Synthesis and bioactivity of novel N,N′-diacylhydrazine derivatives containing furan(II)

Article abstract of DOI:10.1002/cjoc.201090214

Diacylhydrazines have been found as molting hormone analogs since RH-5849 was reported as the first nonsteroidal ecdysone agonist in 1988. Optimizations on diacylhydrizines with benzoheterocycle containing oxygen were widely explored in recent years. In o

Full text of DOI:10.1002/cjoc.201090214

FULL PAPER
Synthesis and Bioactivity of Novel N,N′-Diacylhydrazine
Derivatives Containing Furan (II)
Li, Xichena(李希晨)
Yang, Xinlinga,c(杨新玲)
Cui, Zininga(崔紫宁)
Li, Yinga(李映)
He, Hongwu*,b(贺红武)
Ling, Yun*,a(凌云)
a Key Laboratory of Pesticide Chemistry and Application, Ministry of Agriculture, Department of Applied
Chemistry, College of Science, China Agricultural University, Beijing 100193, China
b Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Institute of Pesticide Chemistry,
College of Chemistry, Central China Normal University, Wuhan, Hubei 430079, China
c The State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
Diacylhydrazines have been found as molting hormone analogs since RH-5849 was reported as the first non-
steroidal ecdysone agonist in 1988. Optimizations on diacylhydrizines with benzoheterocycle containing oxygen
were widely explored in recent years. In order to find novel compounds with high bioactivity, a series of mono- (I)
and di-acylhydrazine (II) derivatives containing furan were designed and synthesized. Their structures were con-
firmed by 1H NMR, IR, elemental analyses and single crystal X-ray diffraction analyses (II7). The bioassay results
showed that some of the mono-acylhydrazine (I) derivatives exhibited good larvicidal activity against Culex pipiens
pallens at 10 mg/L and better than those of di-acylhydrazines (II). Generally, the anti-tumor activity of
di-acylhydrazines (II) was better than that of mono-acylhydrazines (I).
Keywords acylhydrazine, furan, synthesis, larvicidal activity, anti-tumor activity
Introduction
pharmacological activity.11-17 Due to these broad-spec-
trum activity, the furan group is widely applied in mo-
lecular design for pesticide and medicine. Therefore, we
displaced part A of RH-5849 with 5-substituted furan
for designing novel compounds with good biological
activity. Our previous work21 indicated that some dia-
cylhydrazine containing furan showed insecticidal and
anti-tumor activity.
Diacylhydrazines have been found as molting hor-
mone analogs by mimicing the action of
20-hydroxyecdysone (20E)1 since N'-tert-butyl-N,N'-
dibenzoylhydrazine (RH-5849) was reported as the first
nonsteroidal ecdysone agonist in 1988.2,3 The subse-
quent synthesis of RH-5992 (tebufenozide)4 became the
first commercialized diacylhydrazine insect growth
regulators (IGRs) by Rohm&Haas Company. As a new
class of IGRs, structures of diacylhydrazines are gener-
ally composed of three parts (part A, part B and acylhy-
drazine bridge), as shown in Table 1. In recent years,
the optimization was focused on part A,5-10 which re-
sulted in several commercial products such as RH-2485
(methoxyfenozide), ANS-118 (chromafenozide) and
JS-118. The replacement of part A with benzoheterocy-
cle containing oxygen brings the recent products
ANS-118 and JS-118. This indicates that the displace-
ment of part A with aromatic heterocycle containing
oxygen is worth exploring.
In this paper, we will report
a series of
mono-acylhydrazine (I) and di-acylhydrazine (II) de-
rivatives containing furan and investigate the different
activity between I and II (Table 1).
Experimental
Materials and methods
The melting points (m.p.) were measured with a
Cole-Parmer melting point apparatus (USA) and the
1
thermometer was uncorrected. H NMR spectra were
obtained from a Bruker Advance DPX 300 Hz spec-
trometer (Switzerland), using tetramethylsilane (TMS)
as internal standard and DMSO-d6 as the solvent. Infra-
red spectra (IR) were measured by a Shimadzu IR-435
spectrometer (Japan) using potassium bromide (KBr)
Furan group is an electron-rich group in which oxy-
gen can easily form hydrogen bond with various types
of biological enzymes. The derivatives of furan substi-
tuted at 2- and 5-position are frequently found in natural
products and exhibit insecticidal, antibacterial and
disk. Frequencies (υ) were reported in cm－ and the ab-
1
breviations s, m, and w were frequently used meaning
*
E-mail: lyun@cau.edu.cn
Received December 16, 2009; revised March 4, 2010; accepted March 23, 2010.
Project supported by the National Key Project for Basic Research (Nos. 2003CB114400, 2010CB126104), the National High Technology Research
and Development Program of China (No. 2006AA10A201) and the National Natural Science Foundation of China (Nos. 20672138 and 20972185).
Chin. J. Chem. 2010, 28, 1233— 1239
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Li et al.
FULL PAPER
strong, medium, and week absorption, respectively.
Elemental analyses (C, H and N) were carried out with a
Flash EA 1112 elemental analyzer (Italy) by the Ana-
lytical Center of the Institute of Chemistry, Chinese
Academy of Sciences. The X-ray crystal diffraction data
were collected with a Rigaku Saturn diffractometer (Ja-
pan) at 113(2) K and the crystal structures were calcu-
lated using the SHELXL program package and refined
by full-matrix least squares procedures at Nankai Uni-
versity. The solvents and reagents were mainly pur-
chased from the Beijing Chemical Reagents Co.,
(China).
5-(substituted phenyl)-2-furoyl acid (10 mmol) was re-
fluxed in toluene (20 mL) for 5 h. After removing the
extra thionyl chloride and solvent under reduced pres-
sure, the residue was purified by recrystallization from
dichloromethane to get the substituted furoyl chloride.
General synthetic procedure for N'-tert-butyl-N-[5-
(substituted phenyl)-2-furoyl]hydrazine (I and Ib)19
Solution of dilute aqueous sodium hydroxide (10%,
16 mmol) was added dropwise to the stirred solution of
tert-butylhydrazine hydrochloride (16 mmol) in di-
chloromethane (10 mL) at 0 ℃. The reaction mixture
was stirred for 30 min, followed by adding dropwise the
solution of 5-(substituted phenyl)-2-furoyl chloride (4
mmol) in dichloromethane (10 mL) and dilute aqueous
sodium hydroxide (10%, 4 mmol) at 0 ℃ simultane-
ously. Then the mixture was stirred at room temperature
for 5 h and filtered to obtain yellow solution. The or-
ganic filtrate was washed with water and dried with an-
hydrous magnesium sulphate overnight. After removing
the solvent, the residue was purified by vacuum column
chromatography on silica gel using a mixture of petro-
leum ether (60—90 ℃) and ethyl acetate as the eluent
(Vpetroleum ether/Vethyl acetate＝3/1) to obtain I and Ib as col-
orless crystals (Table 2).
Table 1 General structure and design strategy of the target
compound
General structure
Compound
Part A
Part B
General synthetic procedure for N'-tert-butyl-N'-
(substituted aroyl)-N-[5-(substituted phenyl)-2-fu-
royl]hydrazine (II1— II9)
RH-5849
Solution of aroyl chloride (5 mmol) in toluene (10
mL) and dilute aqueous sodium hydroxide (40%, 5
mmol) were added dropwise to the stirred solution of
N′-tert-butyl-N-[5-(substituted phenyl)-2-furoyl]-hydr-
azine (I) (5 mmol) in toluene (20 mL) at 0 ℃ simulta-
neously. Then the reaction mixture was stirred at room
temperature for 2 h and filtered to obtain a white solid.
The crude product was washed with water, and the puri-
fied product was obtained by recrystallization from
ether-methanol (Vether/Vmethanol＝1/1). The structures of
title compounds are listed in Table 3.
RH-2485
ANS-118
JS-118
I
Commercial
products
N'-tert-Butyl-N'-(4-chlorobenzoyl)-N-[5-(4-chloro-
phenyl)-2-furoyl]hydrazine (II1): Colorless crystals,
yield 86.3%; m.p. 221.5 — 223.5 ℃ ; 1H NMR
(DMSO-d6) δ: 1.50 (s, 9H, t-Bu), 7.12 (d, J＝3.66 Hz,
1H, FuH), 7.15 (d, J＝3.66 Hz, 1H, FuH), 7.37 (dd, J＝
6.66, 1.83 Hz, 2H, ArH), 7.51 (dd, J＝6.59, 1.94 Hz, 2H,
ArH), 7.57 (dd, J＝6.80, 1.84 Hz, 2H, ArH-Fu), 7.88
(dd, J＝6.75, 1.89 Hz, 2H, ArH-Fu), 10.76 (s, 1H, NH);
IR ν: 3420 (m), 3225 (m), 2960 (w), 2363 (w), 1665 (s),
H
Target
compounds
－
1
1470 (m), 1111 (m), 840 (w), 701 (w) cm . Anal. calcd
for C22H20Cl2N2O3 C 61.26, H 4.67, N 6.49; found C
61.02, H 4.73, N 6.77.
II
N'-tert-Butyl-N'-(3-chlorobenzoyl)-N-[5-(4-chloro-
phenyl)-2-furoyl]hydrazine (II2): Colorless crystals,
1
yield 85.0%; m.p. 195—197 ℃; H NMR (DMSO-d6)
General synthetic procedure for 5-(substituted
phenyl)-2-furoyl chloride18
δ: 1.50 (s, 9H, t-Bu), 7.11 (d, J＝3.66 Hz, 1H, FuH),
7.15 (d, J＝3.69 Hz, 1H, FuH), 7.30—7.44 (m, 3H,
ArH), 7.54—7.58 (m, 3H, ArH＋2ArH-Fu), 7.86—7.91
A mixture of thionyl chloride (30 mmol) and
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1233— 1239

Synthesis and Bioactivity of Novel N,N′-Diacylhydrazine Derivatives
Table 2 Selected bond lengths, angles and torsion angles of compound II7
Bond angles/(°) Torsion angles/(°)
C(10)-O(1)-C(7) C(11)-N(1)-N(2)-C(16)
Bond length/Å
O(2)— C(11)
1.2225(16)
1.2322(16)
1.3614(18)
1.3994(15)
1.5111(17)
1.3778(18)
1.462(2)
106.60(11)
120.22(11)
116.79(11)
122.12(11)
116.40(10)
121.12(12)
123.86(12)
121.03(13)
59.87(16)
96.44(14)
4.1(2)
O(3)— C(16)
N(1)— C(11)
N(1)— N(2)
N(2)— C(12)
N(2)— C(16)
C(6)— C(7)
C(11)-N(1)-N(2)
C(16)-N(2)-N(1)
C(16)-N(2)-C(12)
N(1)-N(2)-C(12)
C(6)-C(1)-Cl(1)
O(2)-C(11)-N(1)
O(3)-C(16)-N(2)
C(11)-N(1)-N(2)-C(12)
N(2)-N(1)-C(11)-O(2)
N(1)-N(2)-C(16)-O(3)
N(2)-N(1)-C(11)-C(10)
N(1)-N(2)-C(16)-C(17)
Cl(1)-C(1)-C(6)-C(7)
O(1)-C(10)-C(11)-N(1)
－
－
－
155.08(13)
177.20(11)
27.01(18)
－
3.6(2)
C(10)— C(11)
1.4669(19)
－
12.79(18)
－
Table 3 Structures of the compounds and larvicidal activity
against Culex pipiens pallens
(w), 805 (w), 700 (w) cm 1. Anal. calcd for
C22H20Cl2N2O3: C 61.26, H 4.67, N 6.49; found C 60.93,
H 4.74, N 6.70.
Larvicidal activity/% LC50/
Compd.
R1
R2
－
1
N'-tert-Butyl-N'-(4-methylbenzoyl)-N-[5-(4-chloro-
phenyl)-2-furoyl]hydrazine (II4): Colorless crystals,
yield 81.2%; m.p. 133.5 — 135.5 ℃ ; 1H NMR
(DMSO-d6) δ: 1.49 (s, 9H, t-Bu), 2.21 (s, 3H, CH3),
7.07—7.11 (m, 3H, FuH＋ArH), 7.15 (d, J＝3.66 Hz,
1H, ArH), 7.40—7.43 (m, 2H, ArH), 7.53—7.58 (m, 2H,
ArH-Fu), 7.86—7.91 (m, 2H, ArH-Fu), 10.70 (s, 1H,
NH); IR ν: 3450 (m), 3280 (w), 2623 (m), 2341 (m),
at 10 mg/L
85
(mg•L )
I1
I2
4-Cl
2-Cl
3-Cl
4-F
—
—
—
—
—
—
—
—
—
—
—
100
82.5
75
5.51
I3
—
I4
—
I5
4-CH3
4-Cl
2-Cl
3-Cl
4-F
20
—
Ib1
Ib2
Ib3
Ib4
Ib5
II1
II2
II3
II4
II5
II6
II7
100
100
10
3.95
－
1
1664 (s), 1471 (m), 1304 (m), 918 (w), 829 (w) cm .
Anal. calcd for C23H23ClN2O3: C 67.23, H 5.64, N 6.82;
found C 67.10, H 5.73, N 6.67.
7.16
—
—
—
—
—
—
—
—
—
—
60
N'-tert-Butyl-N'-benzoyl-N-[5-(4-chlorophenyl)-2-
furoyl]hydrazine (II5): Colorless crystals, yield 86.4%;
4-CH3
20
1
m.p. 258—260.5 ℃; H NMR (DMSO-d6) δ: 1.51 (s,
4-Cl 4-ClC6H4
4-Cl 3-ClC6H4
4-Cl 2-ClC6H4
4-Cl 4-CH3C6H4
20
9H, t-Bu), 7.10 (dd, J＝9.15, 3.66 Hz, 2H, FuH), 7.26—
7.30 (m, 3H, ArH), 7.47—7.50 (m, 2H, ArH), 7.55 (dd,
J＝6.74, 2.02 Hz, 2H, ArH-Fu), 7.87 (dd, J＝6.72, 2.04
Hz, 2H, ArH-Fu), 10.70 (s, 1H, NH); IR ν: 3230 (m),
2890 (w), 1685 (s), 1520 (m), 1475 (m), 1295 (m), 1080
30
50
40
4-Cl
C6H5
35
－
1
(w), 800 (m) cm . Anal. calcd for C22H21ClN2O3: C
66.58, H 5.33, N 7.06; found C 66.44, H 5.37, N 7.11.
N'-tert-Butyl-N'-(4-chlorobenzoyl)-N-[5-(2-chloro-
phenyl)-2-furoyl]hydrazine (II6): Colorless crystals,
yield 88.3%; m.p. 229.5 — 230.5 ℃ ; 1H NMR
(DMSO-d6) δ: 1.50 (s, 9H, t-Bu), 7.19 (brs, 2H, FuH),
7.36—7.53 (m, 6H, 4ArH＋2ArH-Fu), 7.59 (dd, J＝
7.88, 1.37 Hz, 1H, ArH-Fu), 7.98 (dd, J＝7.80, 1.74 Hz,
1H, ArH-Fu), 10.78 (s, 1H, NH); IR ν: 3380 (m), 2970
(m), 1680 (s), 1620 (s), 1520 (m), 1460 (m), 1390 (m),
2-Cl 4-ClC6H4
2-Cl 4-CH3C6H4
30
35
II8
4-Cl
4-F
25
—
II9
20
—
RH-5849
—
—
100
2.31
－
1
(m, 2H, ArH-Fu), 10.77 (s, 1H, NH); IR ν: 3260 (m),
1360 (m), 1290 (m), 1040 (m), 800 (w), 750 (m) cm .
Anal. calcd for C22H20Cl2N2O3: C 61.26, H 4.67, N 6.49;
found C 60.97, H 4.83, N 6.31.
2890 (w), 1668 (s), 1460 (s), 1300 (m), 906 (w), 813 (m)
－
1
cm . Anal. calcd for C22H20Cl2N2O3: C 61.26, H 4.67,
N 6.49; found C 60.72, H 5.11, N 6.27.
N'-tert-Butyl-N'-(4-methylbenzoyl)-N-[5-(2-chloro-
phenyl)-2-furoyl]hydrazine (II7): Colorless crystals,
yield 79.5%; m.p. 192.5 — 194.5 ℃ ; 1H NMR
(DMSO-d6) δ: 1.50 (s, 9H, t-Bu), 2.22 (s, 3H, CH3),
7.10 (d, J＝8.13 Hz, 2H, ArH), 7.19 (brs, 2H, FuH),
7.40—7.54 (m, 4H, 2ArH＋2ArH-Fu), 7.59 (dd, J＝
7.52, 1.34 Hz, 1H, ArH-Fu), 8.01 (dd, J＝7.77, 1.77 Hz,
1H, ArH-Fu), 10.73 (s, 1H, NH); IR ν: 3450 (m), 2930
(m), 1670 (s), 1630 (s), 1520 (m), 1460 (m), 1370 (m),
N'-tert-Butyl-N'-(2-chlorobenzoyl)-N-[5-(4-chloro-
phenyl)-2-furoyl]hydrazine (II3): Colorless crystals,
yield 82.6%; m.p. 180.5—181 ℃; 1H NMR (DMSO-d6)
δ: 1.53 (s, 9H, t-Bu), 7.07 (d, J＝3.63 Hz, 1H, FuH),
7.12 (d, J＝3.66 Hz, 1H, FuH), 7.22—7.28 (m, 3H,
ArH), 7.37—7.40 (m, 1H, ArH), 7.54 (dd, J＝6.71, 1.97
Hz, 2H, ArH-Fu), 7.84 (dd, J＝6.69, 1.98 Hz, 2H,
ArH-Fu), 10.61 (s, 1H, NH); IR ν: 3230 (m), 2980 (w),
1660 (s), 1520 (m), 1450 (m), 1360 (m), 1080 (m), 970
－
1
1280 (m), 1020 (m), 820 (m), 760 (m) cm . Anal. calcd
Chin. J. Chem. 2010, 28, 1233— 1239
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Li et al.
FULL PAPER
for C23H23ClN2O3: C 67.23, H 5.64, N 6.82; found C
67.13, H 5.70, N 6.76.
µmol/L, the title compounds I1—I5, Ib2—Ib5 and II1—
II9 were screened for the preliminary anticancer activity
against four different cell lines in vitro: human promye-
locyticfina leukemic cell line (HL-60), human gastric
carcinoma cell line (BGC-823), human hepatocellular
carcinoma cell line (Bel-7402), and human naso-
pharyngeal carcinoma cell line (KB).
The four human cancer cell lines were incubated in a
RPMI-1640 medium supplemented with 10% fetal bo-
vine serum, penicillin (100 U/mL), and streptomycin
(100 µg/mL) at 37 ℃ in humidified incubators in an
atmosphere of 5% CO2. The experiments were per-
formed on exponentially growing cancer cells
(1×104—2.5×104 cells/mL) which were inoculated in
96-well culture plates (180 µL/well). After 24 h 20 µL
of the culture medium containing the compounds were
added to the wells (RPMI-1640 medium in control cells),
then the cells were incubated for 48 h. Numbers of vi-
able cancer cells were evaluated by MTT22 (HL-60 cell)
and SRB23 ( Bel-7402, BGC-823 and KB cells) assays.
N'-tert-Butyl-N'-(thiophene-2-carbonyl)-N-[5-(4-chlo-
rophenyl)-2-furoyl]hydrazine (II8): Colorless crystals,
1
yield 90.7%; m.p. 279—281 ℃; H NMR (DMSO-d6)
δ: 1.50 (s, 9H, t-Bu), 7.04 (dd, J＝5.06, 3.80 Hz, 1H,
Thiophene-H), 7.24 (d, J＝3.66 Hz, 1H, FuH), 7.39 (d,
J＝3.66 Hz, 1H, FuH), 7.58—7.62 (m, 2H, ArH-Fu),
7.67 (dd, J＝5.04, 1.32 Hz, 1H, Thiophene-H), 7.72 (dd,
J＝3.78, 1.32 Hz, 1H, Thiophene-H), 7.97—8.02 (m,
2H, ArH-Fu), 11.16 (s, 1H, NH); IR ν: 3240 (m), 2900
(w), 1688 (s), 1610 (s), 1460 (m), 1290 (m), 820 (w),
－
1
750 (w) cm . Anal. calcd for C20H19ClN2O3S: C 59.62,
H 4.75, N 6.95; found C 59.72, H 4.93, N 6.85.
N'-tert-Butyl-N'-(thiophene-2-carbonyl)-N-[5-(4-fluo-
rophenyl)-2-furoyl]hydrazine (II9): Colorless crystals,
1
yield 87.8%; m.p. 252—253 ℃; H NMR (DMSO-d6)
δ: 1.50 (s, 9H, t-Bu), 7.04 (dd, J＝5.03, 3.80 Hz, 1H,
Thiophene-H), 7.17 (d, J＝3.66 Hz, 1H, FuH), 7.34—
7.40 (m, 3H, FuH＋2ArH-Fu), 7.67 (dd, J＝5.09, 1.31
Hz, 1H, Thiophene-H), 7.72 (dd, J＝3.78, 1.32 Hz, 1H,
Thiophene-H), 8.00—8.05 (m, 2H, ArH-Fu), 11.11 (s,
1H, NH); IR ν: 3250 (m), 2930 (m), 1660 (s), 1480 (s),
Results and discussion
－
1
1305 (m), 1210 (m), 820 (m), 730 (m) cm . Anal. calcd
for C20H19FN2O3S: C 62.16, H 4.96, N 7.25; found C
62.03, H 4.85, N 7.41.
Chemistry
The synthetic route of the novel acylhydrazines I
and II is shown in Scheme 1. The intermediate
5-substituted phenyl-2-furoyl chloride was obtained
from 5-substituted phenyl-2-furoyl acid which was pre-
pared according to the published method.24,25 Com-
pounds of type I were synthesized in yields of 52.3%—
69.3% by the reaction of appropriate 5-substituted
phenyl-2-furoyl chloride with tert-butyl hydrazine hy-
drochloride in toluene, using sodium hydroxide as the
base. Compound I was purified by column chromatog-
raphy on silica gel using 3∶ 1 petroleum ether (60—90
℃)/ethyl acetate as the eluent. Meanwhile, the byprod-
uct Ib, an isomer of compound I, was obtained in yields
of 18.6%—30.7%. Our previous research had shown
that different acid acceptors could affect the ratio of I to
Biological protocols
Larvicidal activity against Culex pipiens
pallens20,21 The larvicidal activity of chemicals I1—I5,
Ib1—Ib5 and II1—I9 were evaluated at test concentration
of 10 mg/L against the fourth-instar Culex pipiens
pallens by the water immersion method under condi-
tions of (27±2) ℃, photoperiod of 10∶14 (light∶
dark), and relative humidity 50%—70%. All the test
beakers containing ten Culex pipiens pallens were
evaluated in 8 d after treatment for the average percent-
age mortality of four replicates in each dosage. The
commercialized insecticide RH-5849 was tested as a
control under the same condition.
Anti-tumor activity21 At the concentration of 10
Scheme 1 The synthetic route of the title compounds
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Chin. J. Chem. 2010, 28, 1233— 1239

Synthesis and Bioactivity of Novel N,N′-Diacylhydrazine Derivatives
Ib. In particular, sodium ethoxide afforded the highest
yield of I.19
as a control. The results are reported in Table 3. Gener-
ally, the larvicidal activity of mono-acylhydrazines (I)
were higher than those of di-acylhydrazines (II). For
example, compounds I2, Ib1 and Ib2 exhibited 100%
mortality, which is equal to that of RH-5849 at 10 mg/L.
But their LC50 values are higher than that of RH-5849,
which means their activity is still lower than RH-5849.
Anti-tumor activity As mentioned above, furan is
an active group. Some of its derivatives show excellent
anti-tumor activity. Thus, anti-tumor activity of the new
compounds was tested in vitro at 10 µmol/L against four
human cell lines [promyelocyticfina leukemic cell
(HL-60), hepatocellular carcinoma cell (Bel-7402),
gastric carcinoma cell (BGC-823), and nasopharyngeal
carcinoma cell (KB)]. The results are reported in Table
4. All the compounds showed very poor activity against
leukaemia cell (HL-60) and gastric cancer cell
(BCG-823), with the only exception of compound II5.
Instead, several compounds exhibited good inhibitory
activity against liver cancer cell (Bel-7402) and naso-
pharyngeal carcinoma cell (KB) at 10 µmol/L. For in-
stance, the inhibitory rate of Ib2 against liver cancer cell
was 83.44%; those of II1 and II2 against nasopharyn-
geal carcinoma cell were 81.92% and 85.87%, respec-
tively. Generally, the anti-tumor activity of
di-acylhydrazines (II) was higher than those of
mono-acylhydrazines (I). The most interesting result
was that I2 and Ib2 exhibited not only good anti-tumor
activity against liver cancer cell (Bel-7402) and naso-
pharyngeal carcinoma cell (KB), but also good lar-
vicidal activity against Culex pipiens pallens.
Compounds of type II were synthesized in good
yields (79.5%—90.7%) by reaction of compound I with
various substituted aroyl chlorides, using sodium
hydroxide as acid acceptor. All the compounds of type
II were purified by recrystallization from 1∶1 diethyl
ether/methanol. The structures of all the synthesized
1
compounds were confirmed by H NMR, IR and ele-
mental analysis.
Colorless needle crystals of compound II7 were used
for single X-ray diffraction analysis. The crystal struc-
ture and cell structures of II7 are shown in Figure 1,
while bond lengths, angles and torsion angles are re-
ported in Table 2. Compound II7 contains three ring
planes: (a) composed of C(1), C(2), C(3), C(4), C(5)
and C6; (b) composed of C(7), C(8), C(9), C(10) and
O(1), and (c) composed of C(17), C(18), C(19), C(20),
C(21) and C(22). The dihedral angles between the
(a)/(b), (b)/(c) and (a)/(c) planes are 152.2°, 123.3° and
29.7°, respectively. Instead, the dihedral angle between
the benzene and the furan rings in the crystal structure
of I1 is 15.35°.26
Conclusion
In summary, a series of novel mono- and
di-acylhydrazines containing furan were developed by
replacing of part A of commercial diacylhydrazines
with 5-substituted furan. At 10 mg/L, the larvicidal ac-
tivity
against
Culex
pipiens
pallens
of
mono-acylhydrazines (I) were generally higher than
those of di-acylhydrazines (II). Compounds I2, Ib1 and
Ib2 exhibited 100% mortality, which was equal to that of
RH-5849. But their activity is still lower since their
LC50 values were higher than that of RH-5849. Prelimi-
nary bioassay of anti-tumor activity in vitro showed that
several new compounds were active against liver cancer
cell (Bel-7402) and nasopharyngeal carcinoma cell (KB)
at the tested concentration, such as the inhibitory rates
of Ib2, II1 and II2 were higher than 80%. Generally, the
anti-tumor activity of di-acylhydrazines (II) was better
than that of mono-acylhydrazines (I). The most inter-
esting result was that I2 and Ib2 exhibited both larvicidal
and anti-tumor activity.
Figure 1 Molecular structure and cell structures of compound
II7.
Bioassay
Larvicidal activity The synthesized compounds
were tested for larvicidal activity against Culex pipiens
pallens at the concentration of 10 mg/L, using RH-5849
Chin. J. Chem. 2010, 28, 1233— 1239
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1237

Li et al.
FULL PAPER
Table 4 The inhibitory rate against four human cancer cell lines
Inhibitory rate (%) at 10 µmol/L
Compd.
R1
R2
Leukaemia
(HL-60)
Gastric cancer
(BGC-823)
Liver cancer
(Bel-7402)
Nasopharyngeal carcinoma (KB)
I1
I2
4-Cl
2-Cl
3-Cl
4-F
—
－
－
11.39
16.97
4.17
13.89
15.79
23.77
21.05
4.70
8.96
31.72
76.65
18.16
9.00
—
71.27
I3
—
－
－
6.78
9.85
－
7.08
0.62
I4
—
I5
4-CH3
2-Cl
3-Cl
4-F
—
－
－
13.59
1.94
11.47
83.44
3.69
29.07
71.78
28.80
67.90
13.11
81.92
85.87
65.26
79.99
2.92
Ib2
Ib3
Ib4
Ib5
II1
II2
II3
II4
II5
II6
II7
—
—
20.35
5.53
11.54
21.22
18.38
10.37
48.67
20.41
10.89
70.21
37.29
25.10
—
－
69.70
0.53
4-CH3
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
2-Cl
2-Cl
—
1.11
－
－
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-CH3C6H4
C6H5
－
－
14.84
1.87
73.63
75.36
65.81
78.08
3.04
－
－
0.23
15.91
20.95
4.12
4-ClC6H4
4-CH3C6H4
－
－
65.78
62.80
2.33
0.65
26.64
II8
II9
4-Cl
4-F
－
19.09
1.45
5.77
75.13
69.11
70.43
64.67
－
18.91
Acknowledgements
9
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www.cjc.wiley-vch.de
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