Design, synthesis, insecticidal activity and molecular docking of doramectin derivatives

Article abstract of DOI:10.1016/j.bmc.2018.12.040

A series of new doramectin derivatives containing carbamate, ester and sulfonate were synthesized, and their structures were characterized by ¹H and ¹³C nuclear magnetic resonance (NMR) and high-resolution mass spectrum (HRMS). Their insecticidal activities against oriental armyworm, diamondback moth, and corn borer were evaluated and compared with the parent doramectin and commercial avermectins, metolcarb, fenpropathrin. Among all compounds, three compounds (3a, 3g and 3h) showed excellent insecticidal effect. In particular, compound 3g containing cyclopropyl carbamate against oriental armyworm, diamondback moth, and corn borer, exhibited the most promising insecticidal activity with the final mortality rate of 66.67%, 36.67%, 40.00% at the concentration of 12.5 mg/L, respectively. The LC₅₀ values of 3g were 5.8859, 22.3214, and 22.0205 mg/L, showing 6.74, 2.23, 2.21-fold higher potency than parent doramectin (LC₅₀ values of 39.6907, 49.7736, and 48.6129 mg/L) and 6.83, 1.93, 3.36-fold higher potency than commercial avermectins (LC₅₀ values of 40.2489, 42.9922, and 73.9508 mg/L). Additionally, molecular docking simulations revealed that 3g displayed stronger hydrogen-bonding action in binding with the GABA receptor than parent doramectin, which were crucial for keeping high insecticidal activity. The present work demonstrated that these compounds containing alkyl carbamate group could be considered as potential candidates for the development of novel pesticides in the future.

Full text of DOI:10.1016/j.bmc.2018.12.040

Accepted Manuscript
Design, Synthesis, Insecticidal Activity and Molecular Docking of Doramectin
Derivatives
Qi Zhang, Ping Bai, Cheng Zheng, Yao Cheng, Tao Wang, Xiaoxia Lu
PII:
S0968-0896(18)32040-6
https://doi.org/10.1016/j.bmc.2018.12.040
BMC 14689
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 December 2018
24 December 2018
30 December 2018
Please cite this article as: Zhang, Q., Bai, P., Zheng, C., Cheng, Y., Wang, T., Lu, X., Design, Synthesis, Insecticidal
Activity and Molecular Docking of Doramectin Derivatives, Bioorganic & Medicinal Chemistry (2018), doi: https://
doi.org/10.1016/j.bmc.2018.12.040
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com
Design, Synthesis, Insecticidal Activity and Molecular Docking of Doramectin
Derivatives
Qi Zhanga,c, Ping Baia,c, Cheng Zhenga,c, Yao Chenga,c, Tao Wanga,c, and Xiaoxia Lua,b*
a
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, People’s Republic of China.
b
Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan Normal University, Hainan, 571127, People’s Republic of China.
c
University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China.
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of new doramectin derivatives containing carbamate, ester and sulfonate were
1
synthesized, and their structures were characterized by H and 13C nuclear magnetic resonance
Received in revised form
Accepted
Available online
(NMR) and high-resolution mass spectrum (HRMS). Their insecticidal activities against oriental
armyworm, diamondback moth, and corn borer were evaluated and compared with the parent
doramectin and commercial avermectins, metolcarb, fenpropathrin. Among all compounds, three
compounds (3a, 3g and 3h) showed excellent insecticidal effect. In particular, compound 3g
containing cyclopropyl carbamate against oriental armyworm, diamondback moth, and corn
borer, exhibited the most promising insecticidal activity with the final mortality rate of 66.67%,
36.67%, 40.00% at the concentration of 12.5 mg/L, respectively. The LC50 values of 3g were
5.8859, 22.3214, and 22.0205 mg/L, showing 6.74, 2.23, 2.21-fold higher potency than parent
doramectin (LC50 values of 39.6907, 49.7736, and 48.6129 mg/L) and 6.83, 1.93, 3.36-fold
higher potency than commercial avermectins (LC50 values of 40.2489, 42.9922, and 73.9508
mg/L). Additionally, molecular docking simulations revealed that 3g displayed stronger
hydrogen-bonding action in binding with the GABA receptor than parent doramectin, which
were crucial for keeping high insecticidal activity. The present work demonstrated that these
compounds containing alkyl carbamate group could be considered as potential candidates for the
development of novel pesticides in the future.
Keywords:
doramectin derivatives
insecticidal activities
molecular docking
oriental armyworm
diamondback moth
corn borer
2009 Elsevier Ltd. All rights reserved.
O
O
O
O
1. Introduction
H
H
O
O
O
O
O
HO
O
O
O
O
O
HO
O
O
R
O
O
Agricultural production losses caused by pest insects (oriental
armyworm, diamondback moth, corn borer, etc.) occupy a
significant proportion of the total losses.1 By resisting of pest
insects, many chemical pesticides, such as benzoylureas,2,3
phenylpyrazoles,4,5 and insect-growth regulators (IGRs)6-8 play an
important role in the enhancement of crop production, however,
simultaneously increase pest resistance. The fermentation-
derived, large, complex macrocyclic lactones (Figure 1), such as
avermectins,9,10 milbemycins,11 ivermectins12 have attracted
significant attention over the years due to their occurrence as
naturally bioactive products which display high efficiency, no
cross-resistance, and unique mode of action (MoA). In particular,
the mechanism of action of avermectins (AVMs, Figure 1a) is
by binding to glutamate-gated chloride channels expressed on
nematode neurons and pharyngeal muscle cells and disrupting
normal physiological and developmental processes to exert its
biological activities.13 Benefiting from their unique mode of
action, AVMs have no cross-resistance with other commercial
insecticidal agents and have aroused considerable research
interest in exploiting insecticidal agents of this class.14 However,
the unrestricted usage of AVMs insecticides over several decades
has resulted in the development of resistance in insecticide.15
O
O
OH
OH
O
O
H
H
OH
Avermectin
Avermectin
OH
B1a: R=CH3
B1b: R=CH2CH3
Ivermectin
(b)
(a)
H
O
O
H
O
O
O
O
O
HO
R
O
O
O
O
O
OH
O
OH
O
R=CH3 or CH2CH3
O
H
O
H
OH
OH
Milbemycin
Doramectin
(d)
(c)
Figure 1 Chemical structures of microbial metabolites.
Due to better lipophilicity, doramectin (Figure 1c) as a third-
generation of AVMs family with a cyclohexyl group at C-25
position in lieu of sec-butyl or isopropyl of AVMs, has better
biological activity and less resistance than AVMs, which is used
to treat endoparasitic nematodes and ectoparasitic insects in
animals.16,17 It has been reported that GABA receptor is the target
of this macrolide. Thus, we performed docking studies with

C5
GABA
receptor
C5
Doramectin
Avermectins
1.81Å
H-Bond Distance:
2.24Å
H-Bond Distance:
-1
-1
-3.866
Glide Docking Score:
kcal mol
-3.841
Glide Docking Score:
kcal mol
O
H
O
O
O
O
O
25
O
HO
H
4"
O
O
O
O
O
25
O
HO
4"
Third-generation
Higher bioactivity
O
O
R'
R': CH3 or CH3CH2
O
O
O
O
OH
O
OH
5
O
H
5
OH
O
H
Doramectin
OH
Avermectins
O
O
O
O
Combination principles
H
O
O
N
O
O
O
O
25
O
O
H
R
4"
CN
O
O
Fenpropathrin
O
O
OH
Pyrethroid insecticides
Carbaryl
O
O
S
5
I
HN
O
O
H
O
H
N
OH
O
H
O
S
O
O
O
O
O
N
R2
R1
R=
R4
CF3
F
N
R3
N
H
H
CF3
Metolcarb
Flubendiamide
Carbamate insecticides
Phthalimide insecticides
Figure 2 Design of the target compounds.
Schrodinger-Glide and investigate the binding pose of AVMs and
doramectin in the active site of target protein (Plutella xylostella
GABA receptor) by homology modeling based on Human
Glycine Receptor alpha-3 retrieved from the Protein Data Bank
(PDB ID 5TIN). By comparing the docking poses of AVMs and
doramectin, the binding free energy (The glide score is an
empirical scoring function that is an approximation of the ligand
binding free energy) of doramectin (-3.866 kcal mol-1) was lower
than that of AVMs (-3.841 kcal mol-1), and the H-bonding
distance of doramectin (1.81 Å) at the C5-OH was much shorter
than that of AVMs (2.24 Å) (Figure 2). Therefore, we speculate
that doramectin as the lead compound has excellent insecticidal
activity, due to the docking posture bind to GABA receptor better
than AVMs.
Avermectins (AVMs) has been widely used as the lead
molecule for chemical modifications to discover more potent
insecticidal agents due to their remarkable biological activities on
insecticidal and anthelmintic activities. AVMs analogs mainly
modified at C-5,24,25 C-13,26,27 C22～C23,28,29 and C4" position30,
31
have been reported. From the structure-activity relationship
(SAR) study on AVMs analogues, we noted that different
hydroxyls (C5 and C4") have different biological activities and
selectivities. A slight modification at the C5-OH group may
resulted in loss of activity, which indicates free OH group at the
C5 is crucial to activity.25 Whereas, small changes at the C4"-OH
group in the chemical structure of the AVMs often lead to
pronounced differences in physical and biological properties.32,33
Up to present, the modification of C4"-OH is being continually
investigated.
The introduction of new active groups in lead compounds is
an important tool for drug discovery. It is well known that
carbamate, ester, and sulfonate esters which can form H-bonds
are the active groups in common pesticides because of their
respective advantages. The carbamate insecticides (metolcarb,
carbaryl, etc.) can inhibit acetylcholinesterase (AChE) in insects
nervous system by covalently carbamylating the serine residue
within the active site for insecticidal effects.18 Many ester
insecticides, such as pyrethroid insecticide fenpropathrin, bind to
voltage-sensitive sodium channels and modify their gating
kinetics, thereby disrupting nerve function.19 Most sulfone
compounds possess excellent biological activities, such as
insecticidal,20 antifungal,21 and antitumor,22 especially in the field
of pesticides.23
Inspired by these reports, herein, we aim at developing novel
macrolide pesticides by combining principles, introducing active
groups (carbamate, ester, and sulfonate groups) replace the
hydroxyl group at C4"-position (Figure 2). A series of novel
carbamate, ester, and sulfonate based doramectin derivatives are
rationally designed, synthesized, and characterized. The
insecticidal activities of these target compounds against oriental
armyworm, diamondback moth, and corn borer are evaluated.
Furthermore, docking analysis and structure-activity relationship
(SAR) studies are extensively performed on the derivatives to
identify key structural features responsible for their insecticidal
potency.

O
O
H
O
O
O
O
O
O
O
H
HO
O
O
O
O
O
HO
O
O
O
O
O
TBDMSCl, DMAP
CH2Cl2, imidazole, rt
O
OH
OH
O
O
H
OTBS
H
OH
2
(5-O-TBDMS Doramectin)
1
(Doramectin)
3a:
3b:
3c:
3d:
3e:
3f:
R
R
R
R
R
R
1 = CH3
1 = CH3CH2
1 = CH3CH2CH2
1 = n-C4H9
1 = CH3(CH2)7
1 = cyclohexyl
O
O
H
H
O
O
O
O
O
N
O
R1
O
O
O
O
2) NH R /CH Cl ;
1) NPC, DMAP/CH2Cl2;
3) TsOH/CH3OH
2
2
1
2
OH
2
3g:
3h:
R
R
1 = cyclopropyl
1 = CH2=CHCH2
1 = C6H5CH2
3 steps
O
3i:
3j:
R
R
H
OH
3(a-j)
1 = 4-OCH3-C6H5CH2
4a:
4b:
4c:
4d:
4e:
R
2 = 4-F-Ph
R2 = 4-Cl-Ph
2 = 4-Br-Ph
2 = 2-CH3-Ph
R2 = 3-Cl-Ph
O
R
R
H
H
O
O
O
N
O
R2
O
O
O
O
4f:
4g:
R2 = 4-OCH3-Ph
O
O
O
R
2 = Ph
OH
1) R2
-N=
C=O
, DM
AP/
CH
2Cl2; 2) TsOH/CH3OH
4h: R2 = 4-CH3-Ph
2
4i:
4j:
4k:
R2 = 2,6-diisopropylphenyl
R2 = 1-naphthyl
2 steps
O
H
OH
R2 = 4-CF3-Ph
4(a-k)
Scheme 1 General procedure for the synthesis of carbamate derivatives of doramectin (3a-3j) and (4a-4k).
O
S
O
O
O
O
H
H
O
O
O
O
O
O
O
O
O
O
R3
O
R4
O
O
O
O
O
O
O
1) R4SO3Cl, DMAP, DCM, rt
2) TsOH/CH3OH
O
O
1) R3COCl, DMAP, DCM, rt
2) TsOH/CH3OH
2
OH
OH
2
O
O
H
H
OH
OTBS
6(a-d)
6d:
R4= CH3CH2CH2; R4= CH3CH2CH2CH2
5(a-g)
6a:
6b:
6c:
R4= CH3;
R4= CH3CH2;
5a:
5d:
5g:
5b:
5c:
3 = CH2=CH;
R
R
R
3 = CH3;
R
3 = CH3(CH2)2;
R
3 = (CH3)2CH
5f:
R3 = CH3(CH2)4
5e:
3 = cyclohexyl;
3 = C6H5CH2
R
Scheme 3 General procedure for the synthesis of sulfonate
derivatives of doramectin (6a-6d).
Scheme 2 General procedure for the synthesis of ester derivatives of
doramectin (5a-5g).
corresponding aromatic amines. Notably, compound 2 were
reacted with newly prepared aromatic isocyanates using
triphosgene and aromatic amines in the solution of
dichloromethane and saturated sodium bicarbonate without
further purified to afford the target compounds 4a-4k. Finally,
ester and sulfonate derivatives of doramectin 5a-5g and 6a-6d
were obtained by reaction of 2 with different acyl chlorides or
sulfonyl chlorides in the presence of Et3N.
2. Results and discussion
2.1. Chemistry synthesis
Three series of novel carbamate, ester and sulfonate
derivatives of doramectin (3a−3j, 4a−4k, 5a−5g and 6a−6d)
modified at position C4"-OH were prepared as shown in Scheme
1-3. Since structure-activity relationship studies had
demonstrated that the presence of free 5-OH in doramectin
played an important role in insecticidal activity, commercially
available doramectin was first selective protection of hydroxyl
group at the 5-position by using tert-butylchlorodimethylsilane
2.2. Insecticidal activities
All compounds prepared were evaluated for insecticidal
efficacy against oriental armyworm and diamondback moth, and
a few representative compounds 3a, 3g and 3h were further
evaluated for insecticidal efficacy against corn borer, and the
results were listed in Figure 3-4 and Table 1. The LC50 values
for 3a, 3g and 3h were calculated through five different
concentrations and were listed in Table 2. Doramectin,
avermectins, metolcarb and fenpropathrin were used as a positive
control, and leaves treated with acetone alone were used as a
blank control group.
(TBDMS-Cl) as
a protective agent in the presence of
trimethylamine and DMAP to provide 5-O-TBDMS doramectin
2 as described previously.35 For the synthesis of N-aliphatic
substituted carbamate derivatives of doramectin 3a−3j, protective
intermediate 2 was first reacted with bis(4-nitrophenyl) carbonate
(NPC) to produce 4-nitrophenyl intermediate, which was further
nucleophilic substituted with different alkylamine, and the t-
butyldimethylsilyl was deprotected using p-toluenesulfonic acid-
methanol complex according to published procedures.35 The
initial attempt to obtain the N-aromatic substituted carbamate
derivatives of doramectin 4a-4k using similar method like 3a−3j
was not so successful because of the low activities of
As shown in Figure 3, compared with doramectin and
avermectins, most of the alkyl carbamate derivatives of
doramectin except 3e and 3f displayed desirable insecticidal

Figure 3 Insecticidal activities of target compounds against oriental armyworm.
(D: Doramectin; A: Avermectins; F: Fenpropathrin; M: Metolcarb)
activities against oriental armyworm, whereas phenyl carbamate
conditions. 3a, 3g and 3h had LC50 (mg/L) values of 23.8730,
5.8859, and 23.1370, respectively, particularly, the LC50 value of
3g was 6.83-fold as that of avermectins (LC50= 40.2389 mg/L).
The insecticidal activities against oriental armyworm of
compound 3g was far superior to that of metolcarb and inferior to
the insecticidal activity of fenpropathrin.
derivatives tended to be less active. The ester and sulfonate
derivatives of doramectin, 5a-5g and 6a-6d, were less active than
the doramectin and avermectins. Among these derivatives, 3a, 3g
and 3h afforded the best insecticidal activities and had 33.33%,
66.67% and 36.67% mortality at 12.5 mg/L, whereas doramectin
and avermectins had only 13.33% and 16.67% under the same

Figure 4 showed that all compounds prepared displayed
different insecticidal activities against diamondback moth. In
general, the insecticidal activities of alkyl carbamate derivatives
(3a-3d and 3g-3j) were much better than that of phenyl
carbamate derivatives (4a-4e, 4g and 4i-4k), which displayed no
insecticidal activities against diamondback moth at 100 mg/L. In
addition, the insecticidal activities of alkyl carbamate derivatives
(3a-3j) showed almost the same level of activity as the ester
derivatives (5a-5g) and sulfonate derivatives (6a-6c) at 100
mg/L. In particular, compounds (3a, 3g, 3h) exhibited good
Figure 4 Insecticidal activities of target compounds against diamondback moth.
(D: Doramectin; A: Avermectins; F: Fenpropathrin; M: Metolcarb)

our insecticidal assays, for which the activity of the carbamate
was better than that of the ester, and the ester was similar to the
sulfonate. Therefore, the binding between the compound 3g and
the target protein was the best one among these compounds in the
docking simulation.
insecticidal activities against diamondback moth with mortality
16.67%, 36.67% and 20.00% at 12.5 mg/L, which was superior
or parallel to that of doramectin (13.33%) and avermectins
(20.00%) under the same concentration. The LC50 values of
compounds 3a, 3g, 3h, doramectin and avermectins against
diamondback moth were 40.2389, 22.3214, 29.9907, 49.7736,
and 42.9922 mg/L, respectively. The compound 3g exhibited
better insecticidal activities than fenpropathrin and metolcarb
against diamondback moth.
3. Conclusions
In summary, 32 doramectin derivatives containing carbamate,
ester, sulfonate groups were synthesized, and their structures
1
were characterized by H NMR, 13C NMR, and high resolution
Since compounds 3a, 3g, and 3h exhibited best insecticidal
activities against oriental armyworm and diamondback moth
among all compounds prepared, the three compounds were
further evaluated for insecticidal efficacy against corn borer in
Table 1. From Table 1, we found that compounds 3a, 3g, and 3h
exhibited better insecticidal activities against corn borer than the
contrast doramectin and avermectins. At the concentration of
12.5 mg/L, compound 3g exhibited high insecticidal activities
against corn borer was 40.00%, while insecticidal activities of
compounds 3a and 3h were equal or superior to the contrast
doramectin (13.33%) and avermectins (10.00%). The LC50 values
in Table 2 showed that the activity of 3g was 3.36-fold as high as
avermectins. The compound 3g also exhibited better insecticidal
activities than fenpropathrin against corn borer.
mass spectrum (HRMS). The insecticidal activities against
oriental armyworm, diamondback moth and corn borer were
evaluated. The results of bioassays indicated that compounds 3a,
3g and 3h exhibited excellent insecticidal activities, especially
the insecticidal activities of compound 3g, which was superior to
the doramectin and commercial avermectins at concentration
12.5 mg/L. Furthermore, the LC50 values of the insecticidal
activities of 3g against oriental armyworm, diamondback moth
and corn borer were 6.83, 1.93, 3.36-fold as high as that of
commercial avermectins, respectively. Molecular docking also
showed that compound 3g could bind well to the target protein
receptor, it may lead to a new insecticide in the future. Future
detailed study of structure activity relationships is in progress at
our group.
2.3. Structure-activity relationship (SAR).
4. Materials and methods
4.1. Instruments
Comparison of the insecticidal activities in Figure 3, Figure
4, and Table 1 showed that substitution patterns of C4" in
doramectin have significant effects on the activity. The
contrasting trends are as follow: (1) the insecticidal activities:
carbamate > ester ≈ sulfonate groups, (2) the activities of short
alkyl groups of compounds were superior to the long alkyl-
substituted compounds, such as, 3a >> 3e, 5a > 5f, 6a > 6d, (3)
aromatic-substituted compounds (4a-4k) exhibited much lower
insecticidal activities than alkyl-substituted compounds (3a-3d,
3g-3j), (4) straight-substituted compound (5b) better than the
branched compound (5c), cyclopropyl-substituted compound (3g)
better than the cyclohexyl-substituted compound (3f), (5) The
insecticidal activity of compound 3g was superior to that of
doramectin and avermectins at the same concentration.
Reaction
progress
was
monitored
by
thin-layer
chromatography (TLC) on silica gel GF254 with ultraviolet (UV)
detection. The melting points were determined on an X-6
precision micro-melting point apparatus (Beijing Fukui
1
Technology Development Co., Ltd) and were uncorrected. H
NMR (400 MHZ) and 13C NMR (100 MHZ) spectra were
obtained using a Bruker 400 spectrometer in CDCl3 solution with
tetramethylsilane as the internal standard. Chemical shifts (δ
values) and coupling constants (J values) were given in parts per
1
million and hertz, respectively. Data for H NMR (400 Hz) were
reported as follows: chemical shift (δ: ppm), multiplicity (s,
singlet; d, doublet; t, triplet; q, quartet; and m, multiplet),
coupling constant (Hz), integration and assignment (H). Data for
13C NMR (100 Hz) were reported in terms of chemical shift (δ:
ppm), with (C) standing for quaternary carbon, (CH) standing for
tertiary carbon, (CH2) standing for secondary carbon, and (CH3)
standing for primary carbon. High resolution mass spectra
（HRMS） data were recorded under on a Micro Q-TOF II mass
spectrometer (the HR-ESI-MS, Bruker, Germany) in the negative
ion detection mode.
2.4. Docking analysis
As described above, 3g was identified as the most promising
pesticide against oriental armyworm, diamondback moth, and
corn borer. To better understand structure-activity relationship of
doramectin derivatives, we carried out a molecular docking study
of three compounds (3g, 5a and 6a) on Plutella xylostella GABA
receptor using Schrodinger-Glide. As shown in Figure 5,
compound 3g, 5a and 6a had a different docking mode.
Considering their molecular structures, the main difference was
in the C4" position, indicating that this position might have a
significant effect on the binding between the ligand and GABA
receptor. To explain this finding, we conducted binding free
energy calculations and compared the binding conformations
among the different compounds. The results (Table 3) revealed
that compound 3g showed the best binding affinity with GABA
receptor. The binding free energy of 3g (-3.964kcal mol-1) was
much lower than that of 5a (-2.467 kcal mol-1) and 6a (-2.791
kcal mol-1). Additionally, the presence of hydrogen bonds might
also explain the structure-activity relationship. The H-bonding
strengths of compounds 3g (1.66 Å, 3.01 Å) was better than that
of 5a (2.06 Å) and 6a (2.14 Å) at C5-OH. Simultaneously,
nitrogen atom on carbamate in compound 3g could form the
N−H···O H-bond (2.12 Å), and no H-bond formed on the ester
group in compound 5a. Although the H-bond (2.49 Å) was
formed on the sulfonate in compound 6a, the binding affinity was
also weaker than that of 3g. The docking results of compounds
3g, 5a, 6a, doramectin and avermectins were in good agreement with
Table 1 Insecticidal activities of target compounds against corn
borer
Compound
200mg/L
86.67%
90.00%
100.00%
90.00%
83.33%
100mg/L
66.67%
80.00%
90.00%
70.00%
50.00%
80%
50mg/L
50.00%
50.00%
70.00%
50.00%
40.00%
50%
25mg/L
36.67%
33.33%
46.67%
33.33%
20.00%
36.67%
0
12.5mg/L
13.33%
20.00%
40.00%
13.33%
10.00%
23.33%
0
Doramectin
3a
3g
3h
Avermectins
Fenpropathrin 100%
Metolcarb 60%
40%
16.67%

Table 2 LC50(mg/L) values of 3a, 3g, 3h, doramectin, and avermectins
Table 3 Glide docking score of 3g, 5a, 6a, doramectin, and
against oriental armyworm, diamondback moth and corn borer
avermectins
Compound
Doramectin
Avermectins
Glide Docking Score (kcal mol-1)
Oriental armyworm
LC50 toxic ratio
Diamondback moth
LC50 toxic ratio
Corn borer
LC50 toxic ratio
-3.866
-3.841
-3.964
-2.467
-2.791
3a
3g
3h
23.8730 1.69
40.2389 1.07
22.3214 1.93
40.9950
22.0205
47.2510
48.6129
73.9508
1.80
3.36
1.57
1.52
1.00
5.8859
6.83
1.74
3g
5a
6a
23.1370
29.9907
49.7736
42.9922
1.43
0.86
1.00
Doramectin 39.6907 1.01
Avermectins 40.2389 1.00
3g
5a
6a
Figure 5 Molecular docking of compounds 3g, 5a, and 6a. The H-bonding distances are shown
as follows: 3g (1.66 Å, 2.12 Å, 3.01 Å); 5a (2.06 Å); 6a (2.14 Å, 2.49 Å)
4.2. General synthesis.
4.2.1.1.
Synthesis
of
2[5-O-(tert-
The general synthetic methods for doramectin derivatives
containing alkyl carbamate (3a-3j), phenyl carbamate (4a-4k),
ester (5a-5g), and sulfonate (6a-6d) groups were shown in
Schemes 1, 2, and 3, and their structures were listed in
Supporting Information. The silica gel chromatography was
performed with a column of 254 mm × 26 mm i.d. (Synthware
glass Co. Ltd., Beijing, China) using 100−140 mesh silica gel
(Sinopharm Chemical reagent Co.Ltd., Shanghai, China).
Aromatic isocyanates were prepared according to the literature
methods.34
butyldimethylsilyl)doramectin].
Imidazole (7.55 g, 111.00 mmol), N, N-dimethypyridin-4-
amine (DMAP, 0.13 g, 1.11 mmol), and tert-butyldimethylsiyl
chloride (TBDMS-Cl, 5.86 g, 38.85 mmol) were added to a
solution of doramectin (10.00 g, 11.12 mmol) in 100 mL of dry
dichloromethane. The mixture was stirred for 10 h at room
temperature and then added water (100 mL) and dichloromethane
(100 mL). The aqueous layer was extracted with dichloromethane
(3 × 50 mL), the combined organic layers were washed with
saturated sodium chloride solution (3 × 50 mL), then dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo
4.2.1. General procedure for the synthesis of alkyl carbamate
derivatives of doramectin (3a-3j) (Scheme 1).35

to give a white solid. The crude product was purified by column
chromatography on a silica gel using mixture of petroleum
10.1 Hz, 1H, H9), 5.80–5.68 (m, 3H, H10, H11, H23), 5.53 (dd, J
= 9.8, 2.5 Hz, 1H, H22), 5.47–5.32 (m, 3H, H3, H19, H1"), 5.04–
4.96 (m, 1H, H15), 4.78 (d, J = 3.8 Hz, 1H, H1'), 4.68 (t, J = 3.3
Hz, 2H, H8a), 4.63 (s, 1H, NHCOO), 4.53 (t, J = 9.4 Hz, 1H,
H4"), 4.29 (d, J = 6.2 Hz, 1H, H5), 4.06 (s, 1H, H7-OH), 3.97 (d,
J = 6.2 Hz, 1H, H6), 3.93 (s, 1H, H13), 3.90–3.73 (m, 3H, H17,
H5', H5"), 3.60 (qd, J = 14.3, 12.0, 4.9 Hz, 2H, H3', H3"), 3.42 (s,
3H, H3'-OMe), 3.37 (s, 3H, H3"-OMe), 3.33–3.19 (m, 3H, H2,
H25, H4'), 2.82 (d, J = 4.7 Hz, 3H, CH3NH), 2.59–2.45 (m, 1H,
H12), 2.27 (ddt, J = 23.7, 13.0, 5.2 Hz, 6H, H5-OH, H16, H24,
H2'a, H2"a), 2.00 (dd, J = 12.2, 4.7 Hz, 1H, H20a), 1.87 (s, 3H,
H4a-CH3), 1.79 (d, J = 7.9 Hz, 3H, H27a, H30a, H31a), 1.73–
1.59 (m, 5H, H18a, H28a, H26, H29), 1.48 (d, J = 6.2 Hz, 4H,
H14a-CH3, H20b), 1.38–1.09 (m, 15H, H2"b, H27b, H28b, H30b,
H31b, H2'b, H5'-Me, H5"-Me, H12a-CH3), 0.92 (d, J = 7.1 Hz,
3H, H24a-CH3), 0.85 (d, J = 12.1 Hz, 1H, H18b). 13C NMR (100
MHz, CDCl3) δ 173.6, 156.5, 139.5, 138.1, 137.9, 136.2, 135.0,
127.7, 124.7, 120.4, 118.2, 118.0, 98.2, 95.7, 94.9, 81.8, 80.5,
80.4(2-C), 79.2, 79.1, 77.2, 75.7, 68.4, 68.3, 68.2, 67.7, 67.2,
66.8, 56.8, 56.5, 45.7, 40.3, 39.7, 38.7, 36.7, 35.0, 34.6, 34.3,
31.4, 30.0, 27.7, 26.9, 26.6, 26.5, 25.5, 20.2, 19.9, 18.3, 17.3,
16.6, 15.1. HRMS (ESI) m/z calcd. for C52H77O15NNa: (M+Na)+,
978.5185; found 978.5231.
ether/ethyl acetate (2:1 by volume) as the eluent to afford 9.12 g
1
(80.9%) of compound 2 as a white foamy solid. H NMR (400
MHz, CDCl3) δ 5.87–5.80 (m, 1H, H9), 5.79–5.66 (m, 3H, H10,
H11, H23), 5.53 (dd, J = 9.9, 2.6 Hz, 1H, H22), 5.41–5.31 (m,
3H, H3, H19, H1"), 5.04–4.97 (m, 1H, H15), 4.78 (dd, J = 4.0,
1.3 Hz, 1H, H1'), 4.68 (dd, J = 14.5, 2.4 Hz, 1H, H8a-a), 4.58 (dd,
J = 14.5, 2.3 Hz, 1H, H8a-b), 4.46–4.39 (m, 1H, H4"), 4.12 (d, J
= 13.1 Hz, 1H, H13), 3.93 (s, 1H, H7-OH), 3.90–3.72 (m, 4H,
H17, H5', H5", H5), 3.61(ddd, J = 11.0, 8.4, 4.6 Hz, 1H, H3'),
3.51–3.44 (m, 1H, H3"), 3.41 (d, J = 2.9 Hz, 6H, H3'-OMe, H3"-
OMe), 3.39 (d, J = 2.4 Hz, 1H, H6), 3.33–3.11 (m, 3H, H2, H25,
H4'), 2,58 (s, 1H, H4"-OH), 2.55–2.47 (m, 1H, H12), 2.37–2.19
(m, 5H, H16, H18a, H2'a, H2"a), 2.04–1.96 (m, 1H, H20a), 1.83–
1.75 (m, 6H, H4a-CH3, H27a, H30a, H31a), 1.73–1.55 (m, 5H,
H24, H28a, H26, H29), 1.52–1.44 (m, 4H, H14a-CH3, H20b),
1.32–1.10 (m, 15H, H2"b, H27b, H28b, H30b, H31b, H2'b, H5'-
Me, H5"-Me, H12a-CH3), 0.98–0.79 (m, 13H, H24a-CH3, H18b,
H-C(CH3)3), 0.13 (s, 6H, H-Si(CH3)2). 13C NMR (100 MHz,
CDCl3) δ 173.9, 140.1, 137.6, 137.5, 136.1, 135.1, 127.7, 124.7,
119.4, 118.2, 117.2, 98.4, 95.7, 94.8, 81.8, 80.4, 80.2, 80.1, 79.3,
78.2, 77.2, 76.1, 69.5, 68.3, 68.2, 68.1, 67.9, 67.2, 56.5, 56.4,
45.7, 40.3, 39.6, 38.7, 36.6, 34.6, 34.4, 34.1, 31.4, 30.0, 27.0,
26.9, 26.6, 26.5, 25.8(3-C), 25.5, 20.3, 20.0, 18.4, 17.6, 16.6,
15.2, -4.5, -4.8.
The target compounds (3b-3j) were synthesized according to a
procedure similar to that used for compound 3a. Their HRMS
data, 1H NMR and 13C NMR date are list in Supporting
Information.
4.2.1.2. Synthesis of [4"-O-(4-nitrophenyl)carbonate-5-O-
(tert-butyldimethylsilyl)doramectin].36
4.2.2. General procedure for the synthesis of phenyl
carbamate derivatives of doramectin (4a-4k) (Scheme 1).35
Bis(4-nitrophenyl) carbonate (NPC, 1.80 g, 5.91 mmol),
DMAP (59.86 mg, 0.49 mmol) were added to a solution of
4.2.2.1. Synthesis of 4-fluorophenyl isocyanate.34
compound
2 (5.00 g, 4.93 mmol) in 50 mL of dry
dichloromethane. The mixture was stirred at room temperature
until TLC indicated the reaction was completed. Water (50 mL)
was added, the aqueous layer was extracted with
dichloromethane (3 × 20 mL), the combined organic layers were
washed with saturated sodium chloride solution (3 × 20 mL),
then dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to give a yellow solid (4.92 g, 84.7%), and
was not purified for use in the next step.
A solution of triphosgene (980.00 mg, 3.30 mmol) in dried
dichloromethane (10 mL) at 0 C was added to a solution of p-
o
fluoroaniline (1.11 g, 10.00 mmol), dichloromethane (75 mL),
and saturated sodium bicarbonate (75 mL). The mixture was
o
stirred at 0 C for 4 h. The aqueous layer was extracted with
dichloromethane (3 × 10 mL), dried over anhydrous magnesium
sulfate, filtered, then add petroleum ether (10 mL), filtered,
concentrated in vacuo to give a white liquid (970.03 mg, 70.7%),
and was not purified for use in the next step.
4.2.1.3. Synthesis of (4"-O-methylcarbonate doramectin)
(3a).35, 37
4.2.2.2. Synthesis of (4"-O-p-fluorophenyl carbamate
doramectin) (4a).35
Methylamine (17.11 mg, 0.55 mmol) and 4"-O-(4-nitrophenyl)
carbonate-5-O-(tert-butyldimethylsilyl) doramectin (500.00 mg,
0.42 mmol) were added in 30 mL of dry dichloromethane. The
mixture was stirred 2 h at room temperature. Water (30 mL) was
added, the aqueous layer was extracted with dichloromethane (3
× 10 mL), the combined organic layers were washed with
saturated sodium chloride solution (3 × 10 mL), then dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo
to give a white solid (310.00 mg, 68.3%). Then, a deprotection
reagent solution of 10 mL of p-toluenesulfonic acid-methanol
complex (0.02 g/mL) was added dropwise to a solution of white
solid (310.00 mg) in methanol (10 mL). The mixture was stirred
1h at room temperature, until TLC indicated the reaction was
completed. Saturated sodium bicarbonate (15 mL) and
dichloromethane (15 mL) were added, the aqueous layer was
extracted with dichloromethane (3 × 10 mL), the combined
organic layers were washed with saturated sodium chloride
solution (3 × 10 mL), then dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to give a white solid.
The crude product was purified by column chromatography on a
silica gel using mixture of petroleum ether/ethyl acetate (2.5:1 by
volume) as the eluent to afford 161.43 mg (58.3%) of compound
P-fluorophenyl isocyanate (134.36 mg, 0.98mmol), compound
2 (500.00 mg, 0.49 mmol), N, N-dimethypyridin-4-amine
(DMAP, 6.02 mg, 0.049 mmol) were added in dried
dichloromethane (15 mL) at room temperature under N2
atmosphere. The mixture was stirred for 6 h. Water (30 mL) was
added, the aqueous layer was extracted with dichloromethane (3
× 10 mL), the combined organic layers were washed with
saturated sodium chloride solution (3 × 10 mL), then dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo
to give a white solid (410.40 mg, 72.8%). Then, a deprotection
reagent solution of 15 mL of p-toluenesulfonic acid-methanol
complex (0.02 g/mL) was added dropwise to a solution of white
solid (410.40 mg) in methanol (10 mL). The mixture was stirred
1 h at room temperature, until TLC indicated the reaction was
completed. Saturated sodium bicarbonate (15 mL) and
dichloromethane (15 mL) were added, the aqueous layer was
extracted with dichloromethane (3 × 10 mL), the combined
organic layers were washed with saturated sodium chloride
solution (3 × 10 mL), then dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to give a white solid.
The crude product was purified by column chromatography on a
silica gel using mixture of petroleum ether/ethyl acetate (2:1 by
1
3a as a white solid. H NMR (400 MHz, CDCl3) δ 5.88 (d, J =

volume) as the eluent to afford 263.92 mg (71.4%) of compound
4a as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J =
8.8, 4.8 Hz, 2H, Ph), 7.00 (t, J = 8.6 Hz, 2H, Ph), 6.59 (s, 1H,
NHCOO), 5.89 (d, J = 10.1 Hz, 1H, H9), 5.84–5.67 (m, 3H,
H10,H11,H23), 5.54 (dd, J = 9.9, 2.5 Hz, 1H, H22), 5.48–5.30
(m, 3H, H3, H19, H1"), 5.01 (d, J = 10.8 Hz, 1H, H15), 4.82–
4.77 (m, 1H, H1'), 4.69 (t, J = 3.4 Hz, 2H, H8a), 4.62 (t, J = 9.4
Hz, 1H, H4"), 4.30 (t, J = 7.2 Hz, 1H, H5), 4.07 (s, 1H, H7-OH),
3.98 (d, J = 6.3 Hz, 1H, H6), 3.95 (s, 1H, H13), 3.92–3.79 (m,
3H, H17, H5', H5"), 3.64 (dt, J = 11.9, 9.2 Hz, 2H, H3', H3"),
3.44 (s, 3H, H3'-OMe), 3.39 (s, 3H, H3"-OMe), 3.35–3.21 (m,
3H, H2, H25, H4'), 2.53 (t, J = 7.4 Hz, 1H, H12), 2.39–2.18 (m,
6H, H5-OH, H16, H24, H2'a, H2"a), 2.05–1.97 (m, 1H, H20a),
1.88 (s, 3H, H4a-CH3), 1.80 (d, J = 9.2 Hz, 3H, H27a, H30a,
H31a), 1.72–1.65 (m, 2H, H18a, H28a), 1.56 (d, J = 3.5 Hz, 3H,
H26, H29), 1.49 (d, J = 6.3 Hz, 4H, H14a-CH3, H20b), 1.38–1.12
(m, 15H, H2"b, H27b, H28b, H30b, H31b, H2'b, H5'-Me, H5"-
Me, H12a-CH3), 0.93 (d, J = 7.1 Hz, 3H, H24a-CH3), 0.86 (d, J =
12.7 Hz, 1H, H18b ). 13C NMR (100 MHz, CDCl3) δ 173.7, 157.6,
152.9, 139.6, 138.1, 137.9, 136.2, 135.0, 133.8, 127.7, 124.7,
120.4, 118.2, 118.0, 115.7(2-CAr), 115.5(2-CAr) , 98.2, 95.7, 94.9,
81.9, 80.5, 80.4(2-C), 79.2, 79.1, 77.2, 75.6, 68.4, 68.3, 68.2,
67.7, 67.1, 66.6, 56.7, 56.5, 45.7, 40.3, 39.7, 38.7, 36.7, 34.9,
34.6, 34.3, 31.4, 30.0, 27.0, 26.6, 26.5, 25.5, 20.2, 19.9, 18.4,
17.4, 16.6, 15.2. HRMS (ESI) m/z calcd. for C57H78O15NFNa:
(M+Na)+, 1058.5248; found 1058.5294.
3.19 (m, 3H, H2, H25, H4'), 2.53 (t, J = 7.8 Hz, 1H, H12), 2.39–
2.17 (m, 6H, H5-OH, H16, H18a, H2'a, H2"a), 2.10 (s, 3H,
CH3CO), 2.00 (dd, J = 12.2, 4.6 Hz, 1H, H20a), 1.88 (s, 3H, H4a-
CH3), 1.80 (d, J = 8.2 Hz, 3H, H27a, H30a, H31a), 1.71–1.62 (m,
3H, H24, H28a, H26), 1.55 (d, J = 3.3 Hz, 3H, H29), 1.49 (d, J =
6.0 Hz, 4H, H14a-CH3, H20b), 1.36–1.08 (m,15H, H2"b, H27b,
H28b, H30b, H31b, H2'b, H5'-Me, H5"-Me, H12a-CH3), 0.93 (d,
J = 7.1 Hz, 3H, H24a-CH3), 0.88–0.81 (m, 1H, H18b). 13C NMR
(100 MHz, CDCl3) δ 173.7, 170.2, 139.5, 138.1, 137.9, 136.2,
135.0, 127.7, 124.7, 120.4, 118.2, 118.0, 98.3, 95.7, 94.8, 81.8,
80.6, 80.4, 79.2, 79.1, 77.2, 76.2, 75.6, 68.4, 68.3, 68.2, 67.7,
67.1, 66.4, 56.8, 56.5, 45.7, 40.3, 39.7, 38.7, 36.7, 35.0, 34.6,
34.3, 31.4, 30.0, 27.0, 26.6, 26.5, 25.5, 21.1, 20.2, 19.9, 18.4,
17.4, 16.6, 15.1. HRMS (ESI) m/z calcd. for C58H81O15NNa:
(M+Na)+, 963.5076; found 963.5115.
The target compounds (5b-5g, 6a-6d) were prepared by
1
following the same procedure as for 5a. Their HRMS data, H
NMR and 13C NMR data are list in Supporting Information.
5. Biological assay
All bioassays were performed on representative test organisms
reared in the laboratory. The bioassays were repeated in triplicate
o
at 25 ± 1 C. The error of the experiments was 5%. Assessments
were made on a dead/alive basis, and mortality rates were
corrected using Abbott’s formula.38 Evaluations were based on a
percentage scale of 0-100, where 0 is no activity, 100 is total kill.
The target compounds (4b-4k) were prepared by following the
1
same procedure as for 4a. Their HRMS data, H NMR and 13
C
5.1. Insecticidal activity against oriental armyworm
(Mythimna sepatara). The insecticidal activities of targets
compounds 3a-3j, 4a-4j, 5a-5g, 6a-6d against oriental
armyworm were evaluated by foliar application using the
reported procedure.39,40 Individual corn leaves were placed on
moistened pieces of filter paper in Petri dishes. The leaves were
then sprayed with the test solution and allowed dry. The dishes
were infested with 10 third-instar oriental armyworm larvae.
Percentage mortalities were evaluated 2 days after treatment.
Each treatment was performed 3 times. For comparative purposes,
doramectin, commercial avermectins, fenpropathrin and
metolcarb were tested under the same condition.
NMR data are list in Supporting Information.
4.2.3. General procedure for the synthesis of ester derivatives
of doramectin (5a-5g) (Scheme 2).35
Synthesis of (4"-O-acetate doramectin) (5a). A solution of
acetyl chloride (116.00 mg, 1.47 mmol) in dried dichloromethane
o
(5 mL) at 0 C was added to a solution of triethylamine (148.74
mg, 1.47 mmol), dichloromethane (15 mL), N, N-
dimethypyridin-4-amine (DMAP, 6.02 mg, 0.049 mmol), and
compound 2 (500.00 mg, 0.49 mmol). The mixture was stirred at
o
0 C for 24 h. Water (30 mL) was added, the aqueous layer was
5.2. Insecticidal activity against diamondback moth (Plutella
xylostella). The insecticidal activities of targets compounds 3a-3j,
4a-4k, 5a-5g, 6a-6d against diamondback moth were evaluated
using the reported procedure.40 Targets compounds were
prepared in acetone at a concentration of 1 mg/mL and added
distilled water containing TW-80 to dilute the different
concentrations. Leaf disks (3 × 3 cm) were cut from fresh
cabbage leaves and then were dipped into the test solution for 10
s. After air drying, the treated leaf disks were placed in a Petri
dish lined with a filter paper, and then, 10 third-instar
diamondback moth larvae were transferred to the Petri dish.
Percentage mortalities were evaluated 2 days after treatment.
Each treatment was performed 3 times. For comparative purposes,
doramectin commercial avermectins, fenpropathrin, and
metolcarb were tested under the same condition.
extracted with dichloromethane (3 × 10 mL), the combined
organic layers were washed with saturated sodium chloride
solution (3 × 10 mL), then dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to give a white solid
(427.17 mg, 82.6%). Then, a deprotection reagent solution of 15
mL of p-toluenesulfonic acid-methanol complex (0.02 g/mL) was
added dropwise to a solution of white solid (427.17 mg) in
methanol (10 mL). The mixture was stirred 1.5 h at room
temperature, until TLC indicated the reaction was completed.
Saturated sodium bicarbonate (15 mL) and dichloromethane (15
mL) were added, the aqueous layer was extracted with
dichloromethane (3 × 10 mL), the combined organic layers were
washed with saturated sodium chloride solution (3 × 10 mL),
then dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to give a white solid. The crude product
was purified by column chromatography on a silica gel using
mixture of petroleum ether/ethyl acetate (3:1 by volume) as the
eluent to afford 294.64 mg (77.3%) of compound 5a as a white
solid. 1H NMR (400 MHz, CDCl3) δ 5.89 (d, J = 10.1 Hz, 1H,
H9), 5.82–5.68 (m, 3H, H10, H11, H23), 5.54 (dd, J = 9.9, 2.5
Hz, 1H, H22), 5.48–5.33 (m, 3H, H3, H19, H1" ), 5.01 (d, J =
10.7 Hz, 1H, H15), 4.79 (d, J = 3.8 Hz, 1H, H1'), 4.74–4.60 (m,
3H, H8a, H4"), 4.30 (t, J = 7.2 Hz, 1H, H5), 4.06 (s, 1H, H7-OH),
3.97 (d, J = 6.2 Hz, 1H, H6), 3.94 (s, 1H, H13), 3.85 (ddt, J = 9.6,
6.4, 3.3 Hz, 3H, H17, H5', H5"), 3.61 (tt, J = 11.1, 5.3 Hz, 2H,
H3', H3"), 3.43 (s, 3H, H3'-OMe ), 3.37 (s, 3H, H3"-OMe), 3.34–
5.3. Insecticidal activity against corn borer (Ostrinia
nubilalis). The insecticidal activities of targets compounds 3a, 3g,
3h against corn borer were evaluated by the leaf-dip method
using the reported procedure.41 Leaf disk (4 × 4 cm) were cut
from fresh corn leaves and dipped into the test solution for 10 s.
After air-drying, the treated leaf disks were placed in a Petri dish,
and then, 10 third-instar corn borers were transferred to the Petri
dish. Percentage mortalities were evaluated 2 days after treatment.
Each treatment was performed 3 times. For comparative purposes,
doramectin, commercial avermectins, fenpropathrin and
metolcarb were tested under the same condition.

17. Eddi, C.; Bianchin, I.; Honer, M. R.; Muniz, R. A.;
Caracostantogolo, J.; Nascimento, Y. A. do, Vet Parasitol, 1993,
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18. Zhao, Q. F.; Yang, G. Q.; Mei, X. D.; Yuan, H. Z.; Ning, J, J.
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233-244.
20. Fitzjohn, S.; Robinson, M. P, WO Patent 1994006783 A1, March
31, 1994.
21. Fry, F. H.; Okarter, N.; Baynton-Smith, C.; Kershaw, M. J.;
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6. Homology modeling and molecular docking
The target sequences of Plutella xylostella Rdl-1(NCBI ID
105389786) subunits was retrieved from the NCBI
database(https://www.ncbi.nlm.nih.gov/gene/105389786). The
sequences were subjected to template search using the BLAST
program of the NCBI (https://www.ncbi.nlm.nih.gov/). Finally,
the crystal structure of Human Glycine Receptor alpha-3 (PDB
ID 5TIN) was chosen as the template to build the 3D structure of
Plutella xylostella GABA receptor. We selected the sequence of
Plutella xylostella Rdl-1 for homology modeling to investigate
the binding mode between compounds and target protein using
Schrodinger-Glide. The crystal structure of Human Glycine
Receptor alpha-3 (PDB ID 5TIN) was derived from the RCSB
Protein Data Bank. The 3D structures of compounds were drawn
by Chem Bio Draw Ultra 12.0 and ChemBio3D Ultra 12.0
software packages (Cambridge Soft, Cambridge, MA, USA). For
Glide docking, the default parameters were used if it was not
mentioned. The best-scoring pose judged by the Glide docking
score was chosen and analyzed using Schrodinger software.
24. Fisher, M. H.; Lusl, A.; Tolman, R. L, Eur Pat Appl, 0008184
1980.
25. Mrozik, H.; Eskola, P.; Fisher, M. H.; Egerton, J. R.; Cifelli, S.;
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Acknowledgements
This work was partly supported by Technology Service
Network Initiative of Chinese Academy of Sciences (No. KFJ-
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Chemistry of Ministry of Education Hainan Normal University,
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O
O
H
O
O
O
N
O
O
O
GABA receptor
H-bond distance
1.66, 2.12, 3.01 Å
C5
Compoun
Oriental armyworm
H-bond
H-bond
Corn bore
Diamondback moth
42.
Highlights
1. 32 doramectin derivatives were synthesized
1
and characterized by H NMR, 13C NMR,
and HRMS.
2. The insecticidal activities, structure-activity
relationship and molecular docking analysis
were discussed.
3. Compound 3g exhibited the most promising
insecticidal activity.
4. Compound 3g has stronger hydrogen-
bonding action and lower binding free
energy.
43.