Novel salicylamide derivatives incorporating neonicotinoid pharmacophore: Design, synthesis, characterization, and biological evaluation

Article abstract of DOI:10.1007/s00044-012-0380-8

A series of novel salicylamide derivatives containing neonicotinoid pharmacophore were designed and synthesized via multi-step reactions. These compounds were characterized by satisfied spectrum analyses mainly including ¹H NMR and ESI-MS. The preliminary bioassays indicated that some of target compounds exhibited excellent insecticidal activities against Heliothis armigera and Plutella xylostella at the dosage of 31.25 μg/mL.

Full text of DOI:10.1007/s00044-012-0380-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3621–3628
DOI 10.1007/s00044-012-0380-8
ORIGINAL RESEARCH
Novel salicylamide derivatives incorporating neonicotinoid
pharmacophore: design, synthesis, characterization,
and biological evaluation
•
Shaoyong Ke Zhigang Zhang Tong Long
•
•
•
Ying Liang Ziwen Yang
Received: 19 September 2012 / Accepted: 16 November 2012 / Published online: 28 November 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of novel salicylamide derivatives con-
taining neonicotinoid pharmacophore were designed and
synthesized via multi-step reactions. These compounds were
characterized by satisfied spectrum analyses mainly includ-
ing 1H NMR and ESI-MS. The preliminary bioassays indi-
cated that some of target compounds exhibited excellent
insecticidal activities against Heliothis armigera and
Plutella xylostella at the dosage of 31.25 lg/mL.
During the last 20 years, this compound has drawn the
attention of researchers because of its ability to induce
systemic acquired resistance (SAR) in plants (Humphreys
and Chapple, 2002; Raskin, 1992; Vlot et al., 2009).
Recently, more and more compounds (Fig. 1) derived from
SA present extensive bio-activities including antibacterial,
antifungal, herbicidal, antimycobacterial, and anti-inflam-
´
matory, among others (Ferriz et al., 2010; Brown et al., 2008;
Parmar et al., 2010; Tang et al., 2010; Guo et al., 2007;
Huang et al., 2007; Zuhair et al., 2009; Cheng et al., 2009;
Zhang et al., 2006).
Keywords Salicylamide derivatives ꢀ
Neonicotinoid pharmacophore ꢀ Synthesis ꢀ
Biological activity
Meanwhile, neonicotinoids insecticides, a new generation
of synthetic insecticides, have attracted considerable atten-
tion for decades (Jeschke and Nauen, 2008; Nauen and
Denholm, 2005; Matsuda et al., 2001). The special chloro-
pyridine and chlorothiazole heterocycles in these compounds
have been demonstrated to be as key pharmacophores. Very
recently, many examples (Wang et al., 2004; Dai et al., 2008;
Shang et al., 2010) have been reported to confirm that the
introduction of these pharmacophores can result in high
activity and broader activity spectra. On the other hand, the
extensive bio-activities of carboxamides scaffold have been
known for a long time (Gucma and Gołe˛biewski, 2010; Ohno
et al., 2010; Ohno et al., 2004; Shiga et al., 2003), and many
commercial agrochemicals (such as Flonicamid, Penthiopy-
rad, Tolfenpyrad, Tiadinil, and Mandipropamid) contain this
unit, and so which have played significantly important role in
agrochemical industry.
Introduction
The application of agrochemicals to protect crops and
vegetables is still an important part of current integrated
pest management (IPM) (Qian et al., 2010). However, a
search for ecofriendly safer alternatives for pest control is
urgently needed with the increase of worldwide emergence
of drug-resistant.
Salicylic acid (SA) is a well-known natural phenolic
compound that distributes in many plants and is now con-
sidered as a hormone-like substance, which plays an
important role in the regulation of plant growth and devel-
opment (Klessig and Malamy, 1994; Tuna et al., 2007).
Thus, based on the aforementioned results, we hypoth-
esized that masking the phenolic hydroxyl in SA by
neonicotinoid pharmacophore may protect the molecule
against extensive first-pass metabolism, broaden its activity
profile and improve its physico-chemical and pharmaco-
kinetic properties. As part of our agrochemistry program
aimed at the search for novel natural product-oriented
Shaoyong Ke and Zhigang Zhang contributed equally to this study.
S. Ke (&) ꢀ Z. Zhang ꢀ T. Long ꢀ Y. Liang ꢀ Z. Yang
National Biopesticide Engineering Research Center,
Hubei Academy of Agricultural Sciences,
Wuhan 430064, People’s Republic of China
e-mail: keshaoyong@163.com
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Med Chem Res (2013) 22:3621–3628
Fig. 1 Representative
examples of bioactive
compounds derived from SA
HO
O
O
O
HN
O
CF3
N
O2N
NH
H
Cl
N
OH
OH
Cl
O
O
O
O
R1
O
N
R
Cl
O
N
H
N
O
O
O
O
R2
O
N
O
Ph
O
N
H
O
O
H
bioactive molecules, we wish to describe herein the mol-
ecule design, convenient synthesis, and bio-evaluation of
novel series of salicylamide derivatives containing neoni-
cotinoid pharmacophore (Fig. 2) as potential plant protec-
tive agents.
278.6 (C14H13ClNO3?, [M?H]?). The compound 4 was
obtained as a white powder, yield 91 %, m.p. 150–151 °C,
ESI-MS: 264.5 (C13H11ClNO3?, [M?H]?).
General synthetic procedure for 2-((6-chloropyridin-3-yl)
methoxy)benzoyl chloride 5
Materials and methods
2-((6-Chloropyridin-3-yl)methoxy)benzoic acid 4 (50 mmol),
10 mL of toluene and thionyl chloride (15 mL) were placed
in a dried round-bottomed flask containing a magnetic stirrer
bar and stirred at about 60 °C for 2 h. Then the superfluous
thionyl chloride was removed by distillation in vacuo at
room temperature, and the residue was dissolved in dry
CH2Cl2 and the solvent removed as before; this proce-
dure was repeated twice to give 2-((6-chloropyridin-3-yl)
methoxy)benzoyl chloride 5, which was used for the next
reaction without further purification.
Instrumentation and chemicals
All chemicals or reagents used for synthesis were com-
mercially available and were of AR grade. Anhydrous
solvents were dried according to standard methods
(Armarego and Chai, 2003) before used. Melting points
(m.p.) were determined with a digital model X-5 apparatus
1
and are uncorrected. H NMR spectra were recorded on a
Brucker spectrometer at 600 MHz with CDCl3 as the sol-
vent and TMS as the internal standard. Chemical shifts are
reported in d (parts per million) values, and coupling
constants nJ are reported in Hertz. Mass spectra were
performed on a MicroMass Quattro microTM API instru-
ment. All reactions were detected by thin-layer chroma-
tography (TLC) on precoated plates, and the spots were
visualized with ultraviolet light.
General synthetic procedure for the target compounds
6a–s
The typical process of synthesis of novel salicylamide
derivatives containing 2-chloro-5-pyridyl moiety 6a–s is
shown as following: the freshly formed acylchloride 5
(2.2 mmol) dissolved in dry dichloromethane was added
dropwise to a solution of the substituted aniline (2 mmol),
Et3N (2.5 mmol), and catalytic amount of DMAP in dry
dichloromethane under ice-bath. The resultant solution was
stirred at room temperature for 2–5 h, which was detected
by TLC. Then the mixture was washed to neutral with
water and dried via anhydrous Na2SO4. After filtered and
concentrated, the organic residue is purified by silica gel
General synthetic procedure for intermediates 3 and 4
The key intermediates methyl 2-((6-chloropyridin-3-yl)
methoxy)benzoate 3 and 2-((6-chloropyridin-3-yl)methoxy)
benzoic acid 4 was routinely prepared according to docu-
ment method (Li et al., 2012). The compound 3 was obtained
as colorless crystal, yield 92 %, m.p. 70–73 °C, ESI-MS:
Fig. 2 Design strategy of
salicylamide derivatives based
on pharmacophore hybrid
Cl
Natural-derived moiety
N
Incorporate with
Bioactive Moiety
R1
O
COOH
OH
N
O
Neonicotinoid
Pharmacophore
R2
Amide scaffold
Salicylic acid
Benzylether-Salicylamide Derivatives
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Med Chem Res (2013) 22:3621–3628
3623
2-((6-Chloropyridin-3-yl)methoxy)-N-
column chromatography (ethyl acetate/petroleum ether) or
recrystallization to give solid or crystal. Their physico-
chemical properties and the spectra data are as follows:
(4-isopropylphenyl)benzamide 6e
This compound was obtained as brown solid following the
above method, yield 74 %, m.p. 124.5–126.7 °C; 1H NMR
(600 MHz, CDCl3) d 9.47 (s, 1H, NH), 8.57 (s, 1H, Py–H),
8.30 (d, J = 7.8 Hz, 1H, Py–H), 7.83 (d, J = 8.4 Hz, 1H,
Py–H), 7.52–7.09 (m, 8H, Ph–H), 5.25 (s, 2H, OCH2), 2.87
(t, J = 6.6 Hz, 1H, CH), 1.23 (q, J = 6.2 Hz, 6H, CH3);
ESI-MS: calcd for C22H21ClN2O2 ([M]?), 381.0; found
381.8.
2-((6-Chloropyridin-3-yl)methoxy)-N-(4-
methoxyphenyl)benzamide 6a
This compound was obtained as grayest solid following the
above method, yield 91 %, m.p. 135.6–137.2 °C; 1H NMR
(600 MHz, CDCl3) d 9.41 (s, 1H, NH), 8.57 (s, 1H, Py–H),
8.29 (d, J = 7.8 Hz, 1H, Py–H), 7.82 (d, J = 7.8 Hz, 1H,
Py–H), 7.52–7.19 (m, 6H, Ph–H), 7.09 (d, J = 8.4 Hz, 1H,
Ph–H), 6.83 (d, J = 9 Hz, 1H, Ph–H), 5.25 (s, 2H, OCH2),
3.79 (s, 2H, OCH3); ESI-MS: calcd for C20H17ClN2O3
([M]?), 369.1; found 369.7.
2-((6-Chloropyridin-3-yl)methoxy)-N-(4-
(trifluoromethyl)phenyl)benzamide 6f
This compound was obtained as yellowish solid following
1
the above method, yield 85 %, m.p. 108.6–111.3 °C; H
2-((6-Chloropyridin-3-yl)methoxy)-N-
NMR (600 MHz, CDCl3) d 9.72 (s, 1H, NH), 8.60 (d,
4J = 1.8 Hz, 1H, Py–H), 8.30 (d, J = 6.6 Hz, 1H, Py–H),
7.83 (q, J = 8.4 Hz, 1H, Py–H), 7.57–7.42 (m, 6H, Ph–H),
7.23 (t, J = 7.2 Hz, 1H, Ph–H), 7.12 (d, J = 7.8 Hz, 1H,
Ph–H), 5.28 (s, 2H, OCH2); ESI-MS: calcd for
C20H14ClF3N2O2 ([M]?), 407.1; found 407.8.
phenylbenzamide 6b
This compound was obtained as yellowish solid following
1
the above method, yield 86 %, m.p. 162.3–163.8 °C; H
NMR (600 MHz, CDCl3) d 9.52 (s, 1H, NH), 8.57 (s, 1H,
Py–H), 8.30 (d, J = 7.8 Hz, 1H, Py–H), 7.83 (d,
J = 7.8 Hz, 1H, Py–H), 7.53–7.08 (m, 9H, Ph–H), 5.26 (s,
2H, OCH2); ESI-MS: calcd for C19H15ClN2O2 ([M]?),
339.1; found 339.6.
N-(3,5-Bis(trifluoromethyl)phenyl)-2-((6-chloropyridin-3-yl)
methoxy)benzamide 6g
This compound was obtained as light yellow crystal fol-
lowing the above method, yield 90 %, m.p. 169.1–170.3 °C;
1H NMR (600 MHz, CDCl3) d 9.98 (s, 1H, NH), 8.60 (d,
4J = 1.8 Hz, 1H, Py–H), 8.31 (d, J = 7.8 Hz, 1H, Py–H),
7.88 (q, J = 7.8 Hz, 1H, Py–H), 7.78 (s, 2H, Ph–H),
7.60–7.48 (m, 3H, Ph–H), 7.25–7.14 (m, 2H, Ph–H), 5.28 (s,
2H, OCH2); ESI-MS: calcd for C21H13ClF6N2O2 ([M]?),
475.1; found 475.9.
2-((6-Chloropyridin-3-yl)methoxy)-N-
cyclohexylbenzamide 6c
This compound was obtained as white powder following
1
the above method, yield 88 %, m.p. 133.8–136.2 °C; H
NMR (600 MHz, CDCl3) d 8.53 (s, 1H, NH), 8.19 (q,
J = 7.8 Hz, 1H, Py–H), 7.79 (q, J = 7.8 Hz, 1H, Py–H),
7.46–7.42 (m, 3H, Ph–H and Py–H), 7.14 (t, J = 7.8 Hz,
1H, Ph–H), 7.03 (d, J = 8.4 Hz, 1H, Ph–H), 5.16 (s, 2H,
OCH2), 3.96 (t, J = 3.9 Hz, 1H, N–CH), 1.83 (d,
J = 9 Hz, 2H, Cy–H), 1.51–1.32 (m, 5H, Cy–H),
1.13–1.00 (m, 3H, Cy–H); ESI-MS: calcd for
C19H21ClN2O2 ([M]?), 345.1; found 345.7.
2-((6-Chloropyridin-3-yl)methoxy)-N-(pyridin-2-yl)
benzamide 6h
This compound was obtained as light-brown solid follow-
ing the above method, yield 76 %, m.p. 153.2–154.5 °C;
1H NMR (600 MHz, CDCl3) d 8.51 (s, 1H, NH), 8.36 (s,
1H, Py–H), 7.93 (d, J = 7.2 Hz, 1H, Py–H), 7.79 (d,
J = 8.4 Hz, 1H, Py–H), 7.59–7.57 (m, 2H, Py–H),
7.18–7.01 (m, 6H, Ph–H and Py–H), 5.08 (s, 2H, OCH2);
ESI-MS: calcd for C18H14ClN3O2 ([M]?), 340.1; found
339.7.
N-(4-Bromophenyl)-2-((6-chloropyridin-3-yl)
methoxy)benzamide 6d
This compound was obtained as light yellow solid following
1
the above method, yield 82 %, m.p. 114.7–116.4 °C; H
NMR (600 MHz, CDCl3) d 9.56 (s, 1H, NH), 8.58 (s, 1H,
Py–H), 8.28 (d, J = 7.2 Hz, 1H, Py–H), 7.81 (q, J = 7.2 Hz,
1H, Py–H), 7.53 (t, J = 7.8 Hz, 1H, Ph–H), 7.44 (d,
J = 8.4 Hz, 1H, Ph–H), 7.39 (d, J = 9 Hz, 2H, Ph–H),
7.23–7.20 (m, 3H, Ph–H), 7.10 (d, J = 8.4 Hz, 1H, Ph–H),
5.26 (s, 2H, OCH2); ESI-MS: calcd for C19H14BrClN2O2
([M]?), 417.0; found 417.6.
2-((6-Chloropyridin-3-yl)methoxy)-N-o-
tolylbenzamide 6i
This compound was obtained as yellow crystal following
1
the above method, yield 85 %, m.p. 152.6–153.8 °C; H
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Med Chem Res (2013) 22:3621–3628
NMR (600 MHz, CDCl3) d 9.26 (s, 1H, NH), 8.52 (s, 1H,
Py–H), 8.33 (d, J = 7.8 Hz, 1H, Py–H), 8.11 (d,
J = 7.8 Hz, 1H, Py–H), 7.76 (q, J = 8.4 Hz, 1H, Ph–H),
7.50 (t, J = 7.2 Hz, 1H, Ph–H), 7.38 (d, J = 8.4 Hz, 1H,
Ph–H), 7.25–7.04 (m, 5H, Ph–H), 5.30 (s, 2H, OCH2), 1.92
(s, 3H, CH3); ESI-MS: calcd for C20H17ClN2O2 ([M]?),
353.1; found 353.7.
J = 7.8 Hz, 1H, Py–H), 7.58–7.51 (m, 2H, Ph–H), 7.31 (s,
2H, Ph–H), 7.22 (t, J = 7.2 Hz, 1H, Ph–H), 7.12 (d,
J = 8.4 Hz, 1H, Ph–H), 6.04 (t, J = 52.50 Hz, 1H, CHF2),
5.26 (s, 2H, OCH2); ESI-MS: calcd for C21H13Cl3F4N2O3
([M-OCF2CHF2]?), 405.0; found 405.4.
2-((6-Chloropyridin-3-yl)methoxy)-N-
isopropylbenzamide 6n
N-(4-Chloro-2-methylphenyl)-2-((6-chloropyridin-3-yl)
methoxy)benzamide 6j
This compound was obtained as white powder following the
1
above method, yield 83 %, m.p. 93.5–95.0 °C; H NMR
This compound was obtained as white solid following the
above method, yield 92 %, m.p. 106.8–109.4 °C; 1H NMR
(600 MHz, CDCl3) d 9.26 (s, 1H, NH), 8.52 (s, 1H, Py–H),
8.32 (d, J = 7.2 Hz, 1H, Py–H), 8.09 (d, J = 8.4 Hz, 1H,
Py–H), 7.75 (d, J = 7.8 Hz, 1H, Ph–H), 7.52 (t, J = 7.2 Hz,
1H, Ph–H), 7.39 (d, J = 8.4 Hz, 1H, Ph–H), 7.22–7.02
(m, 4H, Ph–H), 5.29 (s, 2H, OCH2), 1.85 (s, 3H, CH3); ESI-
MS: calcd for C20H16Cl2N2O2 ([M]?), 387.1; found 387.4.
(600 MHz, CDCl3) d 8.53 (s, 1H, NH), 8.19 (q, 4J = 1.8 Hz,
J = 7.6 Hz, 1H, Py–H), 7.79 (q, 4J = 2.4 Hz, J = 8.4 Hz,
1H, Py–H), 7.47–7.40 (m, 3H, Ph–H and Py–H), 7.14 (t,
J = 7.8 Hz, 1H, Ph–H), 7.03 (d, J = 8.4 Hz, 1H, Ph–H),
5.17 (s, 2H, OCH2), 4.21 (q, J = 6.6 Hz, 1H, N–CH), 1.07
(d, J = 6.6 Hz, 6H, CH(CH3)2); ESI-MS: calcd for
C16H17ClN2O2 ([M]?), 305.1; found 305.4.
2-((6-Chloropyridin-3-yl)methoxy)-N,N-
2-((6-Chloropyridin-3-yl)methoxy)-N-
diisopropylbenzamide 6o
(4-fluorophenyl)benzamide 6k
This compound was obtained as white powder following
1
This compound was obtained as white solid following the
above method, yield 82 %, m.p. 140.3–143.5 °C; 1H NMR
(600 MHz, CDCl3) d 9.52 (s, 1H, NH), 8.58 (d,
4J = 1.8 Hz, 1H, Py–H), 8.29 (q, 4J = 1.2 Hz,
J = 6.6 Hz, 1H, Py–H), 7.82 (q, 4J = 2.1 Hz, J = 6.0 Hz,
1H, Py–H), 7.54–7.29 (m, 4H, Ph–H), 7.20 (t, J = 7.8 Hz,
1H, Ph–H), 7.10 (d, J = 8.4 Hz, 1H, Ph–H), 6.98 (t,
J = 8.4 Hz, 2H, Ph–H), 5.26 (s, 2H, OCH2); ESI-MS:
calcd for C19H14ClFN2O2 ([M]?), 357.1; found 357.4.
the above method, yield 86 %, m.p. 138.0–139.5 °C; H
NMR (600 MHz, CDCl3) d 8.43 (s, 1H, Py–H), 7.81 (d,
J = 7.8 Hz, 1H, Py–H), 7.35–7.30 (m, 2H, Py–H and
Ph–H), 7.19 (d, J = 7.2 Hz, 1H, Ph–H), 7.03 (t,
J = 7.2 Hz, 1H, Ph–H), 6.95 (d, J = 8.4 Hz, 1H, Ph–H),
5.08 (s, 2H, OCH2), 3.69 (q, J = 7.2 Hz, 1H, N–CH), 3.46
(q, J = 7.2 Hz, 1H, N–CH), 1.55 (d, J = 6.6 Hz, 3H,
CH3), 1.48 (d, J = 6.0 Hz, 3H, CH3), 1.03 (q, J = 7.2 Hz,
6H, CH(CH3)2); ESI-MS: calcd for C19H23ClN2O2 ([M]?),
347.1; found 347.5.
2-((6-Chloropyridin-3-yl)methoxy)-N-
f(4-iodophenyl)benzamide 6l
2-((6-Chloropyridin-3-yl)methoxy)-N,N-
diethylbenzamide 6p
This compound was obtained as colorless crystal following
1
the above method, yield 78 %, m.p. 146.5–148.3 °C; H
This compound was obtained as white solid following the
above method, yield 80 %, m.p. 100.5–101.0 °C; 1H NMR
NMR (600 MHz, CDCl3) d 9.56 (s, 1H, NH), 8.58 (d,
4J = 2.4 Hz, 1H, Py–H), 8.28 (d, J = 7.8 Hz, 1H, Py–H),
7.82 (d, J = 6.0 Hz, 1H, Py–H), 7.58–7.53 (m, 3H, Ph–H),
7.44 (d, J = 8.4 Hz, 1H, Ph–H), 7.21 (t, J = 7.5 Hz, 1H,
Ph–H), 7.11 (d, J = 8.4 Hz, 3H, Ph–H), 5.26 (s, 2H, OCH2);
ESI-MS: calcd for C19H14ClIN2O2 ([M]?), 465.0; found
465.4.
4
(600 MHz, CDCl3) d 8.42 (d, J = 1.8 Hz, 1H, Py–H),
7.76 (q, J = 1.8 Hz, J = 7.0 Hz, 1H, Py–H), 7.35–7.24
4
(m, 3H, Py–H and Ph–H), 7.05 (t, J = 7.2 Hz, 1H, Ph–H),
6.96 (d, J = 7.8 Hz, 1H, Ph–H), 5.09 (s, 2H, OCH2), 3.74
(bs, 1H, N–CH2), 3.35 (bs, 1H, N–CH2), 3.16–3.10 (m, 2H,
CH2), 1.18 (t, J = 7.2 Hz, 3H, CH3), 1.01 (t, J = 7.2 Hz,
3H, CH3); ESI-MS: calcd for C17H19ClN2O2 ([M]?),
319.1; found 319.4.
2-((6-Chloropyridin-3-yl)methoxy)-N-(3,5-dichloro-4-
(1,1,2,2-tetrafluoroethoxy)phenyl)benzamide 6m
2-((6-Chloropyridin-3-yl)methoxy)-N-(cyanomethyl)-N-
This compound was obtained as white powder following
1
the above method, yield 76 %, m.p. 183.5–185.0 °C; H
phenylbenzamide 6q
NMR (600 MHz, CDCl3) d 9.75 (s, 1H, NH), 8.61 (s, 1H,
Py–H), 8.27 (d, J = 7.2 Hz, 1H, Py–H), 7.87 (d,
This compound was obtained as white solid following the
above method, yield 73 %, m.p. 134–136 °C; 1H NMR
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Med Chem Res (2013) 22:3621–3628
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(600 MHz, CDCl3) d 8.35 (s, 1H, Py–H), 7.80 (d,
J = 8.4 Hz, 1H, Py–H), 7.41 (d, J = 7.8 Hz, 1H, Py–H),
7.25–6.90 (m, 8H, Ph–H), 6.70 (d, J = 7.8 Hz, 1H, Ph–H),
4.92 (s, 2H, OCH2), 4.74 (s, 2H, CNCH2); ESI-MS: calcd
for C21H16ClN3O2 ([M]?), 378.1; found 378.5.
culture plates was closed with a plastic cover. Mortality in
these assays was recorded at 96 h, and each treatment was
replicated three times.
Results and discussion
(2-((6-Chloropyridin-3-yl)methoxy)phenyl)(piperidin-1-yl)
methanone 6r
Synthesis of salicylamide derivatives
This compound was obtained as colorless crystal following
1
In this study, a series of novel salicylamide derivatives were
constructed by reacting functionalized SA with various
amines or its derivatives. The general method for the
preparation of salicylamide derivatives containing chloro-
pyridine moiety 6a–s are outlined in Scheme 1.
the above method, yield 83 %, m.p. 116.8–118.2 °C; H
NMR (600 MHz, CDCl3) d 8.42 (s, 1H, Py–H), 7.76 (q,
4J = 1.8 Hz, J = 7.4 Hz, 1H, Py–H), 7.39–7.25 (m, 3H,
Ph–H and Py–H), 7.05 (t, J = 7.6 Hz, 1H, Ph–H), 6.94 (d,
J = 8.4 Hz, 1H, Ph–H), 5.12 (s, 2H, OCH2), 3.76–3.08 (m,
4H, CH2), 1.61–1.39 (m, 6H, CH2); ESI-MS: calcd for
C18H19ClN2O2 ([M]?), 331.1; found 331.5.
The key intermediate 2-((6-chloropyridin-3-yl)methoxy)
benzoic acid 4 was routinely prepared from SA via three
steps including esterification, alkylation, and hydrolysis
reactions. Then the compound 4 was treated with thionyl
chloride to provide the corresponding acid chloride 5,
which is further used to couple with various aromatic or
heteroaromatic amines typically in the presence of trieth-
ylamine to give salicylamide derivatives 6a–s. Yields were
usually good except in cases of weakly nucleophilic aro-
matic amines with electron-withdrawing group, and some
side reactions took place because of degradation of acid
chlorides. All the target salicylamide derivatives 6a–s gave
satisfactory chemical analyses, and the chemical structures
of the synthesized compounds were summarized in
Table 1.
(2-((6-Chloropyridin-3-
yl)methoxy)phenyl)(morpholino)methanone 6s
This compound was obtained as yellowish crystal follow-
ing the above method, yield 80 %, m.p. 124.3–125.6 °C;
1H NMR (600 MHz, CDCl3) d 8.42 (s, 1H, Py–H), 7.74 (q,
4J = 1.8 Hz, J = 8.2 Hz, 1H, Py–H), 7.38–7.28 (m, 3H,
Ph–H and Py–H), 7.07 (t, J = 7.2 Hz, 1H, Ph–H), 6.96 (d,
J = 7.8 Hz, 1H, Ph–H), 5.12 (s, 2H, OCH2), 3.81–3.67 (m,
4H, CH2), 3.52 (s, 2H, CH2), 3.26 (s, 2H, CH2); ESI-MS:
calcd for C17H17ClN2O3 ([M]?), 333.1; found 333.4.
Biological assay
Spectroscopy
Heliothis armigera and Plutella xylostella from our labo-
ratory cultivate were used as general tested species. The
standard assay (Xu et al., 2003; Huang et al., 2010) was
performed by placing artificial diets (300 lL) in a 24-well
or 96-well microtiter plates, which were covered with the
solution of different tested concentration compounds in
ethanol (20 lL). Ethanol alone was used as a control.
When the ethanol was completely evaporated leaving the
effective compounds as a coat on the surface of the artifi-
cial diets, the tested species were introduced and the
Structures of target compounds 6a–s were confirmed by
1
their H NMR and ESI-MS spectra, and the H NMR and
1
ESI-MS spectra analyses were consistent with the assigned
1
structures. Their H NMR spectra showed distinctive sig-
nals of methylene between oxygen and chloropyridine ring,
which presented a singlet at about 4.92–5.29 ppm. The
1
signals at 6.04–8.61 ppm in the H NMR spectra of com-
pounds 6a–s were assigned to the aromatic proton in
aryl(het)-cycles moieties. For some compounds, the signals
that appeared in their 1H NMR spectra in the range
Scheme 1 General synthetic
route for novel salicylamide
derivatives 6a–s
Cl
O
O
Cl
O
O
Cl
NaOH
MeOH
N
O
N
OH
O
H2SO4
K2CO3, MeCN
92%
MeOH/H2O
91%
OH
1
OH
Cl
88%
2
3
R1
N
HO
O
Cl
O
Cl
N
O
Cl
R2
SOCl2
Amine
O
N
O
O
N
Et3N, DMAP, DCM
73-92%
4
5
6a-s
123

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Med Chem Res (2013) 22:3621–3628
Table 1 The chemical structure of salicylamide derivatives 6a–s
Entry
Compounds
Substituents
R1
Appearance
Mp (°C)
Yield (%)a
R2
1
6a
6b
6c
6d
6e
6f
4-MeO-Ph
H
Grayst solid
135.6–137.2
162.3–163.8
133.8–136.2
114.7–116.4
124.5–126.7
108.6–111.3
169.1–170.3
153.2–154.5
152.6–153.8
106.8–108.4
140.3–143.5
146.5–148.3
183.5–185.0
93.5–95.0
91
86
88
82
74
85
90
76
85
92
82
78
76
83
86
80
73
83
80
2
Ph
H
Yellowish solid
White powder
Yellow solid
3
Cy
H
4
4-Br-Ph
4-iPr-Ph
H
5
H
Brown solid
6
4-CF3-Ph
H
Yellowish solid
Yellow crystal
Light-brown solid
Yellow crystal
White solid
7
6g
6h
6i
3,5-(CF3)2-Ph
H
8
2-Py
H
9
2-Me-Ph
H
10
11
12
13
14
15
16
17
18
19
a
6j
2-Me-4-Cl-Ph
H
6k
6l
4-F-Ph
H
White solid
4-I-Ph
H
Colorless crystal
White powder
White powder
White powder
White solid
6m
6n
6o
6p
6q
6r
6s
3,5-Cl2-4-CHF2CF2O-Ph
iPr
iPr
H
H
iPr
Et
CNCH2
138.0–139.5
100.5–101.0
134.0–136.0
116.8–118.2
124.3–125.6
Et
Ph
White solid
–(CH2)5–
–(CH2)2O(CH2)2–
Colorless crystal
Yellowish crystal
Isolated yields
8.51–9.98 ppm were attributed to the N–H protons of the
amide.
activities, which are worth to further research on systemic
assay for development novel pests control agents.
In addition, from the structural profiles, some electron-
withdrawing groups and electron-donating substituents
were introduced into the molecules for exploring the
influence of structural changes on activities. As the results
described in Table 1, the different substituent at the
periphery of the molecules 6a–s can lead to the obviously
different insecticidal activities. Generally, the amines with
lager substituents at the contraposition of phenyl ring
showed comparatively good insecticidal activities, which
can be further demonstrated from the activities of com-
pounds 6d, 6e, and 6f. However, compound 6a bearing a
4-methoxyphenyl groups also presented good activity
against P. xylostella. The highest activity was found for
compounds with electron-withdrawing groups, and was
particularly outstanding in case of p-CF3 substituted amine
6f. On the other hand, the substitution pattern was also
crucial. Most of amines with a group at position 4 were
active, whereas 2-substituted products (6h and 6i) were
devoid of activity. Especially, the compound containing
two CF3 groups on the phenyl ring 6g (Entry 7), which
exhibited diametrically opposite results on the best one 6f
(Entry 6).
Structure–activity relationship
The bioactivity of synthesized salicylamide derivatives
6a–s against selective agricultural pests mainly including
H. armigera and P. xylostella were evaluated according to
the standard method (Xu et al., 2003; Huang et al., 2010),
and the bioassay results are listed in Table 2.
As we can see from Table 2, the preliminary assay
showed that most of target molecules (such as compounds
6a, 6b, 6e, 6k, 6l, 6m, and 6n) displayed obviously good
and selective insecticidal activity against P. xylostella, but
presented low activities against H. armigera. For H. ar-
migera, compounds 6d, 6e, and 6f exhibited good insecti-
cidal activities, and up to the seventh, fifth, and seventh
levels at the concentration of 31.25 lg/mL, respectively.
For P. xylostella, compounds 6a, 6d, and 6f presented
better activities at the same level of concentrations, espe-
cially compound 6f is still has good insecticidal activity
(ninth level) at lower concentration. On the other hand,
compounds 6l, 6m, 6n, and 6o have better activities against
P. xylostella than that of H. armigera. By comprehensive
consideration all activities against P. xylostella and
H. armigera, compounds 6d, 6e, and 6f showed better
All the structure evolution here was to replace the
substituents on amines (Fig. 3). According to the results
123

Med Chem Res (2013) 22:3621–3628
3627
Table 2 Insecticidal activities of target compounds 6a–s against agricultural pests
Entry
Compounds
Insecticidal activitya (lg/mL)
Heliothis armigera
Plutella xylostella
1,000
500
250
125
62.5
31.25
1,000
500
250
125
62.5
31.25
1
6a
6b
6c
6d
6e
6f
0
0
0
0
0
0
0
0
0
0
0
0
0
7
5
7
0
0
0
0
0
0
0
0
0
0
0
0
0
10
9
10
9
10
5
10
5
9
0
5
0
0
5
0
9
0
0
0
0
0
0
5
0
0
0
0
0
0
2
3
0
0
0
0
0
5
0
0
0
0
4
10
10
10
0
10
9
9
9
7
10
10
10
0
10
10
10
0
10
10
10
0
10
5
10
5
5
7
7
5
6
10
0
10
0
10
0
10
0
10
0
10
0
7
6g
6h
6i
8
0
0
0
0
0
10
0
5
5
0
0
9
0
0
0
0
0
0
0
0
0
10
11
12
13
14
15
16
17
18
19
a
6j
10
5
5
5
0
0
10
10
10
10
10
10
5
5
5
5
0
6k
6l
5
5
5
0
9
5
5
0
0
0
0
0
0
10
10
10
10
0
10
10
10
10
0
5
0
6m
6n
6o
6p
6q
6r
6s
10
5
5
5
0
0
10
5
5
5
0
0
0
0
10
5
10
0
5
5
0
5
0
0
0
0
0
0
10
5
9
5
5
0
0
0
0
0
0
0
0
0
0
5
5
0
0
0
10
5
0
0
0
5
0
0
0
0
Scale: 0 (0–10 % mortality); 1 (11–20 % mortality); 3 (21–40 % mortality); 5 (41–60 % mortality); 7 (61–80 % mortality); 9 (81–99 %
mortality); 10 (100 % mortality)
Fig. 3 General structure-
activity profile for the
salicylamide derivatives
R1
Activity order for the substituents:
Cl
O
N
R2
4-CF3-PhNH2 > 4-Br-PhNH2 = 4-iPr-PhNH2 = 4-MeO-PhNH2 >
3,5-Cl2-4-CHF2CF2O-PhNH2 > 2-Me-4-Cl-PhNH2 = 4-F-PhNH2
= 4-I-PhNH2 >> 3,5-(CF3)2-PhNH2 and 2-Py-NH2
N
O
Heteroarylether-Salicylamide
presented in Table 2, we can obtain the preliminary
structure–activity profile for these salicylamide derivatives.
derivatives, which are promising lead compounds for further
developing novel agrochemicals. Further structural optimi-
zation and activity profiles about the designed novel amide
derivatives are well ongoing in our laboratory.
Conclusion
Acknowledgments We gratefully acknowledge the support of this
work by the Projects in the Youth Science Foundation of Hubei
Academy of Agricultural Sciences (2011NKYJJ19) and the National
Natural Science Foundation of China (31000867). The authors also
gratefully acknowledge the partial support from Hubei Biopesticide
Engineering Research Centre.
In summary, we have described the molecular design, syn-
thesis, and biological evaluation of a series of novel sali-
cylamide
derivatives
containing
neonicotinoid
pharmacophore. Nineteen novel salicylamide derivatives
have been conveniently synthesized, and characterized by
1H NMR, ESI-MS spectra analyses. The preliminary bioas-
say indicated that some of target compounds exhibited
obvious insecticidal activity. To our best knowledge, this
is the first report on the syntheses and insecticidal activity
of neonicotinoid pharmacophore-functional salicylamide
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