Mesoionic pyrido[1,2-a]pyrimidinones: A novel class of insecticides inhibiting nicotinic acetylcholine receptors

Article abstract of DOI:10.1016/j.bmcl.2016.10.031

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species, particularly hemiptera and lepidoptera. Mode-of-action studies showed that they act on nicotinic acetylcholine receptors (nAChRs) primarily as inhibitors. Here we report the discovery, evolution, and preparation of this class of chemistry. Our efforts in structure–activity relationship elucidation and biological activity evaluation are also presented.

Full text of DOI:10.1016/j.bmcl.2016.10.031

Accepted Manuscript
Mesoionic pyrido[1,2-a]pyrimidinones: A novel class of insecticides inhibiting
nicotinic acetylcholine receptors
Wenming Zhang, Caleb W. Holyoke Jr., James Barry, Robert M. Leighty,
Daniel Cordova, Daniel R. Vincent, Kenneth A. Hughes, My-Hanh T. Tong,
Stephen F. McCann, Ming Xu, Twyla A. Briddell, Thomas F. Pahutski, George
P. Lahm
PII:
S0960-894X(16)31059-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.10.031
BMCL 24334
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 September 2016
10 October 2016
11 October 2016
Please cite this article as: Zhang, W., Holyoke, C.W. Jr., Barry, J., Leighty, R.M., Cordova, D., Vincent, D.R.,
Hughes, K.A., Tong, M.T., McCann, S.F., Xu, M., Briddell, T.A., Pahutski, T.F., Lahm, G.P., Mesoionic pyrido[1,2-
a]pyrimidinones: A novel class of insecticides inhibiting nicotinic acetylcholine receptors, Bioorganic & Medicinal
Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.10.031
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Mesoionic pyrido[1,2-a]pyrimidinones: A
novel class of insecticides inhibiting nicotinic
acetylcholine receptors
Leave this area blank for abstract info.
Wenming Zhang*, Caleb W. Holyoke Jr., James Barry, Robert M. Leighty, Daniel Cordova, Daniel R. Vincent,
Kenneth A. Hughes, My-Hanh T. Tong, Stephen F. McCann, Ming Xu, Twyla A. Briddell, Thomas F. Pahutski,
George P. Lahm
29

Bioorganic & Medicinal Chemistry Letters
Mesoionic pyrido[1,2-a]pyrimidinones: A novel class of insecticides inhibiting
nicotinic acetylcholine receptors
Wenming Zhang, Caleb W. Holyoke Jr., James Barry, Robert M. Leighty, Daniel Cordova, Daniel R.
Vincent, Kenneth A. Hughes, My-Hanh T. Tong, Stephen F. McCann, Ming Xu, Twyla A. Briddell,
Thomas F. Pahutski, George P. Lahm
DuPont Crop Protection, Stine-Haskell Research Center, 1090 Elkton Road, Newark, DE 19711, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional
insecticidal activity controlling a number of insect species, particularly hemiptera and
lepidoptera. Mode-of-action studies showed that they act on nicotinic acetylcholine receptors
(nAChRs) primarily as inhibitors. Here we report the discovery, evolution, and preparation of
this class of chemistry. Our efforts in structure-activity relationship elucidation and biological
activity evaluation are also presented.
Keywords:
Mesoionic
2009 Elsevier Ltd. All rights reserved.
Pyrido[1,2-a]pyrimidinone
Insecticide
Acetylcholine receptor
Inhibitor
———
 Corresponding author. Tel.: +1-302-451-5700; fax: +1-302-366-5738; e-mail: wenming.zhang@dupont.com

primarily as inhibitors.
Worldwide population growth, urbanization, demand for
better quality food diet more rich in protein, and yet limits of
arable land and freshwater supplies provide opportunities and
challenges for farmers of tomorrow. The agrochemical tools
growers currently utilize are also under continuous pressure, due
to a number of factors which contribute to loss of existing
products. Such factors include the continuing development of
resistance, the desire for products with more favored
toxicological and environmental profiles, and the need for
effective control options for integrated pest management.
In the early 1990s, DuPont Crop Protection had devoted
efforts to optimizing pyrido[1,2-a]pyrimidinone fungicides A
(see Fig. 1), which led to the discovery of proquinazid (1) and its
launch in 2005 as a potent fungicide for powdery mildew
control.6 At the lead optimization stage, one variation of structure
A pursued was a compound replacing the allyl group in A with a
phenyl group while changing the methyl group to a more desired
n-propyl group, i.e. compound 2 shown in Fig. 1. As depicted in
Scheme 1, 2 was prepared in good yield by an alkylation reaction
of the corresponding parent pyrido[1,2-a]pyrimidinone 3.
However, one by-product was also isolated out of this reaction
and identified as mesoionic pyrido[1,2-a]pyrimidinone 4,7
resulting from unexpected N-alkylation of the pyrido[1,2-
a]pyrimidinone ring nitrogen atom.8 Compound 4 and its close
analogs were tested and showed no interesting pesticidal activity
in the screen at the time. However, in follow-up tests in 2005
against an expanded species list, 4 displayed insecticidal activity
against corn planthopper (Peregrinus maidis (ashmead), CPH)
and diamondback moth (Plutella xylostella (Linnaeus), DBM).
Interesting insecticidal activity of compound 4 combined with an
uncommon yet very intriguing chemical structure prompted us to
further explore its analogs.
The discovery and development of novel pesticides involves a
number of different approaches, ranging from investigations of
known chemical scaffolds,1,2,3 to the high throughput screening of
collections of compounds in the attempt to find new or
previously unknown chemical scaffolds with desired biological
activities.4
A
novel class of mesoionic pyrido[1,2-
a]pyrimidinones has been discovered as potent insecticides
originated from screen of DuPont internal collection of
compounds.5 In this communication, we report the initial
discovery of this class of insecticides. We will also present the
optimization efforts in this area that revealed analogs such as 29
that shows potent insecticidal activities against a number of
insect species and acts on nicotinic acetylcholine receptors
Pyridopyrimidinone
fungicide lead
A
Proquinazid (1)
DuPont Fungicide
2
Figure 1. Pyrido[1,2-a]pyrimidinone fungicide and proquinazid
a
3
2
4
Scheme 1. Reagents and conditions: (a) n-PrI, K2CO3, 25 oC, ~70% (3), < 10% (4).
There are two methods commonly employed for building up
pyrido[1,2-a]pyrimidinone mesoionic rings. The first one is N-
alkylation of parent pyrido[1,2-a]pyrimidinone ring as shown in
Scheme 1. Alternatively, the reaction between N-substituted 2-
aminoamidines with malonic esters at high temperature also
generates desired mesoionic compounds.9 This method was
applied for preparation of compound 4 and its analogs. The
compounds shown in Tables 1-4 were prepared as described in
Schemes 2-6. Synthesis of 1-alkyl compounds is outlined in
Scheme 2. 2-(Propylamino)pyridine (7) was prepared in two
a
b
5
6
7
c
8
4

steps from N-formyl-2-aminopyridine (5) by treatment with
sodium hydride, 1-iodopropane followed by deformylation under
acidic conditions.10 Required diethyl phenylmalonate (8) and its
analogs with various substituents on the phenyl ring were
prepared according to literature.11 Cyclization between 2-
aminopyridine 7 and diethyl phenylmalonate (8) produced
desired mesoionic compound 4 in reasonable yield. Other 1-alkyl
analogs 4a-4j in Table 1 and oxygen-containing analogs 11g-11i
in Table 2 were prepared in a similar fashion.
Scheme 2. Reagents and conditions: (a) NaH, n-PrI, DMF, 0-25 oC; (b) 6 N HCl, 100 oC, 80% for 2 steps; (c) tetralin, 210 oC, 50%.
Mesoionic compounds containing 1-alkoxycarbonylalkyl
groups were prepared as depicted in Scheme 3. 2-Aminopyridine
(9) was mixed with aqueous glyoxal in the presence of ethanol as
co-solvent. The resulting mixture was treated with triflic acid at
elevated temperature to generate the expected product 10 in one-
improvement of a similar reaction reported previously in which
explosive concentrated perchloric acid was utilized as promoter.13
Cyclization between 2-aminopyridine 10 and malonate 8 gave
mesoionic compound 11b in low yield.
8
a
b
9
10
11b
pot in good overall yield.12
The use of triflic acid is an
Scheme 3. Reagents and conditions: (a) CF3SO3H, aqueous glyoxal, EtOH-H2O, 80 oC, 52%; (b) tetralin, 210 oC, 12%.
We then shifted our interest to the preparation of 2,2,2-
trifluoroethyl analog 14. Its synthesis is outlined in Scheme 4. 2-
Aminopyridine (9) was first treated with trifluoroactic anhydride
to convert to N-trifluoroacetamide 12, which, in turn, was
reduced by diborane in THF to generate 2-(2’,2’,2’-
trifluoroethylamino)-pyridine (13).14 Cyclization between 13
and malonate 8 produced mesoionic compound 14.
8
a
b
c
12
9
13
14
o
o
Scheme 4. Reagents and conditions: (a) CF3CO2COCF3, diethyl ether, 25 C, 53%; (b) B2H6 in THF, 25 to 65 C, 52%; (c) tetralin,
210 oC, 15%.
Analogs containing a 5-membered heterocycle ring moiety
presented in Table 3 were prepared starting from modification of
commercially available heterocycle starting materials. 2-
Chlorooxazol-5-yl analog 21 was prepared as outlined in Scheme
5. Ethyl oxazole-5-carboxylate 15 was first converted to 5-
hydroxymethyl oxazole 16 via DIBAL-H reduction.15 16 was
reacted as an alkylating agent with N-Boc-protected 2-
aminopyridine 18 to form 19.16 Cleavage of the Boc group of 19
was achieved through treatment with TFA in CH2Cl2 in the
presence of water.10 The resulting aminopyridine 20 was
subjected to similar cyclization conditions to generate mesoionic
compound 21.
b
a
18
c
15
16
17
19
8
d
e
20
21
then transformed to 5-(bromomethyl)oxazole 17 which further
o
o
Scheme 5. Reagents and conditions: (a) DIBAL-H, THF, - 78 to 25 C; (b) CBr4, PPh3, 2,6-lutidine, acetonitrile, 0 C, 88% for 2
steps; (c) NaH, DMF, 0-25 oC; (d) TFA, CH2Cl2-H2O, 25 oC, 44% for 2 steps; (e) tetralin, 185 oC, 44%.

Preparation of 1,3,4-Thiadiazole analog 27 started from 5-
methyl-1,3,4-thiadiazol-2-amine (22) as described in Scheme 6.
Compound 22 was first converted to 2-chloro-5-methyl-1,3,4-
thiadiazole (23) which,17 in turn, was brominated under radical
reaction conditions to generate bromide 24.18 Then the same
sequence of alkylation, deprotection, and cyclization reactions
provided product 27.
18
b
a
c
22
23
24
25
8
d
e
27
26
Scheme 6. Reagents and conditions: (a) t-BuONO, CuCl2, acetonitrile, 0 to 25 oC, then 20% HCl, 77%; (b) NBS, AIBN, CCl4, 76 oC,
o
46% (16% of dibromination product was also isolated); (c) NaH, DMF, 0-25 oC, 97%; (d) TFA, CH2Cl2-H2O, 25 C, 52%; (e) tetralin,
185 oC, 15%.
Insecticidal activity of mesoionic pyrido[1,2-a]pyrimidinone
compounds is summarized in Tables 1-4. Test compounds were
formulated using a solution containing 10% acetone, 90% water
and 300 ppm of X-77® spreader surfactant (Loveland industries,
Inc. Greeley, Colorado, USA). The formulated compounds were
sprayed on the foliage of plants at 2–5 rates and tests were
replicated three times. Efficacy was evaluated on the following
test units: 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 10-12 day-old rice for 3rd
instar nymphs of brown planthopper (Nilaparvata lugens (Stål),
BPH); 10-12 day-old rice for 3rd instar nymphs of rice green
leafhopper (Nephotettix virescens (Distant), GLH); 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); 12–15 day-old radish plant for
Diamondback moth (Plutella xylostella (Linnaeus), DBM); and
4-5 day-old corn for fall armyworm (Spodoptera frugiperda (J.E.
Smith), FAW).2 Mortality was evaluated 6 days after application
for all insects. Insecticidal activity is reported as an LC50 (the
lethal concentration required for 50% mortality) in ppm (mg/kg).
methylene linkage are listed in Table 3. Depending on the
position of the heteroatom in the ring, a number of analogs, 21a-e
and 27c, show further improved hopper activity. Particularly, 2-
chlorothiazol-5-yl analog 21e shows not only exceptional activity
against all 4 hopper species, but also very potent activity against
two representative lepidoptera species (DBM and FAW). This
result led to dividing two sub-areas out of current program, one
on controlling hopper species and the other on controlling
lepidoptera species.
In Table 4, representative analogs with different classes of
substituents at position-1 are compared with the addition of data
on aphicidal activity. Traditional neonicotinoid insecticide
representative imidacloprid is also included for comparison. The
BPH population in test is resistant to imidacloprid with inferior
activity observed for imidacloprid. Starting from the initial n-
propyl compound 4, with the addition of function groups (ester
11a) or heteroatom (O, F, compounds 11g and 14), to finally
heterocycle moiety (compound 21e), not only has insecticidal
potency been improved significantly, but insecticide spectrum
has also expanded to cover BPH, GLH, FAW and GPA. The
phenyl ring at 3-postion of the mesoionic core tolerates a number
of substituents, including 2’-methoxy group or fluorine atom at
2’- or 4’-position as shown by analogs 28, 29, and 30. Analogs
14, 21f, and 28-30, showed strong activity against BPH
populations resistant to imidacloprid. However, no insecticidal
activity was detected for compounds 32 or 33 when 2-
chlorothiazol-5-yl moiety was changed to 2-chlorothiazol-4-yl or
2,4-dichlorothiazol-5yl groups.
Data in Table 1 shows that 1-alkyl mesoionic compounds in
general controls CPH and DBM better than a number of other
species. n-Propyl and cyclopropylmethyl analogs 4 and 4g
showed the most potent insecticidal activity. Analogs with either
smaller alkyl analogs, compounds 4a-b, or larger groups,
compounds 4e-f and 4h-j, provides decreased insecticidal
activity.
Table 2 indicates that a number of oxygen-containing function
groups are tolerated at 1-position. Methyl acetate analog 11a
maintains the same level of CPH activity as that of n-propyl
compound 4, while the corresponding methyl ether analog 11g
shows 2-fold improvement in CPH activity. 2,2,2-Trifluoroethyl
analog 14, on the other hand, provides remarkably high activity
against all four hopper species tested (CPH, PLH, BPH, GLH).
Because BPH and GLH are two rice pest species of significant
economic importance, potent insecticidal activity observed on 14
was the first breakthrough of this area and warrantied further
exploration of this area for controlling rice hopper pests. A
number of other haloalkyl analogs (14a-c) also show activity
against CPH and PLH.
Mode of action work of representative analogs showed that
this class of mesoionic insecticide binds to the orthosteric site of
the nicotinic acetylcholine (nAChR) receptor.19 Although
mesoionics compete for the same binding site as neonicotinoid
insecticides, their physiological effect differs significantly.
Cordova et al., demonstrated that mesoionic insecticides were
highly potent inhibitors of the American cockroach (Periplaneta
americana) nAChR, with minimal receptor activation at
concentrations below 100 M. The inhibitory action is consistent
with lethargic poisoning symptoms observed across multiple
species. The authors further showed a lack of activation of
Xenopus oocytes expressing Drosophila 2/chick 2 nAChRs.
In summary,
a novel class of mesoionic pyrido[1,2-
Insecticidal potency of mesoionic compounds containing a 5-
membered heterocycle moiety connected to position-1 through a
a]pyrimidinone compounds has been discovered as unique
orthosteric nAChR inhibitors. This class of compounds showed

exceptional insecticidal activity controlling a number of insect
species. Analogs, 21f, 29, and 30, displayed not only potent
cross spectrum insecticidal activity against many different insect
species, but also strong activity against brown planthopper
populations resistant to imidacloprid. These compounds combine
distinct physiological receptor action with outstanding
insecticidal properties and promise to be a valuable addition to
crop protection chemistry.
Table 1. Insecticidal potency of 1-alkyl mesoionic compoundsa
B
Entry
4a
4b
4
R
CPH
106.6
<50
PLH
>50
BPH
GLH
DBM
>250
84.2
28.1
111.8
64.3
92.1
92.1
19.2
92.1
>250
>250
FAW
Me
No data
>50
No data
No data
No data
No data
No data
No data
No data
No data
No data
No data
No data
No data
No data
>50
Et
>50
n-Pr
allyl
i-Pr
10.4
50.4
<50
33.4
<50
>10
4c
4d
4e
4f
No data
No data
>10
>250
<50
>250
n-Bu
i-Bu
CH2-c-Pr
n-Pent
Bn
19.5
52.3
13.5
<250
<50
>250
<50
>250
>50
No data
>250
4g
4h
4i
<50
>10
>250
>250
>250
No data
No data
No data
>250
No data
No data
4j
Ph
>250
Insect LC50 values (ppm) are shown for corn planthopper (Peregrinus maidis (Ashmead), CPH); potato leafhopper (Empoasca
fabae (Harris), PLH); brown planthopper (Nilaparvata lugens (Stål), BPH, imidacloprid-resistant); rice green leafhopper
(Nephotettix virescens (Distant), GLH); Diamondback moth (Plutella xylostella (Linnaeus), DBM); and fall armyworm
(Spodoptera frugiperda (J.E. Smith), FAW).
a LC50 values were obtained for multiple test rates, each tested in replicate (n ≥ 3). LC50 calculations were determined by Probit
analysis using a maximum quasi-likelihood curve fitting algorithm. “<50” means that, at 50 ppm the mortality was 100%,
however no LC50 value was calculated; “>250” means that, at 250 ppm the compound showed no activity, therefor no LC50 value
was calculated, etc.
Table 2. Insecticidal potency of mesoionic compounds containing ester, amide, and ether functions, or haloakyl group at
position-1a
B
Entry
11a
11b
11c
11d
11e
11f
R
CPH
13.3
PLH
>250
<50
BPH
GLH
DBM
>250
>250
>250
>10
FAW
>250
>250
>250
>10
CH3OCOCH2
49.8
No data
No data
No data
No data
No data
No data
CH3CH2OCOCH2
(CH3)2CHOCOCH2
(CH3)2NCOCH2
CH3OCOCH2CH2
CH3CH2OCOCH(CH3)
>250
>250
>50
No data
No data
No data
No data
No data
>250
>50
>250
>250
>250
>250
>250
>250
>250
>250

11g
11h
11i
14
CH3OCH2CH2
6
<50
14.3
20.9
2.2
46
No data
No data
No data
4.5
243.4
>250
243.4
<50
>250
>250
>250
>250
>250
>250
>250
CH3OCH2CH2CH2
CH3OCH2CH(CH3)
CF3CH2
<50
19.4
1
No data
>10
2.4
14a
14b
14c
CF3CH2CH2
<50
<50
50
<50
<50
44.7
>10
No data
No data
No data
>250
<50
(2,2-difluorocyclopropyl)-CH2
CF2ClCFHCH2CH2
No data
>10
31.6
Insect LC50 values (ppm) are shown for corn planthopper (Peregrinus maidis (Ashmead), CPH); potato leafhopper (Empoasca
fabae (Harris), PLH); brown planthopper (Nilaparvata lugens (Stål), BPH, imidacloprid-resistant); rice green leafhopper
(Nephotettix virescens (Distant), GLH); Diamondback moth (Plutella xylostella (Linnaeus), DBM); and fall armyworm
(Spodoptera frugiperda (J.E. Smith), FAW).
a LC50 values were obtained for multiple test rates, each tested in replicate (n ≥ 3). LC50 calculations were determined by Probit
analysis using a maximum quasi-likelihood curve fitting algorithm. “<50” means that, at 50 ppm the mortality was 100%,
however no LC50 value was calculated; “>250” means that, at 250 ppm the compound showed no activity, therefor no LC50 value
was calculated, etc.
Table 3. Insecticidal potency of mesoionic compounds containing a 5-membered heterocycle moiety at position-1a
C
Entry
21
Het
CPH
<50
2.3
PLH
<10
<10
2.7
BPH
>50
3.3
3.7
13.3
2
GLH
DBM
<50
<50
>250
<50
<50
<2
FAW
>250
243.3
>250
>250
>250
6.4
2-chlorooxazol-5-yl
3-methylisoxazol-5-yl
1-methylpyrazol-4-yl
thiazol-5-yl
No data
No data
No data
3.3
21a
21b
21c
21d
21e
21f
0.07
0.6
7.7
2-methylthiazol-5-yl
2-chlorothiazol-5-yl
9.2
<10
<2
No data
9
<2
2.7
2-(3-methoxyphenyl)thiazol-
5-yl
>50
>50
>50
>50
>50
<50
>50
>250
>50
>50
<10
>50
>50
>250
7
No data
No data
No data
>10
No data
No data
No data
No data
No data
No data
No data
No data
No data
No data
>250
>250
>250
243.3
>250
<50
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
21g
21h
21i
4-chloropyrazol-1-yl
2,4-dichlorothiazol-5-yl
2-chlorooxazol-4-yl
21j
27
2-chlorothiazol-4-yl
>10
5-chloro-1,3,4-thiadiazol-2-yl
No data
No data
>10
27a
27b
27c
27d
5-methyl-1,3,4-oxadiazol-2-yl <50
>250
>250
>250
>250
tetrahydrofuran-2-yl
tetrahydrofuran-3-yl
1,3-dioxolan-2-yl
43.7
3.8
>10
<50
55
No data

Insect LC50 values (ppm) are shown for corn planthopper (Peregrinus maidis (Ashmead), CPH); potato leafhopper (Empoasca
fabae (Harris), PLH); brown planthopper (Nilaparvata lugens (Stål), BPH, imidacloprid-resistant); rice green leafhopper
(Nephotettix virescens (Distant), GLH); Diamondback moth (Plutella xylostella (Linnaeus), DBM); and fall armyworm
(Spodoptera frugiperda (J.E. Smith), FAW).
a LC50 values were obtained for multiple test rates, each tested in replicate (n ≥ 3). LC50 calculations were determined by Probit
analysis using a maximum quasi-likelihood curve fitting algorithm. “<50” means that, at 50 ppm the mortality was 100%,
however no LC50 value was calculated; “>250” means that, at 250 ppm the compound showed no activity, therefor no LC50 value
was calculated, etc.
Table 4. Insecticidal potency of mesoionic compounds with different substituents at position-1 or on the 3-phenyl groupa
D
Entry
4
R
R1
H
CPH
10.4
13.3
6
PLH
33.4
>250
<50
2.2
BPH
>10
49.8
46
GLH
No data
No data
No data
4.5
GPA
>250
>250
>250
>250
11.6
<50
CMA
>250
>250
>250
>250
<250
>250
<50
DBM
28.1
>250
243.4
<50
<2
FAW
>50
CH3CH2
11a
11g
14
CH3OCO
H
>250
>250
>250
6.4
CH3OCH2
H
CF3
H
1
2.4
21e
28
2-chlorothiazol-5-yl
2-chlorothiazol-5-yl
2-chlorothiazol-5-yl
2-chlorothiazol-5-yl
2-bromothiazol-5-yl
2-chlorothiazol-4-yl
2,4-dichlorothiazol-5-yl
H
<2
<2
2.7
9
2-MeO
2-F
4-F
2-F
4-F
4-F
0.06
<2
0.75
<2
0.6
4.1
14.4
<0.4
<2
135.8
17.1
9.7
29
0.3
2.5
<50
30
0.1
0.3
1.9
11.2
4.2
<250
<50
31
<10
>50
>50
0.29
30.0
>50
>50
0.53
3.2
No data
No data
No data
0.067
5.6
<50
>250
>250
>2
<250
>250
>250
<250
32
No data
No data
47.4
>250
>250
0.17
>250
>250
0.57
33
imidacloprid
Insect LC50 values (ppm) are shown for corn planthopper (Peregrinus maidis (Ashmead), CPH); potato leafhopper (Empoasca
fabae (Harris), PLH); brown planthopper (Nilaparvata lugens (Stål), BPH, imidacloprid-resistant); rice green leafhopper
(Nephotettix virescens (Distant), GLH); green peach aphid (Myzus persicae (Sulzer) GPA); cotton melon aphid (Aphis gossypii
(Glover), CMA); Diamondback moth (Plutella xylostella (Linnaeus), DBM); and fall armyworm (Spodoptera frugiperda (J.E.
Smith), FAW).
a LC50 values were obtained for multiple test rates, each tested in replicate (n ≥ 3). LC50 calculations were determined by Probit
analysis using a maximum quasi-likelihood curve fitting algorithm. “<50” means that, at 50 ppm the mortality was 100%,
however no LC50 value was calculated; “>250” means that, at 250 ppm the compound showed no activity, therefor no LC50 value
was calculated, etc.
Gregory, V.; Andreassi, J. L.; Sweigard, J. A.; Klyashchitsky, B.
A.; Henry, Y. T. et al.; Bioorg. Med. Chem. 2016, 24, 354.
References and notes
5.
(a) Holyoke, C. W., Jr; Tong, M.-H. T.; Coats, R. A.; Zhang, W.;
McCann, S. F.; Chan, D. M.-T. U. S. Patent 8,552,007, 2013; (b)
Holyoke, C. W., Jr; Zhang, W. U. S. Patent 9,018,220, 2015; (c)
Holyoke, C. W., Jr.; Zhang, W.; Pahutski, T. F., Jr; Lahm, G. P.;
Tong, M-H.; Cordova, D.; Schroeder, M. E.; Benner, E. A.; Rauh,
J. J.; Dietrich, R. F.; Leighty, R. M.; Daly, R. F.; Smith, R. M.;
Vincent, D. R.; Christianson, L. A. In ACS Symposium Series
(2015), 1204(Discovery and Synthesis of Crop Protection
Products); Lyga, J. W.; Theodoridis, G., Eds; American Chemical
Society: Washington, 2015; pp 365-378.
Selby, T. P.; Sternberg, C. G.; Bereznak, J. F.; Coats, R. A.;
Marshall, E. A. In ACS Symposium Series (2007), 948(Synthesis
and Chemistry of Agrochemicals VII); Lyga, J. W.; Theodoridis,
G., Eds; American Chemical Society: Washington, 2007; pp 209-
222.
1.
For example, see discovery of insecticide sulfoxaflor from
sulfoximine scaffold: Zhu, Y.; Loso, M. R.; Watson, G. B.;
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Zhang, W.; Barry, J. D.; Cordova, D.; McCann, S. F.; Benner, E.
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2.
3.
6.
4.
For example, see discovery of oxathiapiprolin fungicide from HTS
screen of a diverse bis-amide compound library: Pasteris, R. J.;
Hanagan, M. A.; Bisaha, J. J.; Finkelstein, B. L.; Hoffman, L. E.;

7.
Mesoionic compounds cannot be satisfactorily represented by one
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drawing pattern as shown for compound 4. This pattern has been
employed in DuPont’s patent filings and has been adopted in
SciFinder database. For a review of mesoionic compounds and
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