Hz, 1H, FuH), 8.60 (dd, J = 2.86, 0.61 Hz, 1H, PyH). Anal.
Calcd. (%) for C14H9FN2O2: C, 65.62; H, 3.54; N, 10.93. Found: C,
65.55; H, 3.55; N, 11.18.
N-5-(2¢-Chlorophenyl)-2-furoyl-1H-pyrazole (Id): light yellow solid,
yield 82.3%, m.p. 114–115 ꢀC. IR (KBr) mmax: 3159.7, 3121.0, 1691.4,
1510.2, 1467.9, 1430.3, 1415.7, 1384.2, 1367.1, 1345.3, 1248.3,
1191.7, 1080.3, 1038.2 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 6.72 (dd,
J = 2.86, 1.53 Hz, 1H, PyH), 7.42 (d, J = 3.83 Hz, 1H, FuH), 7.48–7.58
(m, 2H, ArH-Fu), 7.65–7.68 (m, 1H, ArH-Fu), 7.96–8.00 (m, 1H, ArH-Fu),
8.04 (dd, J = 1.44, 0.51 Hz, 1H, PyH), 8.15 (d, J = 3.83 Hz, 1H, FuH),
8.61 (dd, J = 2.88, 0.52 Hz, 1H, PyH). Anal. Calcd. (%) for C14H9ClN2O2:
C, 61.66; H, 3.33; N, 10.27. Found: C, 61.57; H, 3.36; N, 10.45.
N-5-(4¢-Fluorophenyl)-2-furoyl-1H-pyrazole (Ih): white solid, yield
90.5%, m.p. 145–146 ꢀC. IR (KBr) mmax: 3107.8, 16796, 1606.3,
1571.3, 1525.8, 1483.4, 1418.3, 1381.5, 1344.8, 1265.1, 1233.4,
1192.6, 1162.7, 1105.6, 1083.9, 1039.4 ⁄ cm. 1H NMR (300 MHz,
DMSO-d6) d: 6.71 (dd, J = 2.83, 1.53 Hz, 1H, PyH), 7.33 (d,
J = 3.80 Hz, 1H, FuH), 7.35–7.43 (m, 2H, ArH-Fu), 7.94–8.03 (m, 3H,
2ArH-Fu + PyH), 8.13 (d, J = 3.80 Hz, 1H, FuH), 8.60 (d, J = 2.83 Hz,
1H, PyH). Anal. Calcd. (%) for C14H9FN2O2: C, 65.62; H, 3.54; N,
10.93. Found: C, 65.61; H, 3.72; N, 10.94.
N-5-(3¢-Chlorophenyl)-2-furoyl-1H-pyrazole (Ie): light yellow solid,
yield 86.2%, m.p. 142–143 ꢀC. IR (KBr) mmax: 3152.6, 3103.9,
1684.5, 1512.9, 1462.7, 1433.6, 1415.7, 1382.7, 1365.3, 1343.5,
N-5-(2¢, 4¢-di-Fluorophenyl)-2-furoyl-1H-pyrazole (Ii): brown solid,
yield 90.1%, m.p. 126–127 ꢀC. IR (KBr) mmax: 3146.4, 3070.2,
122
Chem Biol Drug Des 2012; 79: 121–127

Synthesis and Bioactivities of Novel Pyrazole and Triazole Derivatives
1686.1, 1619.1, 1523.3, 1477.9, 1433.2, 1413.0, 1390.5, 1369.9,
N-5-(2¢-Nitrophenyl)-2-furoyl-1H-1,2,4-triazole (IIb): orange solid,
yield 80.2%, m.p. 140–141 ꢀC. IR (KBr) mmax: 3108.1, 1704.6,
1522.9, 1506.8, 1469.3, 1436.2, 1394.6, 1366.5, 1287.8, 1248.4,
1190.4, 1117.1, 1021.3 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 7.28
(d, J = 3.86 Hz,1H,FuH), 7.75–7.80 (m, 1H, ArH-Fu), 7.85–7.90 (m,
1H, ArH-Fu), 7.98–8.01 (m, 1H, ArH-Fu), 8.05–8.09 (m, 1H, ArH-Fu),
8.18 (d, J = 3.86 Hz, 1H, FuH), 8.45 (s, 1H, TrH), 9.45 (s, 1H, TrH).
Anal. Calcd. (%) for C13H8N4O4: C, 54.93; H, 2.84; N, 19.71. Found:
C, 54.71; H, 3.06; N, 19.69.
1345.8, 1267.7, 1235.0, 1210.7, 1194.8, 1149.1, 1116.6, 1085.3,
1035.0 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 6.72 (dd, J = 2.82,
1.49 Hz, 1H, PyH), 7.15 (t, J = 3.65Hz, 1H, FuH), 7.29–7.35 (m, 1H,
ArH-Fu), 7.49–7.56 (m, 1H, ArH-Fu), 7.97–8.05 (m, 2H, ArH-
Fu + PyH), 8.15 (d, J = 3.80 Hz, 1H, FuH), 8.60 (d, J = 2.85 Hz, 1H,
PyH). Anal. Calcd. (%) for C14H8F2N2O2: C, 61.32; H, 2.94; N, 10.22.
Found: C, 61.42; H, 3.11; N, 10.18.
N-5-(2¢, 6¢-di-Fluorophenyl)-2-furoyl-1H-pyrazole (Ij): yellow solid,
yield 86.4%, m.p. 114–115 ꢀC. IR (KBr) mmax: 3161.8, 3138.7,
1692.8, 1621.6, 1585.2, 1559.2, 1512.1, 1472.7, 1448.6, 1415.9,
1385.2, 1345.0, 1262.5, 1239.9, 1207.8, 1086.6, 1040.7 ⁄ cm. 1H
NMR (300 MHz, DMSO-d6) d: 6.72 (dd, J = 2.90, 1.52 Hz, 1H, PyH),
7.19–7.21 (m, 1H, FuH), 7.30–7.37 (m, 2H, ArH-Fu), 7.56–7.64 (m,
1H, ArH-Fu), 8.04 (dd, J = 1.47, 0.51 Hz, 1H,PyH), 8.17 (d,
J = 3.81 Hz, 1H, FuH), 8.60 (dd, J = 2.82, 0.51 Hz, 1H, PyH). Anal.
Calcd. (%) for C14H8F2N2O2: C, 61.32; H, 2.94; N, 10.22. Found: C,
61.33; H, 3.00; N, 10.21.
N-5-(2¢-Chlorophenyl)-2-furoyl-1H-1,2,4-triazole (IIc): light yellow
solid, yield 80.4%, m.p. 121–122 ꢀC. IR (KBr) mmax: 3110.7, 1703.3,
1504.5, 1466.4, 1426.8, 1387.9, 1288.2, 1272.9, 1244.6, 1184.1,
1148.2, 1119.1, 1020.2 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 7.46
(d, J = 3.91 Hz, 1H, FuH), 7.50–7.57 (m, 2H, ArH-Fu), 7.65–7.68 (m,
1H, ArH-Fu), 7.97–8.00 (m, 1H, ArH-Fu), 8.19 (d, J = 3.93 Hz, 1H,
FuH), 8.46 (d, J = 0.22 Hz, 1H, TrH), 9.50 (s, 1H, TrH). Anal. Calcd.
(%) for C13H8ClN3O2: C, 57.05; H, 2.95; N, 15.35. Found: C, 57.25;
H, 3.07; N, 15.04.
N-5-Phenyl-2-furoyl-1H-pyrazole (Ik): brown solid, yield 75.3%, m.p.
97–98 ꢀC. IR (KBr) mmax: 3127.8, 1686.6, 1513.7, 1473.8, 1449.5,
1395.8, 1370.5, 1349.5, 1263.4, 1195.9, 1088.3, 1038.9 ⁄ cm. H NMR
(300 MHz, DMSO-d6) d: 6.71 (dd, J = 2.82, 1.55 Hz, 1H, PyH), 7.35 (d,
J = 3.81 Hz, 1H, FuH), 7.45–7.58 (m, 3H, ArH-Fu), 7.90–7.94 (m, 2H,
ArH-Fu), 8.03 (d, J = 1.55 Hz, 1H, PyH), 8.14 (d, J = 3.81 Hz, 1H, FuH),
8.60 (d, J = 2.84 Hz, 1H, PyH). Anal. Calcd. (%) for C14H10N2O2: C,
70.58; H, 4.23; N, 11.76. Found: C, 70.59; H, 4.46; N, 11.58.
N-5-(3¢-Chlorophenyl)-2-furoyl-1H-1,2,4-triazole (IId): orange solid,
yield 82.5%, m.p. 211–212 ꢀC. IR (KBr) mmax: 3130.7, 3105.4,
1691.4, 1510.4, 1463.0, 1380.9, 1278.5, 1183.9, 1122.5, 1048.2,
1021.2 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 7.50–7.61 (m, 3H,
FuH + 2ArH-Fu), 7.87–7.91 (m, 1H, ArH-Fu), 7.98–7.99 (m, 1H, ArH-
Fu), 8.17 (d, J = 3.90 Hz, 1H, FuH), 8.44 (s, 1H, TrH), 9.48 (d,
J = 0.70 Hz, 1H, TrH). Anal. Calcd. (%) for C13H8ClN3O2: C, 57.05; H,
2.95; N, 15.35. Found: C, 56.90; H, 3.02; N, 14.96.
1
N-5-(4¢-Methylphenyl)-2-furoyl-1H-pyrazole (Il): brown solid, yield
78.6%, m.p. 144–145 ꢀC. IR (KBr) mmax: 3149.5, 1686.8, 1524.1,
1479.5, 1415.7, 1392.8, 1346.6, 1263.3, 1192.1, 1086.5, 1035.6 ⁄ cm.
1H NMR (300 MHz, DMSO-d6) d: 2.37 (s, 3H, CH3), 6.70 (dd,
J = 2.85, 1.53 Hz, 1H, PyH), 7.27 (d, J = 3.81 Hz, 1H, FuH), 7.31–
7.36 (m, 2H, ArH-Fu), 7.79–7.82 (m, 2H, ArH-Fu), 8.02 (dd, J = 1.53,
0.45 Hz, 1H, PyH), 8.13 (d, J = 3.78 Hz, 1H, FuH), 8.59 (dd, J = 2.87,
0.44 Hz, 1H, PyH). Anal. Calcd. (%) for C15H12N2O2: C, 71.42; H,
4.79; N, 11.10. Found: C, 71.25; H, 4.92; N, 10.94.
N-5-(3¢-Fluorophenyl)-2-furoyl-1H-1,2,4-triazole (IIe): light yellow
solid, yield 79.6%, m.p. 184–185 ꢀC. IR (KBr) mmax: 3139.2, 1687.6,
1588.8, 1514.0, 1468.1, 1379.7, 1283.7, 1196.7, 1122.4, 1052.4,
1021.5 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 7.32–7.36 (m, 1H,
ArH-Fu), 7.49 (d, J = 3.87 Hz, 1H, FuH), 7.57–7.64 (m, 1H, ArH-Fu),
7.75–7.79 (m, 2H, ArH-Fu), 8.18 (d, J = 3.87 Hz, 1H, FuH), 8.44 (s,
1H, TrH), 9.49 (s, 1H, TrH). Anal. Calcd. (%) for C13H8FN3O2: C,
60.70; H, 3.13; N, 16.34. Found: C, 60.66; H, 3.26; N, 16.24.
N-5-(4¢-Fluorophenyl)-2-furoyl-1H-1,2,4-triazole (IIf): white solid,
yield 86.9%, m.p. 207–208 ꢀC. IR (KBr) mmax: 3120.0, 1690.2, 1607.5,
1488.2, 1383.5, 1281.2, 1238.4, 1183.3, 1120.7, 1047.1, 1016.2 ⁄ cm.
1H NMR (300 MHz, DMSO-d6) d: 7.38–7.43 (m, 3H, FuH + 2ArH-Fu),
7.98–8.02 (m, 2H, 2ArH-Fu), 8.18 (d, J = 3.90 Hz, 1H, FuH), 8.44
(s, 1H, TrH), 9.48 (s, 1H, TrH). Anal. Calcd. (%) for C13H8FN3O2:
C, 60.70; H, 3.13; N, 16.34. Found: C, 60.40; H, 3.17; N, 16.23.
N-5-(4¢-Methoxyphenyl)-2-furoyl-1H-pyrazole (Im): light yellow solid,
yield 79.2%, m.p. 117–118 ꢀC. IR (KBr) mmax: 3124.5, 1689.2,
1613.0, 1526.6, 1480.8, 1422.1, 1396.3, 1352.7, 1296.6, 1258.8,
1172.6, 1088.4, 1037.3, 1022.0 ⁄ cm. 1H NMR (300 MHz, DMSO-d6)
d: 3.84 (s, 3H, CH3), 6.70 (dd, J = 2.85, 1.54 Hz, 1H, PyH), 7.08–
7.13 (m, 2H, ArH-Fu), 7.19 (d, J = 3.81 Hz, 1H, FuH), 7.83–7.88 (m,
2H, ArH-Fu), 8.01 (dd, J = 1.52, 0.63 Hz,1H, PyH), 8.12 (d,
J = 3.82 Hz, 1H, FuH), 8.58 (dd, J = 2.83, 0.64 Hz, 1H, PyH). Anal.
Calcd. (%) for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C,
67.15; H, 4.71; N, 10.41.
N-5-(2¢, 4¢-di-Fluorophenyl)-2-furoyl-1H-1,2,4-triazole (IIg): light yel-
low solid, yield 88.4%, m.p. 150–151 ꢀC. IR (KBr) mmax: 3124.7,
1708.0, 1618.7, 1601.5, 1510.5, 1480.9, 1436.4, 1383.1, 1272.0,
1183.2, 1150.3, 1121.2, 1046.5, 1019.9 ⁄ cm. 1H NMR (300 MHz,
DMSO-d6) d: 7.19 (t, J = 3.66 Hz, 1H, FuH), 7.29–7.36 (m, 1H, ArH-
Fu), 7.49–7.56 (m, 1H, ArH-Fu), 7.98–8.05 (m, 1H, ArH-Fu), 8.18 (d,
J = 3.90 Hz, 1H, FuH), 8.44 (s, 1H, TrH), 9.48 (s, 1H, TrH). Anal.
Calcd. (%) for C13H7F2N3O2: C, 56.73; H, 2.56; N, 15.27. Found: C,
56.47; H, 2.61; N, 14.94.
N-5-(4¢-Chlorophenyl)-2-furoyl-1H-1,2,4-triazole (IIa): light yellow
solid, yield 86.7%, m.p. 206–207 ꢀC. IR (KBr) mmax: 3120.1, 1691.2,
1602.0, 1509.5, 1473.4, 1415.0, 1380.1, 1279.4, 1182.7, 1119.8,
1098.4, 1043.4, 1013.6 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 7.44
(d, J = 3.88 Hz, 1H, FuH), 7.61–7.64 (m, 2H, ArH-Fu), 7.93–7.97 (m,
2H, ArH-Fu), 8.18 (d, J = 3.88 Hz, 1H, FuH), 8.44 (s, 1H, TrH), 9.48
(s, 1H, TrH). Anal. Calcd. (%) for C13H8ClN3O2: C, 57.05; H, 2.95; N,
15.35. Found: C, 57.33; H, 2.99; N, 15.17.
N-5-(2¢, 6¢-di-Fluorophenyl)-2-furoyl-1H-1,2,4-triazole (IIh): yellow
solid, yield 85.2%, m.p. 141–142 ꢀC. IR (KBr) mmax: 3109.8, 1702.5,
Chem Biol Drug Des 2012; 79: 121–127
123

Cui et al.
1624.8, 1515.7, 1476.0, 1451.0, 1379.0, 1317.9, 1266.8, 1241.4,
1251.0, 1158.8, 1037.4, 1001.8 ⁄ cm. 1H NMR (300 MHz, DMSO-d6)
d: 7.23–7.26 (m, 1H, FuH), 7.32–7.38 (m, 2H, ArH-Fu), 7.61–7.66 (m,
1H, ArH-Fu), 8.21 (d, J = 3.87 Hz, 1H, FuH), 8.45 (s, 1H, TrH), 9.49
(s, 1H, TrH). Anal. Calcd. (%) for C13H7F2N3O2: C, 56.73; H, 2.56; N,
15.27. Found: C, 56.60; H, 2.70; N, 15.02.
The four types of cell lines were grown and maintained in RPMI-
1640 medium supplemented with 10% fetal bovine serum (FBS),
penicillin (100 U ⁄ mL), and streptomycin (100 lg ⁄ mL) at 37 ꢀC in
humidified incubators in an atmosphere of 5% CO2.
All the experiments were performed on exponentially growing can-
cer cells. Numbers of viable cancer cells were determined by MTT
[3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] (19)
and sulforhodamine B (SRB) (20) assays. The cancer cells (1–
2.5 · 104 cells ⁄ mL) were inoculated in 96-well culture plates
(180 lL ⁄ well). After 24 h, 20 lL of culture medium containing com-
pounds of various concentrations was added to the wells, and the
cells were incubated for 48 h; 20 lL of RPMI-1640 medium was
added to the control cells. HL-60 cells were assayed by MTT, and
the Bel-7402, BGC-823, and KB cells were assayed by SRB. The
absorbance of each well was measured using a microculture plate
reader at 570 (MTT) and 540 nm (SRB). The inhibition rate was cal-
culated according to the following formula:
N-5-Phenyl-2-furoyl-1H-1,2,4-triazole (IIi): light yellow solid, yield
79.6%, m.p. 160–161 ꢀC. IR (KBr) mmax: 3138.7, 3108.3, 1690.7,
1513.7, 1481.8, 1452.0, 1378.4, 1280.4, 1266.6, 1179.1, 1119.0,
1047.3, 1016.5 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 7.40 (d,
J = 3.87 Hz, 1H, FuH), 7.49–7.59 (m, 3H, ArH-Fu), 7.93–7.96 (m, 2H,
ArH-Fu), 8.19 (d, J = 3.87 Hz, 1H, FuH), 8.44 (s, 1H, TrH), 9.48 (s,
1H, TrH). Anal. Calcd. (%) for C13H9N3O2: C, 65.27; H, 3.79; N,
17.56. Found: C, 65.18; H, 3.85; N, 17.35.
N-5-(4¢-Methylphenyl)-2-furoyl-1H-1,2,4-triazole (IIj): brown solid, yield
76.4%, m.p. 187–188 ꢀC. IR (KBr) mmax: 3112.5, 1686.9, 1485.4, 1378.6,
1273.5, 1182.5, 1121.0, 1046.1, 1020.9 ⁄ cm. 1H NMR (300 MHz,
DMSO-d6) d: 2.38 (s, 3H, CH3), 7.33–7.38 (m, 3H, FuH + ArH-Fu), 7.83
(d, J = 8.20 Hz, 2H, ArH-Fu), 8.17 (d, J = 3.87 Hz, 1H, FuH), 8.43 (s, 1H,
TrH), 9.46 (s, 1H, TrH). Anal. Calcd. (%) for C14H11N3O2: C, 66.40; H,
4.38; N, 16.59. Found: C, 66.12; H, 4.40; N, 16.66.
Inhibition rate = (ODcontrol ) ODtreated) ⁄ ODcontrol · 100%
Three replicates were performed. The IC50 values of some active
target compounds were evaluated using logit analysis (21).
N-5-(4¢-Methoxyphenyl)-2-furoyl-1H-1,2,4-triazole (IIk): gray solid,
yield 78.1%, m.p. 150–151 ꢀC. IR (KBr) mmax: 3138.0, 1686.5,
1610.2, 1485.1, 1378.1, 1296.2, 1272.6, 1254.5, 1178.4, 1120.9,
1023.2 ⁄ cm. 1H NMR (300 MHz, DMSO-d6) d: 3.84 (s, 3H, CH3),
7.09–7.12 (m, 2H, ArH-Fu), 7.24 (d, J = 3.90 Hz, 1H, FuH), 7.86–7.89
(m, 2H, ArH-Fu), 8.17 (d, J = 3.92 Hz, 1H, FuH), 8.43 (s, 1H, TrH),
9.46 (s, 1H, TrH). Anal. Calcd. (%) for C14H11N3O3: C, 62.45; H, 4.12;
N, 15.61. Found: C, 62.66; H, 4.20; N, 15.65.
Antifungal activity in vivo
Fungicidal activities of the title compounds against Phytophthora
capsici, Fusarium oxysporum, Corynespora cassiicola, and Rhizocto-
nia solanii were evaluated using pot culture test according to refer-
ence (22–25). The fungal stains of P. capsici, F. oxysporum,
C. cassiicola, and R. solanii were provided by Institute of Vegeta-
bles and Flowers, Chinese Academy of Agricultural Science, Beijing,
China. Phytophthora capsici was maintained on oat medium at
17 ꢀC, and F. oxysporum, C. cassiicola, and R. solanii were main-
tained on potato dextrose agar medium at 4 ꢀC. The culture plates
were cultivated at 24 € 1 ꢀC. Four commercial fungicides, procymi-
done, thiophanate-methyl, chlorothalonil, and jinggangmycin, were
evaluated as controls against the aforementioned fungi at the same
condition. Three replicates were performed. The relative inhibition
rate of the circle mycelium compared to blank assay was calculated
via the following equation:
Prediction of toxicity
The database (Prediction System of Carcinogenic Toxicity Version
1.0, Prediction System for Mutagenic Toxicity Version 1.0 and CI-
SOC-LOGP Version 1.0) (18) of Shanghai Institute of Organic Chemis-
try (Chinese Academy of Science, Shanghai, China) was used to
predict the carcinogenic toxicity, mutagenic toxicity, and the ClogP
value of the target compounds. The prediction consists of following
steps: (i) reading a structure file, (ii) generating all structural de-
scriptors, and (iii) calculating corresponding data.
dex ꢀ de0x
Relative inhibition rate ð%Þ ¼
ꢁ 100%
dex
where dex is the extended diameter of the circle mycelium during
the blank assay and de0x is the extended diameter of the circle
mycelium during testing.
Bioactivity
Antitumor activity
All the title compounds were dissolved in DMSO (the final concen-
tration of DMSO in the culture was always <0.1% v ⁄ v, a concentra-
tion that produced no effects on cell growth and proliferation, as
was experimentally confirmed) and screened for preliminary antican-
cer activity against four different cell lines: a human promyelocytic
leukemic cell line (HL-60), a human hepatocellular carcinoma cell
line (Bel-7402), a human gastric carcinoma cell line (BGC-823), and
a human nasopharyngeal carcinoma cell line (KB) at the concentra-
tion of 50.0 lM. The commercial drug doxorubicin was used as a
positive control in the bioassay.
Results and Discussion
Prediction of logP value and toxicity
All the predicted values of title compounds are listed in Table 1.
Compared to our former compounds, such as semicarbazides (logP
values were from 3.07 to 4.53) (12), diacylhydrazines (logP values
were from 2.70 to 6.33) (13–15), and acylhydrazones (logP values
were from 3.45 to 5.25) (16), all the title compounds had favorable
124
Chem Biol Drug Des 2012; 79: 121–127

Synthesis and Bioactivities of Novel Pyrazole and Triazole Derivatives
Table 1: Prediction of toxicity and ClogP values
Carcinogenic toxicity
Mutagenic toxicity
Pred.
(%)
Carcinogenic
possibility
Carcinogenic
impossibility
Pred.
(%)
Mutagenic
possibility
Mutagenic
impossibility
Compound
ClogP
Ia
2.81
1.81
2.12
2.53
2.8
87
85
88
86
88
86
88
87
86
86
87
88
89
85
83
83
85
85
85
83
83
84
86
86
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.893
0.618
0.841
0.91
0.866
0.946
0.811
0.88
0.954
0.956
0.899
0.734
0.766
0.829
0.501
0.854
0.793
0.72
89
89
90
88
89
88
89
89
88
88
88
90
90
88
88
87
88
88
88
88
87
87
89
89
0.02
0.29
0.35
0.01
0.02
0.01
0.05
0.03
0.01
0.01
0.03
0.03
0.02
0.01
0.11
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.08
0.01
0.01
0.12
0.07
0.2
Ib
Ic
Id
Ie
If
2.13
2.28
2.28
2.33
2.18
2.04
2.52
2.07
2.16
1.16
1.89
2.16
1.63
1.64
1.68
1.53
1.4
Ig
Ih
Ii
0.04
0.06
0.25
0.17
0.06
0.06
0.09
0.25
0.02
0.33
0.23
0.15
0.19
0.53
0.42
0.21
0.19
0.27
Ij
Ik
Il
Im
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
0.811
0.92
0.924
0.832
0.632
0.675
1.87
1.42
solubility in common solvents. Their logP values ranged from 1.16
to 2.81, which were lower than most values of our former com-
pounds and showed more solubility in water. It indicated that the
introduction of pyrazole and 1,3,4-triazole could improve the solubil-
ity of this kind of compounds.
considered as non-mutagenic. Otherwise, they were considered to
be mutagenic.
Based on the results in Table 1, most of title compounds were safe.
But the CIP values of IIb and IIj were 0.501 and 0.632, which were
<0.65. That means these two compounds may exhibit potential car-
cinogenic toxicity. The MP valves of Ib, Ic, Ig, and IIb were
greater than their MIP values, suggesting potential mutagenic
toxicity.
For the carcinogenic toxicity, when the predicted value is more
than 70%, and the value of carcinogenic impossibility (CIP) is
more than 0.65, meanwhile, its CIP value is greater than carcino-
genic possibility (CP), and the compound is considered as non-
carcinogenic. Otherwise, they were considered to be carcinogenic.
For the mutagenic toxicity, if the predictability value was more
than 70% and the mutagenic impossibility (MIP) value was
greater than the mutagenic possibility (MP), the compound was
Antitumor activity
The antitumor results of the title compounds against HL-60, BGC-
823, Bel-7402, and KB were listed in Figure 1 (Table S1). Generally,
90
HL-60
Bel-7402
BGC-823
KB
80
70
60
50
40
30
20
10
0
–10
Compounds
Figure 1: Antitumor activity of compounds I and II at 50 lM.
Chem Biol Drug Des 2012; 79: 121–127
125

Cui et al.
100
80
60
40
20
0
–20
–40
Compounds
Fusarium oxysporum
b
a
Phytophthora capsici
Corynespora cassiicola
c
d
Rhizoctonia solanii
a
b
c
Figure 2: Fungicidal activity of compounds I and II at 500 lg ⁄ mL in vivo. *Control fungicides: procymidone; thiophanate-methyl; chlorot-
halonil; jinggangmycin.
d
the activity of title compounds containing 1,3,4-triazole (series II)
was better than that of compounds containing pyrazole (series I).
Among them, the IC50 values of IIa and IIg were 40.82 and
69.28 lM, respectively, against Bel-7402, which showed much bet-
ter activity against Bel-7402 than doxorubicin (Table S1). Compound
IIa also showed favorable activity against BGC-823 with IC50 value
as 54.36 lM (Table S1). All the title compounds did not exhibit
obvious antitumor activity against HL-60 and KB.
(2010CB126104), the National Scientific and Technology Supporting
Program of China (2011BAE06B05-5), the National Natural Science
Foundation of China (21102173), and the State Key Laboratory of
Natural and Biomimetic Drugs (K20100101).
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127