New angular oxazole-fused coumarin derivatives: synthesis and biological activities

Article abstract of DOI:10.1080/14786419.2017.1405408

Twelve angular oxazole-fused coumarin derivatives were designed, synthesised and characterised by ¹H NMR, ¹³C NMR and HRMS. The structure of compound 4a was further confirmed by X-ray single-crystal diffraction. The bioassay experiment results indicated that compounds 4f and 4l have high antifungal activity on the mycelium growth of 4 plant disease fungi. Especially, compound 4l has a stronger antifungal activity compare to the commercial fungicide, Carbendazim. The herbicidal activity experiment showed that 4a and 4b can significantly inhibit the taproot and caulis development of Chenopodium album seedling and have better activities than the commercial herbicide, Acetochlor.

Full text of DOI:10.1080/14786419.2017.1405408

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
New angular oxazole-fused coumarin derivatives:
synthesis and biological activities
Yan Wei, Shi-qiang Li & Shuang-hong Hao
To cite this article: Yan Wei, Shi-qiang Li & Shuang-hong Hao (2017): New angular oxazole-
fused coumarin derivatives: synthesis and biological activities, Natural Product Research, DOI:
10.1080/14786419.2017.1405408
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Date: 30 November 2017, At: 22:47

Natural Product research, 2017
https://doi.org/10.1080/14786419.2017.1405408
New angular oxazole-fused coumarin derivatives: synthesis
and biological activities
Yan Wei, Shi-qiang Li and Shuang-hong Hao
research center of agro-Bionic engineering & technology of shandong Province, college of chemistry &
Pharm., Qingdao agricultural university, Qingdao, china
ABSTRACT
ARTICLE HISTORY
received 18 august 2017
accepted 3 November 2017
Twelve angular oxazole-fused coumarin derivatives were designed,
1
synthesised and characterised by H NMR, 13C NMR and HRMS. The
structure of compound 4a was further confirmed by X-ray single-
crystal diffraction. The bioassay experiment results indicated that
compounds 4f and 4l have high antifungal activity on the mycelium
growth of 4 plant disease fungi. Especially, compound 4l has a
stronger antifungal activity compare to the commercial fungicide,
Carbendazim. The herbicidal activity experiment showed that 4a
and 4b can significantly inhibit the taproot and caulis development
of Chenopodium album seedling and have better activities than the
commercial herbicide, Acetochlor.
KEYWORDS
angular oxazole-fused
coumarin; synthesis;
antifungal activity; herbicidal
activity
1. Introduction
Furanocoumarins constitute a subfamily of coumarin compounds that widely exist in a num-
ber of plant families, e.g. Rutaceae and Umbelliferae. Angular furanocoumarins are one
important category of furanocoumarins with versatile pharmacological effects of antitumor
and antioxidant (Zhou et al. 2011; Shokoohinia et al. 2014), antipsoriatic (Morison 1999),
anti-HIV (Shikishima et al. 2001), antiplatelet (Xiao et al. 2007), antimycobacterial (Guo et al.
2014), as well as agronomical activities of antiphytopathogen, insecticide and allelopathy
(Shimomura et al. 1982; Boulogne et al. 2012; Caboni et al. 2014; Villegas et al. 2015). These
chemicals produced by plant may act as allelopathic defence compounds, i.e. phytoalexins
CONTACT shuang-hong hao
doublered74@sina.com
supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2017.1405408.
© 2017 Informa uK limited, trading as taylor & Francis Group

2
Y. WEI ET AL.
(Shimomura et al. 1982; Desjardins et al. 1989; Sardari et al. 1999; Khatune et al. 2004; Song
et al. 2017).
The benzoxazole scaffold is a core structure which exists in a wide class of natural and
synthetic compounds (Tugba et al. 2016; Belal and Khan 2016). Benzoxazole ring is one of
the most common heterocycles in medicinal chemistry and plays an important role in drug
design (Reddy et al. 2015). In fact, substituted benzoxazoles are associated with diverse
pharmacological activities, viz. antitumor (Sommer et al. 2008), COX-2 inhibition (Srinivas
et al. 2010), antifungal (Jyothi and Ramchander 2013), antibacterial (Balaswamy et al. 2012;
Seenaiah et al. 2017) and anticancer (Kamal et al. 2010), as well as pesticidal activities of
insecticide (Guan et al. 2013;Yang et al. 2015) and herbicide (Youssef et al. 2010; Imramovsky
et al. 2014). The potential bioactivities of these heterocyclic compounds inspire us to design
and synthesise a serial of fused oxazole-containing coumarin derivatives. And the antifungal
and herbicidal activities of these new compounds were tested.
2. Results and discussion
2.1. Synthesis of angular oxazole-fused coumarin derivatives
The synthetic route of title compounds is depicted in Scheme 1. Compound 1 was prepared
by Pechmann reaction from resorcinol and ethyl acetoacetate in the presence of H2SO4.
Compound 2 was obtained by nitration of compound 1 with Conc. HNO3-Conc. H2SO4.
Compound 3 was synthesised by reduction of compound 2 with Na2S. The title compounds
4a–l were prepared by cyclisation of compound 3 with a series of acids catalysed by PPA.
The structures of all target compounds were well characterised by 1H NMR, 13C NMR, HRMS
and mp. Additionally, to confirm the three-dimensional structural information of 4a–l, the
single-crystal structure of 4a was determined by X-ray crystallography as illustrated in
Figure 1. Crystallographic data (excluding structure factors) for the structure of 4a have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
CCDC 1558080.
Scheme 1. synthetic route of target compounds.

NATURAL PRODUCT RESEARCH
3
Figure 1. Molecular structure of compound 4a.
2.2. Antifungal activities
The in vitro antifungal activities were evaluated against Botrytis cinerea, Colletotrichum gloe-
osporioides, Alternaria brassicae and Gaeumannomyces gramini. The results of antifungal
screening test of these new compounds are given in Table 1. As shown, all the synthesised
title compounds exhibited certain inhibition against at least one phytopathogen, especially,
compounds 4f and 4l showed excellent antifungal activities. The EC50 of compound 4f
against the 4 tested phytopathogens are all less than 28 mg·L−1. The EC50 of compound 4l
against B. cinerea, A. brassicae and G. gramini are near or less than 15 mg·L−1. Compound 4l
showed the highest antifungal activity against A. brassicae with EC50 of 0.27 mg·L−1, which
are more active than the commercial fungicide Carbendazim. Furthermore, compounds 4k
and 4i also exhibited good antifungal activity with EC50 of 11.72 mg·L−1 and 16.83 mg·L−1
against C. gloeosporioides and G. gramini, respectively.
For the 2-alkyl substituted compounds 4a–4d, the bulky groups would be unfavourable
for the antifungal activity against C. gloeosporioides but be favourable for the activity against
G. gramini. On the contrary, 2-cyclohexyl substituted compound 4f exhibited much higher
activity than 2-cyclopropyl substituted compound 4e to the test fungus. 2-thienyl-2 substi-
tuted compound 4l showed the highest activity against B. cinerea, A. brassicae and G. gramini.
For the 2-phenyl substituted compounds 4h–4k, electron-withdrawing groups on the ben-
zene ring would increase the activity to C. gloeosporioides and G. gramini but decrease the
activity to B. cinerea and A. brassicae.

4
Y. WEI ET AL.
Table 1. antifungal activity of the title compounds.
EC50/mg·L−1
C. gloeosporioides
Compd.
B. cinerea
A. brassicae
G. gramini
4a
74.8 6.7
141.5 11.8
134.7 12.5
–
76.6 5.3
21.3 1.9
56.6 3.3
40.3 2.8
190.3 16.6
86.4 5.9
102.1 8.1
15.2 1.3
26.8 2.7
45.8 1.2
47.8 7.6
97.7 6.8
–
76.1 4.6
27.9 1.7
–
127.2 9.9
43.6 3.1
78.1 6.4
11.7 7.1
70.8 5.4
1.3 0.1
110.3 8.8
94.4 7.3
223.5 18.7
–
218.5 16.3
26.3 1.9
52.6 4.3
53.2 5.0
96.3 7.2
53.2 4.4
109.0 8.3
0.3 0.0
75.3 5.7
59.7 4.3
70.6 5.3
35.4 2.9
54.0 3.8
25.0 1.4
37.0 2.6
128.4 7.9
16.8 1.3
39.4 4.7
37.4 2.7
14.2 1.1
0.9 0.2
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Carbendazim
47.0 2.3
(–) No activity.
(
) standard deviation.
2.3. Herbicidal activities
As indicated in Table 2, the synthesised title compounds have certain degree of herbicidal
activity against at least 1 kind of weeds D. sanguinalis and C. album. All the compounds
except 4k showed certain level of inhibition against the taproot and caulis development of
dicotyledonous weed C. album. While the activities of the title compounds against mono-
cotyledonous weed D. sanguinalis are weak or ineffective except compound 4j, which has
medium activity against the taproot and caulis development of D. sanguinalis. Compounds
4a, 4f, 4h and 4k exhibiting medium activity against the caulis development of D. sanguinalis
at 100 mg·L−1. 2-alkyl (C numbers < 4) substituted compounds 4a–4c show good to excellent
activities against C. album. And the activities decrease as the C numbers of alkyl substitute
increase. The activities of compound 4a and 4b against C. album are higher than the com-
mercial herbicide Acetochlor. Compound 4g has similar toxic level against C. album as
Table 2. herbicidal activity (%) of the title compounds.
D. sanguinalis
C. album
20 mg·L−1
100 mg·L−1
20 mg·L−1
100 mg·L−1
Compd.
taproot caulis
taproot caulis
taproot caulis
taproot caulis
4a
26
4
6
–
–
33
–
8
–
3
1
1
43
16
7
–
–
32
–
15
–
4
2
1
40
22
28
–
–
27
–
35
–
5
2
2
56
40
25
–
–
51
–
54
–
6
3
2
86
79
62
7
52
19
70
36
29
32
6
8
2
1
6
2
8
4
3
2
80
63
45
8
28
32
59
28
26
30
5
5
4
1
1
3
3
3
3
2
93
83
76
38
74
40
86
53
30
47
3
9
5
4
7
5
5
5
2
5
85
67
58
27
25
37
75
46
37
45
5
6
4
4
3
2
7
4
4
3
4b
4c
4d
4e
4f
3
1
6
1
3
5
4
5
4g
4h
4i
4j
25
27
9
1
2
1
6
47
5
4
1
7
60
6
4
3
7
60
3
5
2
4
4k
23
17
70
36
25
83
55
40
78
–
34
76
–
29
61
–
52
88
–
47
80
4l
7
2
3
5
4
8
3
5
Acetochlor
64
(–) No activity.
(
) standard deviation.

NATURAL PRODUCT RESEARCH
5
herbicide Acetochlor. It is interesting that compound 4j shows good activity against
D. sanguinalis but less toxic against C. album.
3. Experimental
3.1. General
All chemicals were obtained from commercial sources and used without further purification.
Resorcinol, ethyl acetoacetate, Na2S and PPA were supplied by Sinopharm Chemical Reagent
Co., Ltd. The inorganic acids and organic solvents were manufactured by Laiyang Kangde
Chemical Co., Ltd. The organic acids were purchased from SA ChemicalTechnology (Shanghai)
Co., Ltd. Analytical thin-layer chromatography (TLC) was performed with silica gel plates
using silica gel 60 GF254 (Qingdao Haiyang Chemical Co., Ltd.). Melting points were deter-
mined on a WRS-1B digital melting-point apparatus (Shanghai Precision Optical Instrument
Co., Ltd.) and without further calibration. Nuclear magnetic resonance spectra (NMR) were
recorded on a Bruker Avance III HD 500 MHz instrument in CDCl3 (1H at 500 MHz and 13C at
125 MHz) using tetramethylsilane (TMS) as the internal standard. High-resolution mass spec-
tra (HRMS) were carried out with an IonSpec 4.7 T FTMS instrument. Single-crystal structure
was determined by a Bruker AXS D8 QUEST X-ray single-crystal diffractometer.
3.2. General procedure for synthesis of angular oxazole-fused coumarin (4a–l)
4-Methyl-7-hydroxyl-6-amino-courmin (5 mmol), acid (6 mmol) and PPA (5 g) were stirred
at 150 °C for 5.5 h. The reaction mixture was cooled at room temperature. Water (30 mL) was
added, and the mixture was stirred for another 30 min. The resulting emulsion was extracted
with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water (30 mL),
then dried (Na2SO4), filtered and concentrated in vacuo sequentially. The residue was purified
by silica gel column chromatography to give the target compounds 4a–4l. The yield, appear-
ance, m.p., NMR and HRMS date of the synthesised compounds are listed in the supplemen-
tary material of this article.
3.3. Procedure for antifungal and herbicidal activities
The antifungal activities of the title compounds against B. cinerea, C. gloeosporioides, A. bras-
sicae and G. gramini were tested in vitro using the mycelium growth rate test. The test com-
pound was dissolved in acetone to form a series of proper concentration solutions. Then,
1 mL of the solution was added to 100 mL melting potato dextrose agar (PDA) at 45 °C, and
the mixture was shaken up to obtain the required concentration of poisoned medium; 5 mL
of the poisoned medium was poured into 6 cm petri dish and cooled to room temperature
to get a solid plate. After that, a 4 mm activated mycelium disk was inoculated on the PDA
plate and incubated in dark at 28 °C for 48 h. The mycelium elongation radius (mm) of the
fungus settlements was measured, and the growth inhibition rate related to the untreated
control was calculated. Acetone was used as blank control, and Carbendazim was used as
positive control. Each treatment was repeated for 3 times. Furthermore, the effective con-
centrations (EC50) of the synthesised compounds that inhibited mycelium growth by 50%
were obtained according to Finney’s probability value method (Zhang et al. 2013).

6
Y. WEI ET AL.
The herbicidal activities of the synthesised compounds against the taproot and caulis
development of dicotyledonous weed C. album and monocotyledonous weed D. sanguinalis
were determined in vitro (Ma et al. 2010). A suspension of 5 g agar powder in 1 L distilled
water was heated to melt, and then cooled to 40–50 °C. Each title compound was dissolved
by acetone to give stock solution of 10 g·L−1, and 0.1 or 0.5 mL of the stock solution was
added to 50 mL of the melting agar at 45 °C to achieve the required concentrations. Then,
5 mL of the agar-containing compound was added to beaker (10 mL) and cooled, and uni-
form germinating seeds were placed on the surface of the agar mass. The beaker was sealed
by a piece of plastic wrap with several small holes on it, and then, the cultivations were
carried out in an illumination incubator set at 28 1 °C and 50–55% relative humidity for
12 h in the light and 12 h in the dark alternatively for 3 days. Acetone was used as blank
control, and Acetochlor was used as positive control. Each treatment was conducted in three
replicates. After 3 days of cultivation, the taproot and caulis lengths were measured, and the
growth inhibitory rate related to the untreated control was determined.
4. Conclusions
Twelve angular oxazole-fused coumarin derivatives were synthesised, and their antifungal
and herbicidal activities were evaluated. 2-Cyclohexyl substituted product 4f and
2-(Thienyl-2-) substituted product 4l exhibited strong antifungal activity. The compound 4l
has good potential of inhibition on A. brassicae and showed the better results than the
positive fungicide Carbendazim. While 2-ethyl substituted product 4a and 2-propyl substi-
tuted product 4b showed prominent inhibition against the seedling growth of C. album,
which were more active than the commercial herbicide Acetochlor. It is worth mentioning
that 2-(m-F-phenyl) substituted product 4i displayed better herbicidal activity against the
seedling growth of D. sanguinalis.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the National Natural Science Foundation of China [Grant Number
31471808].
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