Discovery, synthesis, and evaluation of N-substituted amino-2(5H)- oxazolones as novel insecticides activating nicotinic acetylcholine receptors

Article abstract of DOI:10.1016/j.bmcl.2014.03.037

N-Substituted amino-2(5H)-oxazolones A are a novel class of insecticides acting as nicotinic acetylcholine receptor (nAChR) agonists and show potent activity against hemipteran insect species. Here we report the discovery and preparation of this class of chemistry. Our efforts in SAR elucidation, biological activity evaluation, as well as mode-of-action studies are also presented.

Full text of DOI:10.1016/j.bmcl.2014.03.037

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2188–2192
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery, synthesis, and evaluation of N-substituted
amino-2(5H)-oxazolones as novel insecticides activating nicotinic
acetylcholine receptors
⇑
Wenming Zhang , James D. Barry, Daniel Cordova, Stephen F. McCann, Eric A. Benner, Kenneth A. Hughes
DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Road, Newark, DE 19711, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Substituted amino-2(5H)-oxazolones A are a novel class of insecticides acting as nicotinic acetylcholine
receptor (nAChR) agonists and show potent activity against hemipteran insect species. Here we report
the discovery and preparation of this class of chemistry. Our efforts in SAR elucidation, biological activity
evaluation, as well as mode-of-action studies are also presented.
Received 31 January 2014
Revised 4 March 2014
Accepted 7 March 2014
Available online 21 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Oxazolone
Insecticide
Neonicotinoid
Acetylcholine receptor
Neonicotinoids are a modern class of insecticides initially dis-
covered in the 1980’s. They target the nicotinic acetylcholine
receptor (nAChR) and act as competitive agonists for acetylcholine.
Commercial neonicotinoids are small polar molecules. They have
rather low logPow values (À0.64 to 1.26) and high water solubility
(0.185–840 g/L at 20 °C). As a result of these physical properties,
neonicotinoids have been used with a range of different applica-
tion techniques to control sucking pest species. Since the first
introduction of imidacloprid (1) into the global crop protection
market in 1991, seven representative members of neonicotinoid
insecticides have achieved a market value of $3640 million in
2011 and represented about 28.5% of the overall world insecticide
sale in that same year (see Fig. 1).1
The rapid adoption of neonicotinoids, however, has resulted in
increasing cases of neonicotinoid resistance among major pests
targeted by this chemistry in recent years. There has been a re-
newed interest in searching for novel neonicotinoid insecticides
to overcome resistance while maintaining attractive physical prop-
erties and biological profiles.2,3
NO2
NO2
N
N
N
O
S
N
N
N
NH
Cl
Cl
Cl
N
Imidacloprid (1)
Thiamethoxam (2)
CN
NO2
N
N
S
N
N
N
H
N
H
Cl
N
Clothianidin (3)
N
Acetamiprid (4)
CN
NO2
N
N
S
N
H
N
H
Cl
Cl
N
O
Thiacloprid (5)
Dinotefuran (6)
NO2
N
N
H
N
In their search for novel neonicotinoid insecticides, researchers
at Nippon Soda reported the N-substituted enaminolactones, such
as 8, as potent insecticides (see Fig. 2).4 Inspired by the enamino-
lactones, we discovered a novel class of N-substituted amino-
2(5H)-oxazolone insecticides A as potent nAChR agonists. Herein
Nitenpyram (7)
Figure 1. Neonicotinoid insecticides.
we describe our discovery of this novel class of compounds. Fur-
ther studies in this area that resulted in the identification of excep-
tionally potent compounds such as 18a will be presented as well.5
The compounds shown in Tables 1–3 were prepared as de-
scribed in Schemes 1–5. 2-Aminopyrrolin-5-ones 13 (13a and
⇑
Corresponding author. Tel.: +1 302 451 5700; fax: +1 302 366 5738.
E-mail address: wenming.zhang@dupont.com (W. Zhang).
http://dx.doi.org/10.1016/j.bmcl.2014.03.037
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

W. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2188–2192
2189
Table 3
O
O
O
Insecticidal potency of substituted amino-2(5H)-oxazolones and other heterocycle
N
analogsa
R1
O
N
N
R2
O
het
Cl
N
N
Y
8
A
X
N
Figure 2. Novel amino heterocycle insecticides.
Cl
N
Table 1
31
Insecticidal potency of substituted amino-2(5H)-oxazolones and other heterocycle
analogsa
Entry
X
Y
GPA
CMA
CPH
PLH
WF
50
51
52
53
54
55
56
57
S
O
CH2
CH2
O
S
NH
O
67.1
55.8
15.2
17.6
>250
>250
>250
11.5
150.5
133.3
6.6
22.8
>250
>250
>250
10.3
>250
>250
92.4
>250
>250
>250
>250
<250
227.2
<250
19.6
48.7
>250
79.7
>250
22.1
>250
>250
>250
>250
>250
>250
>250
122.7
CHCH3
CH2
NH
NH
NMe
NMe
NH
O
Entry
X
Y
R
GPA
CMA
CPH
PLH
WF
Insect LC50 values (ppm) are shown for green peach aphid (Myzus persicae (Sulzer),
GPA), cotton melon aphid (Aphis gossypii Glover, CMA), corn planthopper (Peregrinus
maidis (ashmead), CPH), potato leafhopper (Empoasca fabae Harris, PLH), and
sweetpotato whitefly (Bemisia tabaci (Gennadius), WF).
LC50 values were obtained for multiple test rates, each tested in replicate
(n P 3). LC50 calculations were determined by Probit analysis using a maximum
8
33
13a
13b
18a
18b
Imidacloprid
CH
CH
N
N
N
O
O
CH2
CH2
O
c-Pr
Me
c-Pr
Me
c-Pr
Me
—
2.1
2
0.2
0.5
<250
35.3
3.2
0.6
2.1
<250
<250
0.9
0.6
9
>250
>250
3.5
<2
52.6
70.7
No data
No data
108.8
<250
57.6
>250
3.6
4.7
0.2
a
N
—
O
—
0.5
0.8
6.8
0.3
quasi-likelihood curve fitting algorithm.
0.8
20.2
Insect LC50 values (ppm) are shown for green peach aphid (Myzus persicae (Sulzer),
GPA), cotton melon aphid (Aphis gossypii Glover, CMA), corn planthopper (Peregrinus
maidis (ashmead), CPH), potato leafhopper (Empoasca fabae Harris, PLH), and
sweetpotato whitefly (Bemisia tabaci (Gennadius), WF).
LC50 values were obtained for multiple test rates, each tested in replicate
(n P 3). LC50 calculations were determined by Probit analysis using a maximum
Heating this compound in the dark and in the presence of iodoeth-
ane generated 2-ethoxypyrrolin-5-one 11, which, in turn, reacted
with secondary amines 12 to displace the ethoxy group and gener-
ate the desired 2-aminopyrrolin-5-ones 13 in good yields.7
a
quasi-likelihood curve fitting algorithm.
4-Amino-2(5H)-oxazolones 18 (18a and 18b) were prepared as
described in Scheme 2. Cyclization of glycolamide 14 with diethyl
carbonate in the presence of potassium tert-butoxide in methanol
generated oxazolidinedione 15.8 The amide carbonyl group of
dione 15 was then selectively converted into a thiocarbonyl group
when treated with Lawesson Reagent. The conversion for this step
13b) were the first set of molecules prepared and their synthesis is
outlined in Scheme 1. Reaction between succinimide and silver ni-
trate under basic conditions produced silver succinimide 10.6
Table 2
Insecticidal potency of various substituted amino-2(5H)-oxazolonesa
O
N
O
R1
N
R2
het
A
Entry
R1
het
R2
GPA
CMA
CPH
PLH
WF
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
H
5-Br
6-F
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
5-Thiazolyl
2-Pyridazinyl
4-Pyrazolyl
5-Pyrimidinyl
3-Pyridyl
3-Pyridyl
5-Thiazolyl
3-Pyridyl
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
Me
Et
n-Pr
c-PrCH2
c-Bu
OMe
CHF2CH2
>250
>250
49.3
>250
5.4
<250
>250
18.6
>250
10.9
5.3
<50
<250
7.3
>250
59.2
3
>250
>250
>250
>250
<50
>250
>250
>250
>250
196.9
58.4
78.2
>250
>250
>250
98.5
>250
>250
>250
>250
50
2,6-Cl2
5,6-Cl2
6-Br
2-Cl
5-Me
1-Me
H
6-Cl
6-Cl
2-Cl
6-Cl
6-Cl
6-Cl
3.9
8.8
5.7
<2
6.1
<2
>250
>250
>250
6.4
55.1
>250
>250
>250
14.3
>250
122.4
>250
1.9
45.4
>250
>250
74.5
3.1
>250
No data
>250
1.9
<250
>250
>250
>250
3.3
>250
70.7
>250
6
<250
>250
>250
>250
25.7
3-Pyridyl
3-Pyridyl
Insect LC50 values (ppm) are shown for green peach aphid (Myzus persicae (Sulzer), GPA), cotton melon aphid (Aphis gossypii Glover, CMA), corn planthopper (Peregrinus maidis
(ashmead), CPH), potato leafhopper (Empoasca fabae Harris, PLH), and sweetpotato whitefly (Bemisia tabaci (Gennadius), WF).
a
LC50 values were obtained for multiple test rates, each tested in replicate (n P 3). LC50 calculations were determined by Probit analysis using a maximum quasi-likelihood
curve fitting algorithm.

2190
W. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2188–2192
O
O
N
O
N
The corresponding 5-methyl oxazolone analogs of 18a and 18b
were prepared in a similar way as outlined in Scheme 3. The de-
sired intermediates oxazolidinedione 20 and subsequent thioam-
ide 21 were prepared uneventfully. However, methylation of
thioamide 21 generated the unexpected tautomer 5-methylsulfa-
nyl-3H-oxazol-2-one 22 instead of 5-methylsulfanyl-5H-oxazol-
2-one 24.9 Furthermore, there was no reaction between 3H-oxa-
zol-2-one 22 and amines 12 when they were mixed and subjected
to the same reaction conditions used for the formation of 18. How-
ever, when a catalytic amount of acetic acid was added into the
reaction mixture, the reaction took place and the desired 5-
methyl-4-amino-2(5H)-oxazolones 23 were isolated in yields com-
parable to those from the reactions with the parent oxazol-2-one
17.
a
b
NH
Ag
O
O
O
Et
9
10
11
O
R
N
H
N
Cl
N
12
N
R
c
Cl
N
13
Scheme 1. Reagents and conditions: (a) AgNO3, NaOEt, ethanol, DMSO, 25–5 °C,
88–94%; (b) EtI, chloroform, reflux in the dark, 30%; and (c) toluene, 110 °C, 60–85%.
Thiazolinone analogs 27 were prepared in a more straightfor-
ward way as shown in Scheme 4. Treatment of 2,4-thiazolidinedi-
one 25 with phosphorus pentasulfide generated isorhodanine 26 in
68% yield.10 When 26 was heated in ethanol in the presence of the
required secondary amines 12, desired thiazolinones 27 were iso-
lated in modest yields.11
was reasonably good, but separation of the product 4-thio-oxazol-
idine-2-one 16 from the reaction mixture turned out to be difficult
and a careful crystallization was employed to isolate thioamide 16
in excellent purity. This thioamide was further converted into 4-
methylsulfanyl-5H-oxazol-2-one 17 and subsequent displacement
with required secondary amines provided desired product 4-ami-
no-2(5H)-oxazolones 18 in excellent yields.
Besides the azolinone and thiazolinone five-membered ring sys-
tems, other five-membered ring systems were also prepared as
O
NH
O
O
O
a
b
c
O
O
O
NH
N
HO
NH2
O
S
SMe
14
15
16
17
O
R
N
N
H
O
12
Cl
N
N
R
d
Cl
N
18
Scheme 2. Reagents and conditions: (a) CO(OEt)2, KOBu-t, methanol, 80 °C, 44%; (b) Lawesson reagent, toluene, 110 °C; crystallization; (c) MeI, NaOAc, dichloromethane,
25 °C, 24% for two steps; and (d) chloroform, 61 °C, 85–90%.
O
O
O
O
a
b
c
O
O
O
NH
NH
NH
SMe
HO
NH2
O
S
19
20
21
22
O
R
N
H
O
N
O
O
12
Cl
N
N
N
R
d
Cl
N
SMe
24
23
Scheme 3. Reagents and conditions: (a) CO(OEt)2, KOBu-t, methanol, 80 °C, 98%; (b) Lawesson reagent, toluene, 110 °C; (c) MeI, Hunig’s base, dichloromethane, 25 °C, 98% for
two steps; and (d) chloroform, acetic acid (0.3 equiv), 61 °C, 48–78%.
R
O
N
H
O
O
N
Cl
N
a
12
S
S
S
NH
NH
b
N
R
O
S
Cl
N
25
26
27
Scheme 4. Reagents and conditions: (a) P2S5, toluene, 110 °C, 68%; and (b) ethanol, 80 °C, 18%.

W. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2188–2192
2191
S
O
SMe
N
O
a
b
N
H
Et
Et
N
N
H
O
N
O
Cl
N
Cl
O
N
Cl
N
N
28
30
29
O
O
=
Y
NH NH
NH
MeN NH
MeN
X
N
O
c
Y
X
N
S
N
N
O
Cl
Cl
N
N
O
31
32
Scheme 5. Reagents and conditions: (a) SCNCO2Et, chloroform, 23 °C, 97%; (b) NaH, MeI, THF, 23 °C, 92%; (c) hydroxylamines or hydrazines, 2-propanol, 82 °C, 33–35%.
outlined in Scheme 5. Reaction of secondary amine 28 with eth-
oxycarbonyl isothiocyanate provided intermediate thiourea 29 in
quantitative yield. Alkylation of 29 with iodomethane in the pres-
ence of sodium hydride generated methylthiocarbamate 30 in
excellent yield. This carbamate is a suitable substrate for the de-
sired tandem double displacement and ring formation reactions.
Therefore, treatment of carbamate 30 with hydrazine or hydroxyl-
amine provided the expected cyclization product triazolinones or
oxadiazolinones 31 in moderate yields.12 The corresponding tied-
back analogs, such as oxadiazolinones 32, can be prepared in a sim-
ilar way when the hydroxylamine group is tethered to the amine
moiety in advance.
Insecticidal activity of amino-2(5H)-oxazolones and other het-
erocyclic analogs is summarized in Tables 1–3. Test compounds
were formulated using a solution containing 10% acetone, 90%
water and 300 ppm of a non-ionic surfactant. The formulated com-
pounds were sprayed on the foliage of plants at 2–5 rates and rep-
licated three times. Efficacy was evaluated on the following test
units: 12–15 day-old radish plant for green peach aphid (Myzus
persicae (Sulzer) GPA), 6–7 day-old cotton plant for cotton melon
aphid (Aphis gossypii (Glover), CMA), 3–4 day-old corn for corn
planthopper (Peregrinus maidis (Ashmead) CPH), 5–6 day-old bean
for potato leafhopper (Empoasca fabae (Harris) PLH), and 12–
14 day-old cotton for sweetpotato whitefly (Bemisia tabaci (Genna-
dius) WF). Mortality was evaluated 6 days after application for all
insects except for WF, which was evaluated 12 days after applica-
tion. Insecticidal activity is reported as an LC50 (the lethal concen-
tration required for 50% mortality) in ppm. In general, all
compounds showed better control against aphid species and hop-
per species than whitefly.
Table 1 shows compounds initially prepared in comparison to
Nippon Soda’s enaminolactone compounds 8 and 33. Both 8 and
33 are potent insecticides against all four hemipteran insect spe-
cies tested (GPA, CMA, CPH, and PLH). Novel 2-aminopyrrolin-5-
ones 13a and 13b displayed only weak levels of activity.
4-Amino-2(5H)-oxazolones 18a and 18b, on the other hand,
showed potent insecticidal activity against all four hemipteran in-
sect species tested (GPA, CMA, CPH, and PLH). This result illustrates
that it is critical to maintain the ring oxygen atom so as to form an
ester moiety, which may mimic the nitro group in imidacloprid (1).
Although N-cyclopropyl enaminolactone 8 demonstrated overall
higher levels of insecticidal activity than the corresponding N-
methyl enaminolactone 33 when tested against CMA, CPH, PLH,
and WF, this trend is not as clear for the 4-amino-2(5H)-oxazol-
ones 18a and 18b.
bromo-3-pyridylmethyl compound 39, which provided insecticidal
activity close to the corresponding 6-chloro analog (18a).
Compounds containing N-2-chloro-5-thiazolylmethyl groups
(40) showed anticipated insecticidal activity similar to that of the
N-6-chloro-3-pyridylmethyl analog (18a). Compounds containing
other heterocycles, 2-pyridazinyl 41, 4-pyrazolyl 42, and pyrimid-
inyl 43 showed a significant reduction in activity.
The R2 group attached to the amino nitrogen also played an
important role on the insecticidal activity. Compounds containing
a small alkyl group, methyl 18b, ethyl 44, cyclopropyl 18a, showed
highest activity. The 2,2-difluoroethyl compound 49, showed less
activity on GPA and PLH, while compounds containing larger alkyl
groups, n-propyl 45, cyclopropylmethyl 46, as well as cyclobutyl
47, showed a drastic loss of activity. However, the size of the sub-
stituent is not the only factor responsible for the insecticidal po-
tency because the N-methoxy compound 48, displayed only
marginal activity on CMA with no activity on other species tested.
Finally, we explored a series of analogs which maintained the
carbonyl amidine feature, while containing various heteroatoms
or moieties to make up the five-membered heterocycle rings (Ta-
ble 3). Most variations resulted in loss of activity, while com-
pounds 52, 53, and 57 containing the lactone (or thio-lactone)
function showed reasonably good activity on GPA and CMA.
The most potent analogs approached or were comparable to the
activity of imidacloprid (Table 1). For GPA and CPH, 18a was ꢀ18-
fold and 3-fold less potent than imidacloprid, respectively. For
CMA, 18b was 1.6-fold more potent than imidacloprid. Precise
LC50 values were not obtained for 18b and 40 on PLH, however
both were <2 ppm whereas imidacloprid was determined to be
0.8 ppm. For WF, 49 was ꢀ2.5-fold less potent than imidacloprid.
The assays described in this study were all based on contact
sprays. The neonicotinoid class of chemistry is also known for pos-
sessing physical properties that allow uptake into plants via sys-
temic delivery, either through soil treatment or seed treatment.13
As such, a preliminary study using a soil application of either 18a
or 18b resulted in activity against GPA that was comparable to
the foliar application of these compounds.
Table 4
Comparative potency of nAChR agents at displacing 3H-imidacloprid in GPA
membrane preparations
Compounds
IC50 (nM)
95% Confidence interval
Lower
Upper
18a
40
Imidacloprid
Thiacloprid
Dinotefuran
Sulfoxaflora
310
1115
3
244
811
2
392
1532
4
Based on the activity of amino-2(5H)-oxazolones 18a and 18b, a
series of analogs A containing different substitutions on the amino
group was investigated (Table 2). Compounds 34 through 39 are
analogs containing a N-3-pyridylmethyl group, unsubstituted, or
substituted by one or two halogen atoms at different ring posi-
tions. All these analogs showed a reduction in activity, except 6-
3
2
4
13,300
473
11,655
374
15,162
598
a
For the structure of sulfoxaflor, see Ref. 2c.

2192
W. Zhang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2188–2192
tored.14,15 In this assay 18a induced Ca2+ mobilization indicative
of nAChR agonism (Fig. 3) with EC50 values of 3.4, 0.9 and
0.4 M, obtained for 18a, nicotine and imidacloprid, respectively.
In summary, N-substituted amino-2(5H)-oxazolones A have
l
been discovered as a new class of nAChR agonists. This class of
compounds showed potent activity against several sucking pest
species. Compounds such as 18a and 18b show potential utility
for combatting insect damage in the field.
References and notes
1. For the most recent review on nAChR insecticides, see: (a) Jeschke, P.; Nauen,
R.; Beck, M. E. Angew. Chem. Int. Ed. 2013, 52, 9464; (b) Also see references cited
in (a) for earlier reviews.
2. (a) Zhu, Y.; Rogers, R. B. PCT Intl. Appl. WO 06/060029, 2006; Chem. Abstr. 2005,
143, 386921.; (b) Loso, M. R.; Nugent, B. M.; Huang, J. X.; Rogers, R. B.; Zhu, Y.;
Renga, J. A. M.; Hedge, V. B.; Demark, J. J Chem. Abstr. 2007, 147, 270793; (c)
Zhu, Y.; Loso, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R. B.; Huang, J.;
Gerwick, B. C.; Babcock, J. M.; Kelly, D.; Hegde, V. B., et al J. Agric. Food Chem.
2011, 59, 2950.
3. (a) Jeschke, P.; Velten, R.; Schenke, T.; Schallner, O.; Beck, M.; Malsam, O.;
Nauen, R.; Gorgens, U.; Muller, T.; Arnold, C. PCT Intl. Appl. WO 07/115643,
2007; Chem. Abstr. 2007, 147, 427230; (b) Jeschke, P.; Velten, R.; Schenke, T.;
Schallner, O.; Beck, M.; Pontzen, R.; Malsam, O.; Reckmann, U.; Nauen, R.;
Gorgens, U.; Pitta, L.; Muller, T.; Arnold, C.; Sanwald, E. PCT Intl. Appl. WO 07/
115644, 2007; Chem. Abstr. 2007, 147, 427231; (c) Also see Ref. 1a; (d) Kagabu,
S.; Mitomi, M.; Kitsuda, S. PCT Intl. Appl. WO 12/029672, 2012; Chem. Abstr.
2012, 156, 341853.
Figure 3. Typical Ca2+ mobilization trace of P. americana embryonic neurons
showing nAChR agonist-induced response with nicotine (NIC) and 18a. Neurons
were continuously perfused with saline and test compounds applied during the
periods shown with the solid bar. Compound 18a stimulated nAChR activation with
an EC50 value of 3.4 lM.
As the target of the N-substituted amino-2(5H)-oxazolones was
expected to be nAChRs, 3H-imidacloprid displacement studies
were conducted using GPA membranes. Studies were conducted
using a radioligand concentration approximately equal to the Kd
value of the high affinity binding site for 3H-IMI (2.5 nM). The con-
centration for test compounds ranged from 0.01 to 1000 nM in 10-
fold dilution steps. In this assay the buffer, protein and test com-
pound were allowed to incubate together for 10 min prior to addi-
tion of 3H-imidacloprid. Following a 60-min incubation at room
temperature assay tubes were quenched with 5 ml of ice cold buf-
fer and stored on ice. The tubes were filtered through Whatman
GF/C filters which were washed twice with cold buffer, placed in
scintillation vials and read on a scintillation counter. As shown in
Table 4, 18a displaced 3H-imidacloprid with a 100-fold lower po-
tency than imidacloprid itself. This result is consistent with re-
duced potency of 18a versus imidacloprid in the GPA bioassay. A
second oxazolone analog, 40, was less potent, with an IC50 value
4. Ohishi, H.; Iihama, T.; Ishimitsu, K.; Yamada, T.; Hatano, R.; Takakusa, N.;
Mitsui, J. PCT Intl. Appl. WO 92/00964, 1992; Chem. Abstr. 1992, 117, 7806.
5. (a) Zhang, W.; McCann, S. F. PCT Intl. Appl. WO 10/005692, 2010; Chem. Abstr.
2010, 152, 144659; (b) Zhang, W.; Barry, J. D.; Hughes, K. A.; McCann, S. F.
Presented at the 246th National Meeting of the American Chemical Society,
Indianapolis, IN, September, 2013; paper AGRO-232.
6. (a) Matoba, K.; Yamazaki, T. Chem. Pharm. Bull. 1974, 22, 2999; (b) Crockett, G.
C.; Koch, T. H. Org. Synth. 1980, 59, 132.
7. (a) Swanson, B. J.; Crockett, G. C.; Koch, T. H. J. Org. Chem. 1981, 46, 1082; (b)
Jeschke, P.; Beck, M. E.; Krämer, W.; Wollweber, D.; Erdelen, C.; Turberg, A.;
Hansen, O.; Martin, H.-D.; Sauer, P. DE Patent Appl. DE 01/10119423, 2002;
Chem. Abstr. 2002, 137, 310921.
8. Liu, K.; Meinke, P. T.; Wood, H. B. PCT Intl. Appl. WO 06/014262, 2006; Chem.
Abstr. 2006, 144, 212651.
9. Tahmassebi, D. J. Mol. Struct. (Theochem) 2003, 638, 11.
10. Lesyk, R.; Zimenkovsky, B.; Atamanyuk, D.; Jensen, F.; Kiec-Kononowicz, K.;
Gzella, A. Bioorg. Med. Chem. 2006, 14, 5230.
11. Allah, S. O. A.; Ead, H. A.; Kassab, N. A.; Zayed, M. M. J. Heterocycl. Chem. 1983,
20, 189.
12. Arrowsmith, J. E.; Campbell, S. F.; Cross, P. E.; Burges, R. A.; Gardiner, D. G. J.
Med. Chem. 1989, 32, 562.
13. Elbert, A.; Haas, M.; Springer, B.; Thielert, W.; Nauen, R. Pest Manag. Sci. 2008,
1099, 64.
14. Cordova, D.; Benner, E. A.; Sacher, M. D.; Rauh, J. J.; Sopa, J. S.; Lahm, G. P.;
Selby, T. P.; Stevenson, T. M.; Flexner, L.; Gutteridge, S.; Rhoades, D. F.; Wu, L.;
Smith, R. M.; Tao, Y. Pestic. Biochem. Physiol. 2006, 84, 196.
15. Cordova, D. In Modern Methods in Crop Protection Research; Jeschke, P., Krämer,
W., Schirmer, U., Witschel, M., Eds.; Wiley-VCH: Wenheim, 2013; pp 175–196.
of 1.1 lM compared to 310 nM for 18a.
To determine the functional action on insect nAChRs, 18a was
tested on cultured embryonic neurons from the American cock-
roach, Periplaneta americana. Neurons were loaded with the Ca2+
-
sensitive fluoroprobe, Fura-2 AM, as previously described and
nAChR-induced activation of intracellular Ca2+ influx moni-