Design, synthesis and agricultural evaluation of derivatives of N-Acyl-N-(m-fluoro-benzyl)-6-amino-coumarin

Article abstract of DOI:10.1080/14786419.2020.1806268

ABTRACT: This study aims to design and synthesize a series of N-Acyl-N-(m-fluoro- benzyl)-6- amino-coumarins through the principle of active substructure stitching, which are based on the core structure of N-(m-fluoro-benzyl)-6-amino-coumarin. The structures of target compounds e1–e25 have been characterized by ¹H NMR, ¹³C NMR, ESI-MS and elemental analysis. Meanwhile, their agricultural activity have been evaluated in two weeds (Amaranth and Crabgrass) and four widespread noxious pathogens (V.mali, B.cinerea, F.axysporium and C.bacteria). The herbicidal activity results showed that almost all synthetic molecules have a greater impact on the stem system than on the root. Excellent inhibition rates were discovered from compounds e2–e5 and e20–e23 against Amaranth on stems, which were above 58percent(20 mg/L), 68percent(100 mg/L) respectively. Compounds e2 and e21 also exhibited striking inhibition on stems growth of both weeds. Anti-pathogenic activity showed that all the compounds exerted a better inhibitory activity on B.cinerea at 20 ppm compared to control carbendazim. All the heterocyclic substituted compounds (e17–e24, >57percent) made a better influence than the control (54.1percent) at the100 ppm. This research provides promising herbicidal and anti-pathogenic agents that have the better effects and can be potential for further development.

Full text of DOI:10.1080/14786419.2020.1806268

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Design, synthesis and agricultural evaluation of
derivatives of N-Acyl-N-(m-fluoro-benzyl)-6-amino-
coumarin
Yan Jin , Yin-hao Ding , Jing-jing Dong , Yan Wei , Shuang-hong Hao & Bai-
cheng Feng
To cite this article: Yan Jin , Yin-hao Ding , Jing-jing Dong , Yan Wei , Shuang-hong Hao
& Bai-cheng Feng (2020): Design, synthesis and agricultural evaluation of derivatives
of N-Acyl-N-(m-fluoro-benzyl)-6-amino-coumarin, Natural Product Research, DOI:
10.1080/14786419.2020.1806268
To link to this article: https://doi.org/10.1080/14786419.2020.1806268
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2020.1806268
Design, synthesis and agricultural evaluation of
derivatives of N-Acyl-N-(m-fluoro-benzyl)-6-
amino-coumarin
Yan Jina, Yin-hao Dinga, Jing-jing Donga, Yan Weib, Shuang-hong Haob and
Bai-cheng Fenga
aCollege of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China;
bCollege of Chemistry & Pharmacy, Research Center of Agro-bionic Engineering & Technology of
Shandong Province, Qingdao Agricultural University, Qingdao, China
ABTRACT
ARTICLE HISTORY
Received 8 June 2020
Accepted 29 July 2020
This study aims to design and synthesize a series of N-Acyl-N-(m-
fluoro- benzyl)-6- amino-coumarins through the principle of active
substructure stitching, which are based on the core structure of
N-(m-fluoro-benzyl)-6-amino-coumarin. The structures of target
compounds e1–e25 have been characterized by 1H NMR, 13C
NMR, ESI-MS and elemental analysis. Meanwhile, their agricultural
activity have been evaluated in two weeds (Amaranth and
Crabgrass) and four widespread noxious pathogens (V.mali,
B.cinerea, F.axysporium and C.bacteria). The herbicidal activity
results showed that almost all synthetic molecules have a greater
impact on the stem system than on the root. Excellent inhibition
rates were discovered from compounds e2–e5 and e20–e23
against Amaranth on stems, which were above 58%(20 mg/L),
68%(100mg/L) respectively. Compounds e2 and e21 also exhib-
ited striking inhibition on stems growth of both weeds. Anti-
pathogenic activity showed that all the compounds exerted a bet-
ter inhibitory activity on B.cinerea at 20 ppm compared to control
carbendazim. All the heterocyclic substituted compounds
(e17–e24, >57%) made a better influence than the control
(54.1%) at the100ppm. This research provides promising herbici-
dal and anti-pathogenic agents that have the better effects and
can be potential for further development.
KEYWORDS
Coumarin derivatives;
substructure splicing;
herbicidal activity;
antipathogens
activity; synthesis
CONTACT Bai-cheng Feng
fbc515@163.com Shuang-hong Hao doublered@sina.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2020.1806268.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
Y. JIN ET AL.
1. Introduction
Pesticides have been used at industrial-scale agriculture for a long time, which produ-
ces great benefits to agriculture. However, the large-scale use of pesticides on the
environment has caused many negative effects, including possibly the emergence of
pesticide-resistant pest species and easily the residue of pesticides in plants and
groundwater (Andras et al. 2007). For the sake of the sustainable development of the
agriculture, high efficiency, low toxicity, strong selectivity and easy degradation
become the new direction of the pesticide development based on natural products.
Many natural compounds have been reported to have herbicidal and antibacteria
potential (Ncube et al. 2008; Dayan and Duke 2014).
Coumarin, a main secondary metabolite, is widely present in seeds, roots, and
leaves of many plant species (Chon and Kim 2004; Pergo et al. 2008; Nazemi et al.
2015). It is well known as a versatile biodynamic agent for its benzene ring fused to
ꢀ
a-pyrone ring structure, which possess a conjugated system with electron-rich and
good charge-transport properties (Thakor and Savjani 2014; Hussain et al. 2018).
Owing to the various structures of substitutions or pharmacophore in their basic
nuclei, they are significant in showing effective and diverse of biological activity,
including antimicrobial (Khidre et al. 2017), anti-inflammatory (Bansal et al. 2013), anti-
cancer (Weng and Yuan 2017) and antioxidant properties (Al-Majedy et al. 2016).
Among the various coumarins, Some owning substitutes containing element N and
its derivatives have been studied as anticancer, antimicrobial, antifungal, anti-inflam-
matory agent. For instance, C-7-aminocoumarins were effective as inhibitors against
lung cancer cells hCA I and hCA XII (Carta et al. 2012). C-5 -NH2- substituent deriva-
tives were proved to have antimicrobial activities (Zhang et al. 2010). C-6 nitration
ꢀ
substituted ramifications resulted the antifungal activities (de Araujo et al. 2013). C-6
amino substituted derivatives were also the most effective anticoagulation against
MAO-A (Mattsson et al. 2014). Especially, when the coumarin substitute the 6-site of
with CN, CHO, COOH, or NO2 (electron-withdrawing group), the substituted analogues
have been indicated to influence the TNF-ainhibitory effect of the inflammatory factors
(Cheng et al. 2004).
Besides, application of coumarin analogues in agriculture is becoming more and
more concerned, such as insecticidal weeds and other activities (Liu et al. 2016).
Along with coumarins, researches on amide derivatives have been a hot spot in the
development of pesticides for their broad bioactivities, including insecticidal (Wu et al.
2012), herbicidal (Xu et al. 2008) and antifungal (Fu et al. 2010; Kim et al. 2010).
Currently, some commercial pesticidal compounds have acylamino group in the mole-
cules like Fluopyram, Mepronil and Flutolanil (Figure 1), which are having widely used
on a large scale.
In modern drug designing, substructure splicing is routinely used as a common
means. Many experiments showed that certain synergistic drug combinations may pre-
sent a more potential version than a single drug (Liu et al. 2015). In our previous study
(Wang et al. 2015), several 6-amino-coumarin derivatives with amide bond have been
synthesized and showed excellent activity against A. retroflexus. So we believed that
N-aceyl structure can be an essential part of the coumarin applying in the pesti-
cidal activities.

NATURAL PRODUCT RESEARCH
3
Figure 1. The structure of some commercial pesticidal compounds with acylamino group.
Through the principle of substructure splicing, this paper intends to carry out struc-
tural optimization research by stitching together the substituted alkanes and aromatic
heterocycles with the modified coumarin d. To extend our research on developing
novel amide coumarin derivatives as a herbicidal activity, 25 coumarin derivatives e1-
e25 have been synthesized and their pesticidal activity have been evaluated among
two weeds and four widespread noxious pathogens.
2. Results and discussion
2.1. Chemistry
The target intermediate of N-(m-fluoro-benzyl)-6-amino-coumarin d was prepared as
illustrated in Scheme 1. Preparation of 6-nitrocoumarin a was carried out through
nitration reaction of coumarin and guanidine nitrate in presence of concentrated sul-
furic acid as a catalyst. 6-aminocoumarin was obtained by reducing 6-nitrocoumarin a
with 80% hydrazine hydrate, which using anhydrous ferric chloride and activated car-
bon as a catalyst. Schiff base compound c was synthesized by nucleophilic addition,
rearrangement and elimination between 6-aminocoumarin b and m- fluorobenzalde-
hyde, and then N-(m-fluoro-benzyl)-6-amino- coumarin d was obtained by reduction
reaction of schiff base compound c with sodium borohydride. The target compounds
e1-e25 (Scheme 1 and Table 1) were furnished by the acylation of compounds,
respectively, with a series of acyl chlorides catalyzed by triethylamine.
2.2. Assay of herbicidal activity
As revealed from Table 2, comparing with the widely used herbicides and pesticides
acetochlor(EC), most of the synthetic coumarin derivatives strongly affected the stems

4
Y. JIN ET AL.
Table 1. Structures of compound e1–e25.
Base Structure
Compd.
R
Compd.
R
Compd.
R
e1
e2
e3
e4
e7
e5
e8
e6
e9
e10
e13
e11
e14
e12
e15
e16
e17
e18
e19
e22
e20
e23
e21
e24
e25
of Amaranth and Crabgrass, and showed a dose-dependent inhibitory. Almost all the
synthetic molecules strongly affected the stems system more than that of roots. For
the stem of Amaranth, the inhibition of compounds e2-e5 and e20-e23 caused more
than 58%(20 mg/L), 68%(100 mg/L) respectively, and this effect almost increased as
their concentrations increased, all the above compounds showed excellent inhibition
compared with the control EC(54.4%, 65.9%). It can be seen from this that the inhibi-
tory rates of alkyl and heterocyclic substituted coumarin were greater than that of aryl
substituted, which may be related to the electron-withdrawing effects of the hetero-
cycle. Synchronously, these compounds on stems growth of Crabgrass(e2, e4, e5 and
e21) were discovered with excellent herbicidal activity at low and high concentration
above 75.5% and 86.0% inhibition, which were also higher than the control. By com-
parison, most compounds showed no advantage effect beyong the control at high
concentration on Crabgrass. Interestingly, compounds e2 and e21 exhibited striking
inhibition on stems growth of both weeds. In accordance with these compounds on
roots/stems inhibition of both weeds, the preliminary SAR was based on the following:
when the carbon chain was longer, the activity was weaker, such as haloalkyl substi-
tuted e5>e6, e7>e8, and the trend was also observed in heterocyclic substituted cou-
marin e17>e18. When the carbon chain grows, the electron donating effect of the
carbon chain increases, resulting in a decrease in the overall electron cloud density of
the compound, thereby reducing the activity of the compound.
2.3. Assay of anti-pathogenic activity
Similarly to their herbicidal activity, the most of molecules showed certain inhibitory
effects on B.cinerea, V.mali, F.axysporium and C.bacteria at concentration of 20 ppm

NATURAL PRODUCT RESEARCH
5
and 100 ppm. By comparing and analyzing these data, more abundant experimental
data can be obtained, and the credibility of the experiment is also improved. As
shown in Figure 2, all the synthetic molecules exerted a better inhibitory activity on
B.cinerea than the other three pathogens compared to control carbendazim at two
test concentrations. At the same time, according to the test results on the growth of
four kinds of bacteria, most of these 25 compounds have better antibacterial effect at
high concentration than at low concentration. It can be inferred that within a certain
concentration range, the antibacterial effect of these compounds will increase with
the increase of concentration. For the mycelium growth of B.cinerea, all the com-
pounds showed significant activities beyond control at low concentration. More specif-
ically, all the heterocyclic substituted compounds (e17–e24, >57%) made a great
influence than control(54.1%) at the high concentration, which means that the spliced
active substructure has a significant effect on the anti-pathogenic activity of the sub-
stance. The SAR was similar to herbicidal activities, including e5>e6, e7>e8 and
e17>e18, and so is the principle.
2.4. Crystal structure analysis
Further confirmation of the structure was obtained from X-rays single crystal diffrac-
tion, compound e2 crystalline (CCDC 1838932, Figure 3) were grown by sublimation
of the anhydrous powder at 303 K in ethanol/water solution. The crystals were cooled
to 273 K and screened. The selected high-quality single crystal was placed on a Rigaku
Raxis-Rapid X-ray diffractometer for single crystal X-ray diffraction analysis. Diffraction
data were collected using graphite monochromated Mo ka rays (k ¼ 0.71073 Å) as the
diffraction light source. Absorption correction was performed on all the diffraction
data. The crystal structure was solved by the direct method in the SHELXS-97 program,
and the structure was refined by the SHELXS-97 program. The data for this phase
were collected at 273 K.
3. Experimental
All the experimental section is published as online-only supplemental materials in the
single supplementary file.
4. Conclusions
In summary, a series of novel derivatives of N-Acyl-N-(m-fluoro-benzyl)-6-amino-cou-
marin (e1–e25) was synthesized. At the same time, their herbicidal activities
(Crabgrass and Amaranth) and anti-pathogenic activities (B.cinerea, V.mali, F.axysporium
and C.bacteria) were evaluated. Inhibitory analyses indicated that the substitution of
the short carbon chain led to a more dramatical effect than that of long chain(e5>e6,
e7>e8 and e17>e18). In addition, heterocyclic substituted compounds showed excel-
lent inhibitory activity against pathogen B.cinerea at 100 ppm. Particularly, compounds
e2 and e21 may have potential and selective bioactivity on the two weeds and have

6
Y. JIN ET AL.
anti-pathogen (B. cinerea) activity, which were expected to be recognized as the most
promising pesticide agents.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
We gratefully acknowledge financial support of this work by the National Natural Science
Foundation of China [Grant Number 31471808].
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