Design, step-economical diversity-oriented synthesis of an N-heterocyclic library containing a pyrimidine moiety: Discovery of novel potential herbicidal agents

Article abstract of DOI:10.1039/d1ra02663a

The synthesis of highly diverse libraries has become of paramount importance for obtaining novel leads for drug and agrochemical discovery. Herein, the step-economical diversity-oriented synthesis of a library of various pyrimidine-N-heterocycle hybrids was developed, in which a 4,6-dimethoxypyrimidine core was incorporated into nine kinds of N-heterocycles. A total of 34 structurally diverse compounds were synthesized via a two-step process from very simple and commercially available starting materials. Further, in vivo biological screening of this library identified 11 active compounds that exhibited good post-emergence herbicidal activity against D. sanguinalis at 750 g ai per ha. More importantly, pyrimidine-tetrahydrocarbazole hybrid 5q showed good to excellent herbicidal activity against five test weeds at the same dosage. Pyrimidine-tetrahydrocarbazole hybrids represent a novel class of herbicidal agents that may become promising lead compounds in the herbicidal discovery process.

Full text of DOI:10.1039/d1ra02663a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Design, step-economical diversity-oriented
synthesis of an N-heterocyclic library containing
a pyrimidine moiety: discovery of novel potential
herbicidal agents†
Cite this: RSC Adv., 2021, 11, 15380
*
Dong Ma, Yang Yin, Ying-Lu Chen, Yi-Tao Yan
and Jun Wu
The synthesis of highly diverse libraries has become of paramount importance for obtaining novel leads for
drug and agrochemical discovery. Herein, the step-economical diversity-oriented synthesis of a library of
various pyrimidine–N-heterocycle hybrids was developed, in which a 4,6-dimethoxypyrimidine core was
incorporated into nine kinds of N-heterocycles. A total of 34 structurally diverse compounds were
synthesized via a two-step process from very simple and commercially available starting materials.
Further, in vivo biological screening of this library identified 11 active compounds that exhibited good
post-emergence herbicidal activity against D. sanguinalis at 750 g ai per ha. More importantly,
pyrimidine–tetrahydrocarbazole hybrid 5q showed good to excellent herbicidal activity against five test
weeds at the same dosage. Pyrimidine–tetrahydrocarbazole hybrids represent a novel class of herbicidal
agents that may become promising lead compounds in the herbicidal discovery process.
Received 5th April 2021
Accepted 15th April 2021
DOI: 10.1039/d1ra02663a
rsc.li/rsc-advances
herbicide belonging to the pyrimidinyloxybenzylamine class. It
has been developed in China for post-emergence weed control
Introduction
primarily in oilseed rape.14
Pyrimidine as a core structure widely exists in natural products.1
It has shown prominent pharmaceutical and agricultural
activity,2 and acts as anti-cancer,3 anti-HIV,4 and anti-microbial5
agents, insecticides,6 fungicides7 and herbicides.8 4,6-Dimethox-
ypyrimidine is a key structural motif commonly employed in
herbicide molecular design in the quest for novel highly active
herbicides9 (Fig. 1a). Many commercial herbicides contain this
structural unit. For instance, bispyribac-sodium (BS) is an
inhibitor of acetohydroxyacid synthase (AHAS; EC 2.2.1.6), the
rst enzyme involved in the branched-chain amino acid biosyn-
thesis pathway.10 BS is a broad spectrum pyrimidinyl carboxy
herbicide that has been used in the transplanted and direct
seeded rice crops for selective post-emergence control of grasses,
sedges and broad-leaved weeds.10a,11 Bensulfuron-methyl is also
an AHAS-inhibiting herbicide belonging to the sulfonylurea class.
It is a broad spectrum rice herbicide for pre-emergence or early
post-emergence control of most broad-leaved grasses and sedges
in transplanted or direct-seeded paddy rice.12 Another important
herbicide containing 4,6-dimethoxypyrimidine scaffold is
pyrithiobac-sodium, also an AHAS inhibitor, which is used for
post-emergence control of broad-leaved weeds in cotton cultiva-
tion.13 Furthermore, pyribambenz-propyl is also a highly active
In addition to pyrimidine, other N-heterocycles have also
received considerable attention because of their medicinal and
agrochemical importance,15 including pyrazole, benzimidazole,
indole, tetrahydrocarbazole, etc. (Fig. 1b). For example, top-
ramezone, a safe and efficient HPPD-inhibiting herbicide, was
developed by BASF in 2006 for use in corn eld.16 Similarly, 2-
triuoromethylbenzimidazole derivatives also exhibit impor-
tant herbicidal and insecticidal activities, such as chlorurazole
and fenazaor.17 Indole represents one of the most important
heterocyclic ring which provides privileged scaffolds in agro-
chemistry.18 Indole-3-acetic acid (IAA) is an important phyto-
hormone,19 and thaxtomin A shows effective weed control
ability and exerts no toxicity to rice.20 Moreover, tetrahy-
drocarbazole is a well-known privileged scaffold,21 possessing
many different biological functions such as anti-tumor,22
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China. E-mail:
wujunwu@zju.edu.cn; Fax: +86-571-87951895
† Electronic supplementary information (ESI) available: Experimental procedure
and characterization of synthesized compounds (1H and 13C NMR spectra). See
DOI: 10.1039/d1ra02663a
Fig. 1 Biological molecules containing 4,6-dimethoxypyrimidine and
N-heterocycle scaffolds.
15380 | RSC Adv., 2021, 11, 15380–15386
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Scheme 1 Diversity-based library obtained with a two-step diversity-oriented synthetic strategy.
antibiotics23 and anti-virus.24 Tetrahydrocarbazole also shows
In view of the signicance of 4,6-dimethoxypyrimidine
photosynthesis–inhibitory activity and acts as a herbicide pro- moiety and other bioactive N-heterocyclic skeletons, and as
totype.20a,25 In light of the various biological activities of these N- a continuation of our research on bioactive compounds,1a,26a,29
heterocycles, there is a great need to develop an effective herein, we report the design and efficient synthesis of a novel
method to integrate the 4,6-dimethoxypyrimidine moiety with pyrimidine–N-heterocycle hybrid library. 2-Hydroxybenzyl
various N-heterocycles to obtain a new class of potential alcohol was used as the linkage inspired by pharmacophore
herbicidal agents.
structures of the commercial pyrimidine herbicides in Fig. 1a. A
Diversity-oriented synthesis (DOS), which aims to synthesize series of novel hybrids were synthesized by using a two-step
libraries of diverse small molecules in an efficient manner, is process based on substrate-based approach, and their post-
proved to be an efficient tool for the discovery of novel bioactive emergence herbicidal activity was investigated. Preliminary
molecules in pharmaceutical and agrochemical chemistry.26 In biological tests showed that some compounds exhibited good to
DOS pathway, there are two principal methods for generating signicant herbicidal activity. To our knowledge, this diversity-
skeletal diversity, the reagent-based approach and the oriented synthesis of pyrimidine–N-heterocycle hybrids has not
substrate-based approach.27 The reagent-based approach been reported so far.
involves the use of a same starting material and different
reaction conditions. In the substrate-based approach, a diverse
array of substrates is subjected to the same reaction conditions
to obtain diverse molecular skeletons.28 In this work, we used
Results and discussion
Design
the substrate-based approach to create a N-heterocyclic library
A diversity-oriented synthetic strategy for the construction of
with diverse N-heterocyclic building blocks through diversity-
the diversity-based library is illustrated in Scheme 1. 34 N-
oriented synthesis pathway.
heterocyclic compounds containing 4,6-dimethoxypyrimidine
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 15380–15386 | 15381

View Article Online
RSC Advances
Paper
moiety were achieved, which contained nine kinds of N-
heterocyclic skeletons. Each nal product was prepared from
very simple, commercially available 2-hydroxybenzyl alcohol 1
in only two steps. This process involved N- or C-benzylation
Table 2 A two-step reaction sequence for the diversity-oriented-
synthesis of pyrimidine–N-heterocycle hybrids 5a,b,c,d
reactions between 2-hydroxybenzyl alcohol
1
and N-
heterocycles, followed by the base-catalyzed SNAr to give the
nal products. The compound library was made by using this
efficient parallel synthetic techniques, where 28–241 mg of each
nal product were obtained. All library members were puried
to ensure a high purity by thin-layer chromatography, and the
compounds were fully characterized.
Chemistry
We began the investigation with the synthesis of intermediates
3a–3s from 2-hydroxybenzyl alcohol 1. To test our hypothesis,
the known N-benzylation reaction of 2-hydroxybenzyl alcohol 1
with imidazole 2a30 was chosen as a model to optimize the
reaction conditions. As shown in Table 1, when a mixture of 1
and 2a was heated at 130 ꢀC for 30 min under solvent-free
condition, the desired product 3a was obtained in only 40%
yield (Table 1, entry 1). To increase the yield, the reaction
temperature was further investigated. The yield of the product
3a was effectively improved by elevating the temperature (Table
1, entries 2–4 vs. 1), while higher temperatures led to a signi-
cant decrease in yield (Table 1, entry 5). The reaction time was
also surveyed, and 30 min was selected as the best option, giving
3a in 79% yield (Table 1, entries 6–8 vs. 4). In addition, we found
that a slight excess of 2-hydroxybenzyl alcohol 1 was necessary
to increase the yield (Table 1, entry 4 vs. 9). Therefore, the
optimal conditions were observed with heating at 160 ꢀC for
30 min under solvent-free condition using 1.2 equiv. of 2-
hydroxybenzyl alcohol 1. 3a was then obtained in 60% isolated
yield aer recrystallization from an ethanol–DMF solvent
mixture31 (Table 1, entry 4).
Table 1 Optimization of reaction conditions for intermediate 3aa
Entry
Ratiob
T (ꢀC)
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
8
9
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.0
130
140
150
160
170
160
160
160
160
30
30
30
30
30
10
20
40
30
40
55
76
79(60)d
64
66
76
71
75
a
b
Isolated yield. Reaction conditions: 2a–2e, 2h–2n, 2p (10 mmol), 1
c
(12 mmol), no solvent, 160 ꢀC, 30 min. Reaction conditions: 2f–2g,
2o, 2q–2r (3 mmol), 1 (3.6 mmol), no solvent, 160 ꢀC, 30 min.
d
Reaction conditions:
3 (0.6 mmol), 4 (0.72 mmol), caesium
e
carbonate (0.9 mmol), 1,4-dioxane (10 mL), 110 ꢀC, 30 min. Reaction
a
The reactions were carried out with 4 mmol of 2a under solvent-free
conditions: 2s (2 mmol), 1 (4.8 mmol), no solvent, 160 ꢀC, 30 min.
b
c
condition. The ratio of 2a : 1. The yields of 3a were determined by
1H NMR of the reaction mixture aer work-up using 1,3,5-
d
trimethoxybenzene as internal standard. Isolated yield.
15382 | RSC Adv., 2021, 11, 15380–15386
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
With optimized reaction conditions in hand for the under our previously published SNAr conditions,1a afforded the
synthesis of 3a, we set out to explore the substrate scope of DOS desired products 5a–5s in modest to excellent yields (39–98%).
in a two-step protocol (Table 2). In the rst step, we tried to An important advantage of this expeditious method is the
prepare the intermediate products 3 via the N-benzylation ability to construct different pyrimidine–N-heterocycle hybrids
reaction between 2-hydroxybenzyl alcohol 1 and N-heterocycles 5 only by changing the N-heterocycle component in the rst
2. It was found that the majority of N-heterocycles 2 were step, thus emphasizing the diversity-oriented feature of the
compatible with the optimal conditions, affording the desired protocol. For example, by using imidazoles, we obtained
products 3a–3s in useful isolated yields ranging from 19% to pyrimidine–imidazole hybrids 5a, 5b and 5c in 39%, 43% and
77%. Both electron-donating (CH3) and electron-withdrawing 56% yields, respectively. The pyrimidine–pyrazole hybrid 5d
(Cl, CF3) substituents on the N-heterocycles were tolerated and pyrimidine–1,2,3-triazole hybrid 5e were readily synthe-
under the same conditions. It was noteworthy to point out that sized in 87% and 89% yields. With different N-fused heterocy-
2.4 equiv. of 2-hydroxybenzyl alcohol 1 was required for carba- cles as substrates, a variety of pyrimidine–indoline hybrids 5f–
zole 2s to reach the molten state.
5g, pyrimidine–benzimidazole hybrids 5h–5l, pyrimidine–
Subsequently, we proceeded to evaluate the next trans- indazoles 5m–5o, and pyrimidine–benzotriazole 5p could be
formation. As shown in Table 2, the reaction of the intermediate smoothly prepared. Similarly, it was found that pyrimidine–
products 3 with 4,6-dimethoxy-2-(methylsulfonyl) pyrimidine 4 carbazole hybrids 5q–5s were produced from corresponding
Table 3 Diversity-oriented synthesis of pyrimidine–indole hybrids 8 and 9a,b
a
Reaction conditions: (i) 6 (3 mmol), 1 (3.6 mmol), no solvent, 160 ꢀC, 30 min; (ii) 7 (0.6 mmol), 4 (0.72 mmol), caesium carbonate (0.9 mmol), 1,4-
dioxane (10 mL), 110 ꢀC, 30 min. b Isolated yield.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 15380–15386 | 15383

View Article Online
RSC Advances
Paper
Table 4 Herbicidal activity of 11 active compoundsa
chlorine group on indole ring which hindered the formation
of the di-substituted product. Collectively, we conrmed that
our DOS strategy was suitable for the synthesis of pyrimidine–
indole hybrids, which could be used to populate the areas of
new chemical space.
Post-emergence, 750 g ai per ha
Compound
AT
EC
AR
DS
CT
5a
5e
5j
5n
5o
5q
8e
8h
8i
À
+
À
À
À
À
À
+++
À
+
+
+++
+++
+++
+++
+++
+++
+++
+++
+++
+++
+++
+
+
+
+
+
++++
+
À
Biological assessment
À
+
À
À
+
The post-emergence herbicidal activity of 34 title compounds
was evaluated against several representative weeds at 750 g ai
per ha under greenhouse conditions (see ESI Tables S2 and S3†
for the full data set). On the basis of the preliminary bioassays,
a selection of 11 active compounds was presented in Table 4.
The herbicidal activity evaluation indicated that the active
compounds showed good to excellent herbicidal activity against
the test weeds. When the N-heterocycles were imidazole (5a),
triazole (5e), benzimidazole (5j), indazoles (5n and 5o) and
indoles (8e, 8i, 8k and 9i), compounds exhibited $60% inhi-
bition against the tested monocotyledonous weeds such as
Digitaria sanguinalis at the rate of 750 g ai per ha. It conrms
that N-heterocyclic types, do have an effect on herbicidal
activity. Among them, imidazole, triazole, benzimidazole,
indazole and indole are the preferred N-heterocycles for main-
taining herbicidal activity. The further understanding requires
the study of the interaction between these active molecules and
their possible target. Compound 8h with 4-chloroindole skel-
eton displayed over 60% control efficiency against the tested
dicotyledonous weeds (Abutilon theophrasti and Amaranthus
retroexus) and the tested monocotyledonous weeds (Digitaria
sanguinalis) as well. Compared with other herbicidal indoles 8e,
8i and 8k, 8h exhibited better herbicidal activity than they did. It
suggests that C-3 benzylation of indole and chloro atom at 4-
position on indole ring may be important factors for keeping
herbicidal activity. The structure–activity relationships deserve
further investigation. Very promisingly, compound 5q with
tetrahydrocarbazole skeleton displayed over 60% inhibition
against all tested weeds, and its inhibition rates against Abutilon
theophrasti and Cassia tora were even over 80%. 5q showed
higher herbicidal activity against dicotyledonous plants than
monocotyledons for post-emergence application. Obviously, the
tetrahydrocarbazole skeleton makes a critical contribution to
the herbicidal activity. A possible explanation for the high
herbicidal activity of compound 5q is that the presence of
methylene groups at the tetrahydrocarbazole skeleton increases
the compound's lipophilicity and facilitates their uptake by
plants.25 In generally, the above results enable these active
compounds to be of much potential for the optimization.
Among them, compound 5q with high and broad spectrum
herbicidal activity is the most promising candidate for the
further development of new herbicides.
À
++++
+
+++
À
+++
À
À
+
+++
+
+
+
À
À
+
À
À
À
8k
9i
+
a
AT for Abutilon theophrasti; EC for Echinochloa crusgalli; AR for
Amaranthus retroexus; DS for Digitaria sanguinalis; CT for Cassia tora.
Rating system for the growth inhibition percentage: ++++, $80%; +++,
60–79%; ++, 50–59%; +, 30–49%; À, <30%.
carbazole derivatives. The successful construction of this DOS
library further demonstrates the effectiveness and practicality
of this new methodology.
Indoles are oen found in natural products and synthetic
compounds that exhibit a wide range of biological activity.
Therefore, the divergent generation of indole derivatives with
privileged heterocyclic structures is highly desirable and
possesses great challenges. So we next expanded the scope of
our DOS strategy towards the divergent synthesis of indole
derivatives via N-benzylation, C-2 benzylation and C-3 benzyla-
tion at various points of indole ring, using the same two-step
conditions shown as above (Table 3). We rst designed and
synthesized compound 8a via N-benzylation as a key step. 2,3-
Dimethylindole 6a reacted with 2-hydroxybenzyl alcohol 1
under solvent-free condition to afford the intermediate 7a and
then, reacted with 4 to generate the desired product 8a in 72%
yield. Next, we employed C-2 reactive site of 3-methylindole 6b
for the synthesis of 8b. In this case, the 2-position of indole was
unoccupied, so the C-benzylation of 6b with 1 proceeded at the
2-position forming a C–C bond. Then, the SNAr reaction of 7b
with 4 produced 8b in 60% yield. Finally, we used C-3 reactive
site of indoles 6c–6k for the synthesis of 8c–8k and 9g–9j. When
the 3-position of indole was unoccupied, the C-benzylation of
indole occurred rst at 3-position to generate intermediates 7c–
7k and the mechanism of the regioselectivity has been
explained in a previous report.32 For intermediates 7c–7f, the
SNAr reactions worked efficiently and afforded the desired
products 8c–8f in good yields ranging from 65 to 99%. However,
when the methyl or chlorine groups were attached to C-4, 5 and
6 positions, the SNAr reaction gave the mixtures of the mono-
substituted pyrimidine compounds 8g–8j and the di-
substituted pyrimidine compounds 9g–9j, while the yields of
mono-substituted products were signicantly higher than di-
substituted products under the standard conditions. It is
worth noting that when the C-7 position of indole contained
a chlorine group, only mono-substituted pyrimidine product 8k
was obtained. It is probably due to the steric effect of C-7
Conclusions
In conclusion, this study has achieved the step-economical
diversity-oriented synthesis of 34 novel target compounds 5, 8
and 9 via a two-step process. These target compounds formed
a pyrimidine–N-heterocycle hybrid library with prominent
15384 | RSC Adv., 2021, 11, 15380–15386
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
features of high structural diversity. More importantly, these
novel hybrids have been subjected to the test of in vivo herbi-
cidal activity, resulting in the nding that 11 active compounds
exhibited good to excellent post-emergence herbicidal activity at
750 g ai per ha. Among them, 5q, a novel pyrimidine–tetrahy-
drocarbazole hybrid showed high and broad spectrum herbi-
cidal activity against ve test weeds, especially for effective
control of Abutilon theophrasti and Cassia tora. 5q may become
a novel lead compound for the further development of new
herbicides. To further investigate the mechanism of these active
compounds, enzymatic kinetics and molecular-modelling
experiments are currently underway in our laboratory.
7 (a) S. J. Ryan and Q. Yang, Org. Process Res. Dev., 2019, 23,
2157–2165; (b) L. L. Wang, S. S. Zhao, X. T. Kong, L. L. Cao,
S. Tian, Y. H. Ye and C. H. Qiao, Bioorgan. Med. Chem.,
2018, 26, 875–883.
8 (a) K. J. Li, R. Y. Qu, Y. C. Liu, J. F. Yang, P. Devendar,
Q. Chen, C. W. Niu, Z. Xi and G. F. Yang, J. Agric. Food
Chem., 2018, 66, 3773–3782; (b) L. Xiang, L. Zhang, Q. Wu,
Z. Xu, J. Li, X. Du and Z. Qin, Pest Manage. Sci., 2020, 76,
2058–2067.
9 (a) H. Y. Wang, X. Zhang, Y. L. Guo, Q. H. Tang and L. Lu, J.
Am. Soc. Mass Spectrom., 2006, 17, 253–263; (b) L. Lu, Q. Lu,
Q. Tang, M. Dai and Q. Fu, CN 101367798B, 2009.
10 (a) H. Wang, Z. Guo, W. Shen and Y. Lou, Pestic. Biochem.
Physiol., 2019, 153, 28–35; (b) T. Lonhienne, M. D. Garcia,
G. Pierens, M. Mobli, A. Nouwens and L. W. Guddat, Proc.
Natl. Acad. Sci. U. S. A., 2018, 115, E1945–E1954; (c)
M. D. Garcia, A. Nouwens, T. G. Lonhienne and
L. W. Guddat, Proc. Natl. Acad. Sci. U. S. A., 2017, 114,
E1091–E1100.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
´
´
´
˜
´
11 (a) S. Gomez, D. Fernandez, D. Pena, A. Albarran and
This work was nancially supported by the National Natural
Science Foundation of China (No. 31471807).
´
˜
A. Lopez-Pineiro, Soil Tillage Res., 2019, 194, 104333; (b)
F. Ahmad, N. Ashraf, R. B. Zhou and Y. Da-Chuan, J.
Environ. Manage., 2019, 244, 383–390; (c) D. Pradhan,
R. K. Singh and S. K. Verma, Bull. Environ. Contam.
Toxicol., 2020, 105, 715–720.
Notes and references
1 (a) J.-P. Meng, W.-W. Wang, Y.-L. Chen, S. Bera and J. Wu, 12 (a) M. D. Osuna, F. Vidotto, A. J. Fischer, D. E. Bayer, R. De
Org. Chem. Front., 2020, 7, 267–272; (b) I. M. Lagoja, Chem.
Biodiversity, 2005, 2, 1–50.
2 (a) Z. Z. Yan, A. P. Liu, Y. C. Ou, J. M. Li, H. B. Yi, N. Zhang,
M. H. Liu, L. Huang, J. W. Ren, W. D. Liu and A. X. Hu,
Bioorgan. Med. Chem., 2019, 27, 3218–3228; (b)
H. u. Rashid, M. A. U. Martines, A. P. Duarte, J. Jorge,
Prado and A. Ferrero, Pestic. Biochem. Physiol., 2002, 73, 9–
17; (b) F. P. Zhu, J. L. Duan, X. Z. Yuan, X. S. Shi, Z. L. Han
and S. G. Wang, Chemosphere, 2018, 199, 138–146; (c)
F. Ding, W. Liu, Y. Li, L. Zhang and Y. Sun, J. Lumin., 2010,
130, 2013–2021; (d) F. Deng and K. K. Hatzios, Pestic.
Biochem. Physiol., 2002, 74, 102–115.
S. Rasool, R. Muhammad, N. Ahmad and M. N. Umar, RSC 13 (a) A. K. Sharma, L. Wen, L. R. Hall, J. G. Allan and B. J. Clark,
Adv., 2021, 11, 6060–6098; (c) M. Monier, D. Abdel-Latif,
A. El-Mekabaty and K. M. Elattar, RSC Adv., 2019, 9, 30835–
30867.
3 (a) R. Kaur, P. Kaur, S. Sharma, G. Singh, S. Mehndiratta,
P. M. S. Bedi and K. Nepali, Recent Pat. Anti-Cancer Drug
Discovery, 2015, 10, 23–71; (b) M. Rashid, A. Husain,
M. Shaharyar, R. Mishra, A. Hussain and O. Afzal, Eur. J.
Med. Chem., 2014, 83, 630–645.
4 (a) P. Herdewijn, J. Balzarini, M. Baba, R. Pauwels,
A. Vanaerschot, G. Janssen and E. Declercq, J. Med. Chem.,
1988, 31, 2040–2048; (b) X. Y. Lu, J. P. Yang, D. W. Kang,
P. Gao, D. Daelemans, E. De Clercq, C. Pannecouque,
P. Zhan and X. Y. Liu, Bioorgan. Med. Chem., 2018, 26,
2051–2060.
5 (a) B. Veeraswamy, D. Madhu, G. J. Dev, Y. Poornachandra,
G. S. Kumar, C. G. Kumar and B. Narsaiah, Bioorg. Med.
Chem. Lett., 2018, 28, 1670–1675; (b) U. Sankappa Rai,
J. Agric. Food Chem., 2016, 64, 5793–5802; (b) C. J. Matocha
and L. R. Hossner, J. Agric. Food Chem., 1999, 47, 1755–1759.
14 (a) L. Yue, W. Qi, Q. Ye, H. Wang, W. Wang and A. Han,
Pestic. Biochem. Physiol., 2012, 104, 44–49; (b) L. Xu,
J. Y. Shou, R. A. Gill, X. Guo, U. Najeeb and W. J. Zhou, J.
Zhejiang Univ., Sci., B, 2019, 20, 71–83; (c) J. Wu, J. Cheng
and L. Lu, J. Agric. Food Chem., 2006, 54, 5954–5957.
15 (a) X. H. Liu, X. Y. Xu, C. X. Tan, J. Q. Weng, J. H. Xin and
J. Chen, Pest Manage. Sci., 2015, 71, 292–301; (b) K. Boujdi,
´
N. El Brahmi, J. Graton, D. Dubreuil, S. Collet, M. Mathe-
Allainmat, M. Akssira, J. Lebreton and S. El Kazzouli, RSC
Adv., 2021, 11, 7107–7114; (c) W. Yang, Y. Zhao, Z. Zhou,
L. Li, L. Cui and H. Luo, RSC Adv., 2021, 11, 8701–8707.
16 (a) B. He, D. Wang, W. Yang, Q. Chen and G. Yang, Chin. J.
Org. Chem., 2017, 37, 2895–2904; (b) Y. Fu, K. H. Yi,
M. Q. Li, M. X. Wang, Y. W. Hou and F. Ye, Chin. J. Struct.
Chem., 2018, 37, 1550–1556.
A. M. Isloor, P. shetty, A. M. Vijesh, N. Prabhu, S. Isloor, 17 (a) D. T. Saggers, D. E. Burton, J. C. L. Ludgate, A. J. Lambie,
M. Thiageeswaran and H. K. Fun, Eur. J. Med. Chem., 2010,
45, 2695–2699.
6 (a) X. H. Liu, Q. Wang, Z. H. Sun, D. E. Wedge, J. J. Becnel,
G. T. Newbold and A. Percival, Nature, 1965, 208, 1166–1169;
(b) D. W. Bowker and J. E. Casida, J. Agric. Food Chem., 1969,
17, 956–966.
A. S. Estep, C. X. Tan and J. Q. Weng, Pest Manage. Sci., 18 H. Peng, K. Jiang, G. Zhen, F. Wang and B. Yin, RSC Adv.,
2017, 73, 953–959; (b) Y. Xu, J.-C. Yang, L.-H. Ren,
S.-L. Hao and C.-L. Liu, Agrochemicals, 2011, 50, 474–478.
2020, 10, 11750–11754.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 15380–15386 | 15385

View Article Online
RSC Advances
Paper
19 (a) D. Duca, J. Lorv, C. L. Patten, D. Rose and B. R. Glick,
Antonie van Leeuwenhoek, 2014, 106, 85–125; (b) Y. Zhao,
Mol. Plant, 2012, 5, 334–338.
Q. Zhang, M. Gartland, L. Walton, C. Talarico,
W. Lawrence, D. Selleseth, N. Coffield, J. Leary, K. Moniri,
S. Singer, J. Strum, K. Gudmundsson, K. Biron,
K. R. Romines and P. Sethna, Antivir. Res., 2009, 82, 1–11.
20 (a) J. M. de Souza, B. R. Fazolo, J. W. F. Lacerda, M. S. Moura,
A. C. R. Dos Santos, L. G. de Vasconcelos, P. T. de Sousa 25 M. Mendes, B. R. Fazolo, J. M. de Souza, L. G. de
Junior, E. L. Dall'Oglio, A. Ali, O. M. Sampaio and
L. C. C. Vieira, Photochem. Photobiol., 2020, 96, 1233–1242;
(b) H. Zhang, Q. Wang, X. Ning, H. Hang, J. Ma, X. Yang,
Vasconcelos, P. T. de Sousa Junior, E. L. Dall'Oglio,
M. A. Soares, O. M. Sampaio and L. C. C. Vieira,
Photochem. Photobiol. Sci., 2019, 18, 1350–1358.
X. Lu, J. Zhang, Y. Li, C. Niu, H. Song, X. Wang and 26 (a) X. He, X. Chen, S. Lin, X. Mo, P. Zhou, Z. Zhang, Y. Lu,
P. G. Wang, J. Agric. Food Chem., 2015, 63, 3734–3741; (c)
R. R. King, C. H. Lawrence and J. A. Gray, J. Agric. Food
Chem., 2001, 49, 2298–2301.
Y. Yang, H. Gu, Z. Shang, Y. Lou and J. Wu,
ChemistryOpen, 2017, 6, 102–111; (b) D. Brossard,
P. Retailleau, V. Dumontet, P. Breton, S. Desrat and
F. Roussi, Org. Biomol. Chem., 2017, 15, 5585–5592.
21 (a) L. Su, J. Li, Z. Zhou, D. Huang, Y. Zhang, H. Pei, W. Guo,
H. Wu, X. Wang, M. Liu, C. G. Yang and Y. Chen, Eur. J. Med. 27 W. R. J. D. Galloway, A. Isidro-Llobet and D. R. Spring, Nat.
Chem., 2019, 162, 203–211; (b) W. Peng, Q. Liu, F. Yin, C. Shi, Commun., 2010, 1, 80.
L. Ji, L. Qu, C. Wang, H. Luo, L. Kong and X. Wang, RSC Adv., 28 L. Laraia, L. Robke and H. Waldmann, Chem, 2018, 4, 705–
2021, 11, 8356–8361. 730.
22 (a) H. B. El-Nassan, J. Enzyme Inhib. Med. Chem., 2015, 30, 29 (a) W. Wang, P. Zhou, X. Mo, L. Hu, N. Jin, X. Chen, Z. Yu,
308–315; (b) J. Chen, J. S. Lou, T. Liu, R. Wu, X. W. Dong,
Q. J. He, B. Yang and Y. Z. Hu, Arch. Pharm. Chem. Life Sci.,
2009, 342, 165–172; (c) M. R. Kulkarni, M. S. Mane,
U. Ghosh, R. Sharma, N. P. Lad, A. Srivastava, A. Kulkarni-
Almeida, P. S. Kharkar, V. M. Khedkar and S. S. Pandit,
Eur. J. Med. Chem., 2017, 134, 366–378.
J. Meng, M. Erb, Z. Shang, A. M. R. Gatehouse, J. Wu and
Y. Lou, Proc. Natl. Acad. Sci. U. S. A., 2020, 117, 12017–
12028; (b) S.-B. Lin, W.-W. Wang, J.-P. Meng, X.-W. Li,
J. Wu and X.-L. Sun, Tetrahedron Lett., 2019, 60, 151309; (c)
S. Lin, X. He, J. Meng, H. Gu, P. Zhang and J. Wu, Eur. J.
Org. Chem., 2017, 2017, 443–447.
23 (a) Z. Yin, L. R. Whittell, Y. Wang, S. Jergic, M. Liu, 30 (a) V. A. Osyanin, P. P. Purygin and Z. P. Belousova,
E. J. Harry, N. E. Dixon, J. L. Beck, M. J. Kelso and
A. J. Oakley, J. Med. Chem., 2014, 57, 2799–2806; (b) Z. Yin,
L. R. Whittell, Y. Wang, S. Jergic, C. Ma, P. J. Lewis,
Cheminform, 2004, 35, DOI: 10.1002/chin.200417109; (b)
N. E. Sidorina and V. A. Osyanin, Chem. Heterocycl.
Compd., 2007, 43, 1065–1071.
N. E. Dixon, J. L. Beck, M. J. Kelso and A. J. Oakley, J. Med. 31 V. A. Osyanin, E. S. Selezneva, Z. P. Belousova, L. F. Zarina,
Chem., 2015, 58, 4693–4702.
24 (a) K. S. Gudmundsson, P. R. Sebahar, L. D. Richardson,
N. E. Krel and P. P. Purygin, Pharm. Chem. J., 2003, 37,
482–484.
J. G. Catalano, S. D. Boggs, A. Spaltenstein, P. B. Sethna, 32 V. A. Osyanin, N. E. Sidorina and Y. N. Klimochkin, Russ. J.
K. W. Brown, R. Harvey and K. R. Romines, Bioorg. Med.
Chem. Lett., 2009, 19, 3489–3492; (b) R. Harvey, K. Brown,
Gen. Chem., 2011, 81, 115–121.
15386 | RSC Adv., 2021, 11, 15380–15386
© 2021 The Author(s). Published by the Royal Society of Chemistry