4-Aminoquinolines Bearing a 1,3-Benzodioxole Moiety: Synthesis and Biological Evaluation as Potential Antifungal Agents

Article abstract of DOI:10.1002/cbdv.202100106

In search of new environmentally friendly and effective antifungal agents, a series of 4-aminoquinolines bearing a 1,3-benzodioxole moiety were prepared and their structures were fully elucidated by spectroscopic analyses. The antifungal activities of all

Full text of DOI:10.1002/cbdv.202100106

DOI: 10.1002/cbdv.202100106
FULL PAPER
4-Aminoquinolines Bearing a 1,3-Benzodioxole Moiety: Synthesis and
Biological Evaluation as Potential Antifungal Agents
Rui Yang,*a Zhuolin Li,a Jialing Xie,a Jianchuan Liu,a Tianhong Qin,a Junda Liu,a Haiying Du,b and
Haoyun Yea
a
College of Materials, Chemistry and Chemical Engineering, Chengdu University of Technology, Chengdu
610059, P. R. China, e-mail: yangrui15@cdut.edu.cn
College of Ecological Environment, Chengdu University of Technology, Chengdu 610059, P. R. China
b
In search of new environmentally friendly and effective antifungal agents, a series of 4-aminoquinolines
bearing a 1,3-benzodioxole moiety were prepared and their structures were fully elucidated by spectroscopic
analyses. The antifungal activities of all the target compounds against five phytopathogenic fungi were
evaluated in vitro. The results revealed that most of the newly synthesized compounds exhibited obvious
inhibitory activities at the concentration of 50 μg/mL. Among them, 6-(furan-2-yl)-N-(4-methylphenyl)-2H-[1,3]
dioxolo[4,5-g]quinolin-8-amine hydrochloride (7m) displayed more promising antifungal potency with EC50
values of 10.3 and 14.0 μg/mL against C. lunata and A. alternate, respectively. Particularly, the EC50 value of 7m
against C. lunata was 7.3-fold as potent as the standard azoxystrobin. There were some significant morphological
alterations in the mycelia of C. lunata when treated with 7m at 50 μg/mL. Additionally, the preliminary
structure–activity relationships (SARs) were also discussed. Thus, this study suggests that 4-aminoquinolines
bearing a 1,3-benzodioxole moiety are interesting scaffolds for the development of novel antifungal agents.
Keywords: 4-aminoquinoline, 1,3-benzodioxole, antifungal activity, structure–activity relationship.
molecules,[6,7] and have also become a class of
preferred lead compounds for new agricultural
Introduction
Fungal diseases are a major threat to agricultural chemicals.[8–10] Quinoline is a common core in many
production worldwide, which not only result in a large natural compounds and has diverse biological activ-
reduction in grain yield, but also may pose great risks ities, such as antibacterial,[11,12] antifungal,[13,14]
to the environment and human security.[1–3] Although antiviral,[15,16] antitumor,[17,18] antimalarial,[19,20] and
many synthetic fungicides play an important role in anti-inflammatory activities.[21] The excellent biological
crop protection, drug resistance and residue are properties of quinolines have also been well demon-
becoming more and more serious with the long-term strated by a large number of practical applications,
or irrational use of these agents.[4,5] In order to solve such as quinoxyfen (a commercial agricultural fungi-
these serious problems, the discovery of novel envi- cide), tebufloquin (fungicide), 8-hydroxyquinoline cop-
ronmentally friendly and high-efficiency antifungal per (bactericide), hyquincarb (insecticide), fenazaquin
agents is an imperative and challenging task.
(insecticide), quinclorac (herbicide), and ethoxyquin
For decades, heterocyclic compounds play an (feed additive). Furthermore, 1,3-benzodioxole moiety
important role in the development of medicine and is a common natural component from dietary plants
pesticide. Among them, quinoline derivatives have such as peppers, sesame seeds and carrots.[22] The
always been one of the most prominent bioactive representative bioactive molecules containing this
fragment are piperine, sanguinarine, chelerythrine,
podophyllotoxin, steganacin, combretastatin A-2, and
so on (Figure 1). They possess antioxidative, antibacte-
rial, antifungal, antitumor and other biological
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/cbdv.202100106
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Chem. Biodiversity 2021, 18, e2100106
Figure 1. Some bioactive compounds containing a 1,3-benzodioxole moiety.
activities.[23–28] In particular, the good bioavailability tuted-6,7-methylenedioxyquinolin-4-amine
hydro-
and low mammalian toxicity is of great interest.[22,29]
chlorides 6a–6j and 7a–7n were prepared by nucleo-
Previous studies of our working group investigated philic substitution of the key intermediates 5a–5o
some 2,4-disubstituted quinolines as potential anti- with suitable primary amine in moderate to good
fungal agents.[14,30] It was found that quinoline deriva- yields. The structures of all target compounds were
1
tives with a phenyl substitution at position 2 and an characterized by means of IR, H-NMR, 13C-NMR and
aniline moiety at position 4 were potent antifungal HR-MS spectra.
candidates and the aniline moiety at position 4 played
a key role in antifungal potency, which were of great
Antifungal Activity and StructureÀ Activity Relationships
value for further study. Encouraged by above men-
tioned, herein, a series of 4-aminoquinolines bearing a As described in Table 1, all the target compounds (6a–
1,3-benzodioxole moiety were prepared and evaluated 6j and 7a–7n), as well as the positive control
for their antifungal activities against five phytopatho- azoxystrobin (a commercial agricultural fungicide),
genic fungi in vitro.
were screened in vitro for their antifungal activities
against five phytopathogenic fungi (P. piricola, A.
brassicae, C. lunata, P. grisea and A. alternate) at 50 μg/
mL by using mycelium growth rate method.[14,30] The
results revealed that most of the newly synthesized
compounds exhibited moderate to excellent inhibitory
Results and Discussion
Chemistry
The preparation of target compounds has been activities at the concentration of 50 μg/mL, and many
accomplished in four steps (Scheme 1) according to of them displayed comparable or more superior
similar procedures described previously.[30] Firstly, the antifungal profiles compared with the positive control,
amides 3a–3o were obtained from ammonolysis of particularly for A. brassicae, C. lunata and A. alternate.
the corresponding acyl chlorides 2a–2o with 1-(6- Among compounds 6a–6j, compounds 6f and 6i
amino-2H-1,3-benzodioxol-5-yl)ethan-1-one (1) in the possessed potent and broad-spectrum antifungal
presence of triethylamine in good to excellent yields. activities against the five tested fungi with the
Then, intramolecular aldol condensation of amides inhibition rates of >51.1%. For example, the inhibition
3a–3o afforded quinolinones 4a–4o in moderate to rates of compound 6f against P. piricola, C. lunata and
good yields, which were then converted into the A. alternate were 72.3%, 71.4% and 65.5%, respec-
corresponding 4-chloroquinolines 5a–5o in good tively, and the inhibition rates of compound 6i against
yields by using phosphorus oxychloride in refluxing P. piricola, C. lunata and A. alternate were 56.4%,
dioxane. Finally, the target compounds N,2-disubsti- 70.7%, and 62.9%, respectively. Their antifungal
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Chem. Biodiversity 2021, 18, e2100106
Scheme 1. Synthetic route of target compounds 6a–6j and 7a–7n. Reagents and conditions: a) Et3N, CH2Cl2, r.t., overnight. b)
2
°
NaOH, 1,4-dioxane, 110 C, 2 h. c) POCl3, 1,4-dioxane, reflux 10 h. d) R À NH2, 1,4-dioxane, reflux 8–36 h.
potencies were superior to the positive control potencies were comparable or superior to the precur-
azoxystrobin against the corresponding fungal strains sor 6f and azoxystrobin.
in most cases. Besides, compound 6a also displayed
Moreover, the EC50 values of some potent com-
potent antifungal activities against C. lunata and A. pounds with inhibition rates >60% at 50 μg/mL were
alternate with the inhibition rates of 71.5% and 63.1%, further studied against C. lunata and A. alternate. As
respectively. Subsequently, in order to further inves- shown in Table 2, the results indicated that all of the
tigate the influence of C-2 substituents (Scheme 1: R1) twelve tested compounds displayed good to excellent
on the antifungal potency, compounds 7a–7n were inhibitory activities, with EC50 values of 10.3–43.0 μg/
prepared by derivatization from compound 6f. To our mL except for compound 7a against A. alternate.
delight, the majority of compounds 7a–7n exhibited Notably, the EC50 values (10.3–28.4 μg/mL) of all
good to excellent antifungal activities against most of tested compounds against C. lunata were more potent
the tested fungal stains. The inhibition rates of each than the positive control azoxystrobin (EC50 =74.9 μg/
compound in this series against at least three strains mL). Particularly, compound 7m exhibited 7.3-fold as
of tested fungi were over 50% except for compounds potent as azoxystrobin against C. lunata. As for A.
7j, 7k and 7l. Among them, compounds 7e and 7m alternate, most of the tested compounds did not
showed more promising and broad-spectrum antifun- exhibit superior antifungal activities (EC50 =24.3–
gal activities against each of the tested fungi, whose 43.0 μg/mL) over the positive control (EC50 =16.0 μg/
inhibition rates were almost more than 60%. Partic- mL) except for compound 7m (EC50 =14.0 μg/mL). In
ularly, compound 7m displayed the highest inhibition addition, the effects of compound 7m against C.
rates of 74.2, 76.7%, 69.9% and 73.7% against P. lunata and A. alternate at different concentrations
piricola, C. lunata, P. grisea and A. alternate, respec- were displayed in Figure 2. It is apparent that the
tively. Compound 7b exhibited better activities than inhibitory activities increased in a concentration
all other analogs against A. brassicae with the inhib- dependent manner.
ition rate of 72.3%. In addition, compounds 7f, 7g, 7h
From the results in Tables 1 and 2, some interesting
and 7i also displayed impressive antifungal activities SARs could be derived. Firstly, the substituent in para
against A. brassicae, C. lunata and A. alternate, whose position at the aniline moiety was very important for
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Table 1. Inhibition rates of target compounds against five phytopathogenic fungi at 50 μg/mL.
Compounds
Average Inhibition rate (%�SD)[a]
P. piricola[b]
A. brassicae[c]
C. lunata[d]
P. grisea[e]
A. alternate[f]
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
41.3�0.69
45.4�1.5
34.1�1.8
32.2�2.3
26.9�1.8
72.3�1.9
47.5�0.42
32.2�1.5
56.4�1.9
35.2�1.6
36.1�0.62
46.0�1.4
52.5�0.61
51.7�1.1
54.8�0.0
48.9�0.62
49.1�1.2
51.9�2.3
64.8�0.43
41.7�1.2
47.9�0.67
52.1�1.9
74.2�0.74
51.3�1.3
68.6�1.7
57.8�0.21
59.1�1.7
24.7�1.4
26.5�2.2
52.2�1.6
55.3�0.26
36.9�1.3
23.3�1.2
58.1�0.52
41.2�1.8
53.4�0.89
72.3�0.40
59.3�1.7
30.4�1.7
70.8�1.2
57.9�2.0
62.1�1.8
62.4�1.1
65.9�1.4
39.0�0.89
49.3�1.2
37.2�1.5
70.0�0.91
54.1�0.80
48.8�0.42
71.5�0.40
55.1�2.0
43.4�1.2
44.5�2.0
21.3�1.2
22.4�2.3
37.1�1.8
56.7�1.6
43.0�1.2
29.0�0.38
51.1�1.1
31.1�0.44
45.2�1.4
63.7�1.3
36.3�1.4
66.1�1.1
61.8�0.42
41.6�1.9
49.5�1.4
48.8�1.1
49.5�0.91
27.6�1.1
44.4�2.0
38.1�0.74
69.9�1.1
52.1�0.53
52.9�1.0
63.1�1.7
54.5�0.78
34.7�1.7
23.7�1.8
40.9�2.2
65.5�1.2
46.5�1.5
21.0�1.9
62.9�0.69
34.0�0.72
53.8�0.73
65.8�1.9
56.4�0.49
62.4�1.7
68.9�1.5
65.8�1.4
62.7�0.47
62.0�0.83
60.5�1.0
30.8�0.56
24.4�1.0
40.8�1.5
73.7�1.2
44.2�1.1
54.7�0.47
30.9�1.4
35.6�1.4
53.0�0.63
71.4�0.33
54.6�0.67
29.8�0.31
70.7�0.0
47.1�0.78
64.3�0.10
65.0�1.4
57.0�0.30
71.8�2.0
74.2�1.3
71.1�0.30
72.5�0.72
68.9�0.33
73.5�0.78
33.3�1.8
42.1�0.71
44.3�1.4
76.7�1.6
50.8�1.4
Azoxystrobin
44.9�0.0
[a] Values are means�standard deviation of three replicates. [b] P. piricola: Physalospora piricola; [c] A. brassicae: Alternaria brassicae;
[d] C. lunata: Curvularia lunata; [e] P. grisea: Pyricularia grisea; [f] A. alternate: Alternaria alternate.
Table 2. EC50 values of some potent compounds against C. lunata and A. alternate.
Compound
C. lunata
EC50 (μg/mL)
A. alternate
EC50 (μg/mL)
Toxic regression equation
r2
Toxic regression equation
r2
6a
6f
6i
7a
7b
7d
7e
7f
7g
7h
7i
7m
28.4�1.6
y=1.9150x–3.5281
y=1.7907x–2.7938
y=1.5367x–1.7033
y=1.1927x–0.2183
y=1.4674x–1.4999
y=1.5071x–1.5116
y=1.5860x–1.8856
y=1.4610x–1.3590
y=1.6617x–2.2424
y=1.1822x–0.1208
y=1.7648x–2.8246
y=0.7952x+1.8094
y=0.7624x+1.2819
0.9970
0.9996
0.9942
0.9951
0.9995
0.9984
0.9903
0.9908
0.9938
0.9906
0.9910
0.9995
0.9982
43.0�0.42
28.2�0.0
27.9�0.37
y=2.7196x–7.6087
y=1.6501x–2.3405
y=1.5319x–1.8137
–
y=1.5031x–1.7062
y=1.6278x–2.2479
y=1.4628x–1.4070
y=1.6285x–2.2871
y=1.8728x–3.4857
y=1.3214x–0.9085
y=1.6035x–2.3130
y=1.0851x+0.5004
y=0.2271x+4.0451
0.9912
0.9955
0.9938
–
0.9927
0.9949
0.9972
0.9906
0.9950
0.9938
0.9934
0.9987
0.9972
22.5�0.18
22.7�0.58
23.8�0.67
26.9�0.38
21.1�0.23
22.1�0.38
22.6�0.86
23.0�0.040
21.7�0.45
26.8�0.055
10.3�0.53
74.9�0.91
[a]
–
28.7�0.41
28.3�0.43
24.3�0.061
30.5�0.42
33.4�0.71
29.2�0.83
36.2�0.50
14.0�0.35
16.0�0.82
Azoxystrobin
[a]
–: not detected.
the antifungal activity. Generally, the 4-methyl and 4- of products 7a–7n, derived from 6f (4-CH3), possessed
tert-butyl substituted compounds 6f and 6i achieved good to excellent antifungal activities with few
higher potencies than the others in this series. The exceptions. Secondly, the substituent at position 2 of
trend could also be supported by the fact that the set the quinoline scaffold was an important modulator of
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Figure 2. The growth inhibition of C. lunata (A) and A. alternate (B) by compound 7m at different concentrations.
the antifungal activity as well. When a small residue 2- (Figure 3, A) were relatively smooth and the chromatin
furyl was introduced at position 2, compound 7m was regular and equipped with a uniform color,
displayed about 2-fold as active as the precursor 6f as whereas there was conspicuous shrinkage, coarseness
shown in Table 2. Whereas, by the exchange of 2-furyl and nonuniform color when treated with compound
with a similar small residue 2-thienyl (7n), a significant 7m (Figure 3, B).
reduction could be observed. Meanwhile, it is found
that the introduction of a bulky substituent or
cyclohexyl at position 2 resulted in drastically reduced
Conclusions
potencies, such as compounds 7j (4-t-BuÀ Ph), 7k (2-
naphthyl) and 7l (cyclohexyl). Furthermore, only minor In summary, a series of 4-aminoquinolines bearing a
differences in the inhibitory activities were observed 1,3-benzodioxole moiety were prepared and evaluated
for the introduction of fluorophenyl (7a–7c), tolyl for their antifungal activities against five phytopatho-
(7d–7f) and methoxyphenyl (7g–7i).
genic fungi in vitro. Most of the target compounds
In addition, as shown in Figure 3, the mycelial showed moderate to excellent inhibitory activities at
morphology alterations of C. lunata treated with the concentration of 50 μg/mL, and some of them
°
compound 7m at 50 μg/mL for 24 h at 28 C were displayed comparable or more superior antifungal
observed by microscopy. It is obvious that the mycelia potencies compared with the commercial fungicide
exposed to compound 7m showed significant mor- azoxystrobin. Among them, compound 7m exhibited
phological alterations, compared with the untreated more promising and broad-spectrum antifungal activ-
control. The surfaces of mycelia in the untreated group ities against all tested fungi, and the EC50 values of it
°
Figure 3. Mycelial morphology of C. lunata: (A) is untreated, (B) is treated with compound 7m at 50 μg/mL for 24 h at 28 C.
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against C. lunata and A. alternate were 10.3 and was collected and washed with water and a cold
14.0 μg/mL, respectively. SARs analysis revealed that mixture of CH2Cl2 and AcOEt (1:1, v/v) to give the
the substituent in para position at the aniline moiety pure products 4a–4o in 52–93% yields, respectively.
and the substituent at position 2 of the quinoline
scaffold played key roles in the antifungal activities
Synthesis of Intermediates 5a–5o
together.
A mixture of POCl3 (50 mL) and the respective
quinolinone 4a–4o (0.05 mol) in 1,4-dioxane (30 mL)
Experimental Section
was refluxed for 10 h. After cooling, the most solvent
was removed by evaporation and the residue was
carefully poured into cold water. Then, the mixture
Reagents and Instruments
All chemicals and reagents were of analytical grade was slowly neutralized with a cold solution of NaOH
and obtained from commercial resources. Anhydrous and extracted with CH2Cl2 (3×80 mL). The organic
solvents were dried according to standard methods layer was dried with Na2SO4, filtered, and evaporated
before use. Thin-layer chromatography (TLC) was used under reduced pressure. The residue was recrystallized
to monitor the progression of the reactions on silica from petroleum ether/ethyl acetate (20:1, v/v) to yield
gel plates (GF254, Qingdao Haiyang Chemical Co., Ltd., 5a–5o in 55–93% yields, respectively.
China). Melting points were detected on a X-4 melting
point apparatus (Shanghai instrument physical optics
General Procedure for the Synthesis of Target Com-
instrument Co., Ltd., China) and were uncorrected. IR
pounds 6a–6j and 7a–7n
spectra were performed on a Agilent Cary 630 FT-IR
1
spectrometer with KBr disks. H- and 13C-NMR spectra To a solution of 4-chloroquinoline 5a–5o (3 mmol) in
were recorded on a Bruker Advance 400 or 600 1,4-dioxane (8 mL), the respective primary amine
instrument using CDCl3, CD3OD or (D6)DMSO as (5 mmol) was added, and the mixture was refluxed for
deuterated solvent. HR-MS-ESI spectra were carried several hours until the reaction was complete accord-
out with a SCIEX X500R QTOF mass spectrometer.
ing to TLC analysis (8–36 h). The solid formed was
filtered and washed with petroleum ether/ethyl
acetate (5:1, v/v) to obtain the target compounds 6a–
6j and 7a–7n in 41–96% yields, respectively.
Synthesis of Intermediates 3a–3o
To a mixture of 1-(6-amino-2H-1,3-benzodioxol-5-yl)
ethan-1-one (1; 0.1 mol), triethylamine (0.1 mol) and
Spectroscopic data of all the target compounds
anhydrous CH2Cl2 (100 mL), a solution of acyl chloride and intermediates 3, 4 and 5 can be found in the
2a–2o (0.1 mol) in anhydrous CH2Cl2 (50 mL) was Supporting Information.
added dropwise in an ice bath. The solution was
stirred overnight at room temperature and then
extracted with CH2Cl2 (3×80 mL). The combined
Antifungal Activity
organic layers were washed with water (3×100 mL), All title compounds were evaluated for their antifungal
then, dried with Na2SO4. After removal of the solvent activities against five phytopathogenic fungi (Physalo-
under reduced pressure, the crude product was spora piricola, Alternaria brassicae, Curvularia lunata,
recrystallized from petroleum ether/ethyl acetate Pyricularia grisea and Alternaria alternate) by using
(10:1, v/v) to afford 3a–3o in 64–98% yields, mycelium growth rate method as reported
respectively.
previously.[14,30] Azoxystrobin, a commercial agricultur-
al fungicide, was used as the positive control. Each of
the tested compounds was dissolved in 20 mL of
sterile water containing 1 mL of dimethyl sulfoxide
Synthesis of Intermediates 4a–4o
A mixture of NaOH (0.27 mol) and the respective (DMSO), and the solution as described above was
amide 3a–3o (0.09 mol) in 1,4-dioxane (200 mL) was mixed with 180 mL of sterilized potato dextrose agar
refluxed for 2 h until the reaction was complete. Then, (PDA) medium to fix the final concentration of the title
the solvent was removed under vacuum and the compound at 50 μg/mL. Meanwhile, 0.5% DMSO in
residue was dissolved in water, adjusted to pH=5–6 PDA medium (180 mL PDA+20 mL sterile water
by addition of diluted HCl. With acidification of the containing 5% DMSO) was served as the blank control.
solution, copious precipitate appeared. The precipitate The prepared medium was then poured into sterilized
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References
Petri dishes. Subsequently, a 5-mm-diameter mycelium
disk was inoculated to the center of the medium to
[1] M. C. Fisher, D. A. Henk, C. J. Briggs, J. S. Brownstein, L. C.
Madoff, S. L. McCraw, S. J. Gurr, ‘Emerging fungal threats to
animal, plant and ecosystem health’, Nature 2012, 484,
186–194.
[2] V. S. Brauer, C. P. Rezende, A. M. Pessoni, R. G. De Paula,
K. S. Rangappa, S. C. Nayaka, V. K. Gupta, F. Almeida,
‘Antifungal agents in agriculture: Friends and foes of public
health’, Biomolecules 2019, 9, 521.
[3] Y. Li, Z. F. Luo, B. L. Luo, Q. Lan, J. D. Fan, W. Xue, J. Miao, Y.
Li, L. Tang, L. L. Fan, ‘Design, synthesis and antifungal
activities of 6-substituted 3-butylphthalide derivatives
against phytopathogenic fungi’, Chem. Biodiversity 2020,
17, e2000435.
°
incubate at 28 C for 72 h. Each treatment was
repeated three times. After 72 h of incubation, the
colony diameter of each fungus was measured, and
the growth inhibition rate of mycelia was calculated
according to the following formula.
Inhibition rate (%)=(CÀ T)/(CÀ 5)×100%, where C
represents the colony diameter in the blank control
group, and T represents the colony diameter in the
compound-treated group.
[4] M. C. Fisher, N. J. Hawkins, D. Sanglard, S. J. Gurr, ‘World-
wide emergence of resistance to antifungal drugs chal-
lenges human health and food security’, Science 2018, 360,
739–742.
[5] O. V. Kholodniak, M. S. Kazunin, F. Meyer, S. I. Kovalenko,
K. G. Steffens, ‘Novel N-cycloalkylcarbonyl-N’-arylthioureas:
Synthesis, design, antifungal activity and gene toxicity’,
Chem. Biodiversity 2020, 17, e2000212.
[6] A. Dorababu, ‘Recent update on antibacterial and anti-
fungal activity of quinoline scaffolds’, Arch. Pharm. 2020,
e2000232.
[7] L. M. Nainwal, S. Tasneem, W. Akhtar, G. Verma, M. F. Khan,
S. Parvez, M. Shaquiquzzaman, M. Akhter, M. M. Alam,
‘Green recipes to quinoline: A review’, Eur. J. Med. Chem.
2019, 164, 121–170.
[8] M. S. C. Pedras, A. Abdoli, V. K. Sarma-Mamillapalle, ‘Inhib-
itors of the detoxifying enzyme of the phytoalexin
brassinin based on quinoline and isoquinoline scaffolds’,
Molecules 2017, 22, 1345.
[9] S. Lawrance, S. Varghese, E. M. Varghese, A. K. Asok, M. S.
Jisha, ‘Quinoline derivatives producing Pseudomonas aeru-
ginosa H6 as an efficient bioherbicide for weed manage-
ment’, Biocatal. Agric. Biotechnol. 2019, 18, 101096.
[10] G. Z. Yang, J. K. Zhu, X. D. Yin, Y. F. Yan, Y. L. Wang, X. F.
Shang, Y. Q. Liu, Z. M. Zhao, J. W. Peng, H. Liu, ‘Design,
synthesis, and antifungal evaluation of novel quinoline
derivatives inspired from natural quinine alkaloids’, J. Agric.
Food Chem. 2019, 67, 11340–11353.
Determination of EC50: A series of concentration
gradients of some potent compounds were prepared
by serial dilution method, containing 100, 70, 50, 35,
25, 12.5 and 6.25 μg/mL. Antifungal toxicity regression
equations were established by the linear least-square
fitting method for lg[concentration (ng/mL)] values vs.
the probit values of the corresponding inhibition rate.
And the EC50 values were analyzed by the GraphPad
Prism 7.0 software (GraphPad Software, San Diego, CA,
USA).
Morphological observation: The C. lunata strain was
inoculated in potato dextrose broth (PDB) medium
°
and shaking cultured at 28 C for 24 h. Then com-
pound 7m was added to one of the above PDB
medium to fix the final concentration at 50 μg/mL.
And they were shaking cultured for another 24 h at
°
28 C. Subsequently, an optical microscope was used
to observe the mycelial morphology of C. lunata with
and without 7m treatment.
Acknowledgements
This study was funded by the National Natural Science
Foundation of China (No. 31601670) and the Youth
Development Foundation of Chengdu University of
Technology.
[11] P. N. Balaji, D. Ranganayakulu, G. V. S. Reddy, ‘Synthesis,
in vitro evaluation for anthelmintic and antimicrobial
activity for the novel thiazolidine-4-one incorporate sub-
stituted chloro-quinoline’, Asian J. Pharm. Pharmacol. 2017,
3, 9–15.
[12] S. Mudaliar, K. H. Chikhalia, N. K. Shah, ‘Synthesis of 2-, 3-
or 4-phenylsubtituted chalcones based on 4-phenylamino-
6-nitro-2-[(E)-2-phenylvinyl]quinoline, evaluation of their
antimicrobial and antifungal activity’, Lett. Drug Des.
Discovery 2016, 13, 818–823.
[13] S. B. Al-Juboory, A. A. R. M. Kubba, ‘Synthesis, character-
ization and antifungal evaluation of some novel quinolone
derivatives derived from ethyl p-aminobenzoate’, Pharma
Chem. 2016, 8, 63–66.
Author Contribution Statement
Rui Yang conceived the experiments and prepared the
manuscript. Zhuolin Li, Jialing Xie, and Haoyun Ye
performed the experiments. Jianchuan Liu and Tian-
hong Qin carried out the antifungal assays. Junda Liu
and Haiying Du analyzed the data and revised the
manuscript.
[14] R. Yang, Y. N. Ma, T. Huang, W. Xie, X. Zhang, G. S. Huang,
X. D. Liu, ‘Synthesis and antifungal activities of 4-thioquino-
line compounds’, Chin. J. Org. Chem. 2018, 38, 2143–2150.
www.cb.wiley.com
(7 of 8) e2100106
© 2021 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2021, 18, e2100106
[15] N. G. Jentsch, A. P. Hart, J. D. Hume, J. Sun, K. A. McNeely,
cancer evaluation of novel 1,3-benzodioxoles and 1,4-
benzodioxines’, Eur. J. Pharm. Sci. 2019, 139, 105045.
[24] L. M. Mariz Gomes da Silva, J. F. de Oliveira, W. L. Silva, A. L.
da Silva, A. S. A. de Almeida Junior, V. H. Barbosa Dos San-
tos, L. C. Alves, F. A. Brayner Dos Santos, V. M. A. Costa,
A. L. Aires, M. de Lima, M. Albuquerque, ‘New 1,3-benzo-
dioxole derivatives: Synthesis, evaluation of in vitro schisto-
somicidal activity and ultrastructural analysis’, Chem.-Biol.
Interact. 2018, 283, 20–29.
[25] S. Dutta Gupta, G. B. Rao, M. K. Bommaka, N. M. Raghaven-
dra, S. Aleti, ‘Eco-sustainable synthesis and biological
evaluation of 2-phenyl 1,3-benzodioxole derivatives as
anticancer, DNA binding and antibacterial agents’, Arabian
J. Chem. 2016, 9, S1875–S1883.
[26] S. S. Sulthana, S. A. Antony, C. Balachandran, S. S. Shafi,
‘Thiophene and benzodioxole appended thiazolyl-pyrazo-
line compounds: Microwave assisted synthesis, antimicro-
bial and molecular docking studies’, Bioorg. Med. Chem.
Lett. 2015, 25, 2753–2757.
[27] A. C. L. Leite, K. P. da Silva, I. A. de Souza, J. M. de Araujo,
D. J. Brondani, ‘Synthesis, antitumour and antimicrobial
activities of new peptidyl derivatives containing the 1,3-
benzodioxole system’, Eur. J. Med. Chem. 2004, 39, 1059–
1065.
[28] Z. Y. Liu, J. P. Cao, X. T. Yan, W. Q. Cheng, X. G. Wang, R. G.
Yang, Y. Guo, ‘Discovery of natural product-based fungi-
cides (II): Semisynthesis and biological activity of sarisan
attached 3-phenylisoxazolines as antifungal agents’, Chem.
Biodiversity 2020, 17, e2000763.
[29] M. D. Altintop, B. Sever, G. Akalin Ciftci, K. Kucukoglu, A.
Ozdemir, S. S. Soleimani, H. Nadaroglu, Z. A. Kaplancikli,
‘Synthesis and evaluation of new benzodioxole-based
dithiocarbamate derivatives as potential anticancer agents
and hCAÀ I and hCA-II inhibitors’, Eur. J. Med. Chem. 2017,
125, 190–196.
C. Lama, J. A. Pigza, M. G. Donahue, J. J. Kessl, ‘Synthesis
and evaluation of aryl quinolines as HIV-1 integrase multi-
merization inhibitors’, ACS Med. Chem. Lett. 2018, 9, 1007–
1012.
[16] P. Das, X. Y. Deng, L. Zhang, M. G. Roth, B. M. A. Fontoura,
M. A. Phillips, J. K. De Brabander, ‘SAR-based optimization
of a 4-quinoline carboxylic acid analog with potent
antiviral activity’, ACS Med. Chem. Lett. 2013, 4, 517–521.
[17] D. Liu, A. Q. Xue, Z. X. Liu, Y. Zhang, P. H. Peng, H. F. Wang,
‘Synthesis and anti-tumor activity evaluation of novel 7-
fluoro-4-(1-piperazinyl) quinolines’, Lett. Drug Des. Discov-
ery 2019, 16, 663–669.
[18] A. Deronic, S. Tahvili, T. Leanderson, F. Ivars, ‘The anti-
tumor effect of the quinoline-3-carboxamide tasquinimod:
Blockade of recruitment of CD11b+ Ly6Chi cells to tumor
tissue reduces tumor growth’, BMC Cancer 2016, 16, 440.
[19] J. E. Charris, M. C. Monasterios, M. E. Acosta, M. A. Rodri-
guez, N. D. Gamboa, G. P. Martinez, H. R. Rojas, M. R.
Mijares, J. B. De Sanctis, ‘Antimalarial, antiproliferative, and
apoptotic activity of quinoline-chalcone and quinoline-
pyrazoline hybrids. A dual action’, Med. Chem. Res. 2019,
28, 2050–2066.
[20] B. Baragana, N. R. Norcross, C. Wilson, A. Porzelle, I.
Hallyburton, R. Grimaldi, M. Osuna-Cabello, S. Norval, J.
Riley, L. Stojanovski, F. R. C. Simeons, P. G. Wyatt, M. J.
Delves, S. Meister, S. Duffy, V. M. Avery, E. A. Winzeler, R. E.
Sinden, S. Wittlin, J. A. Frearson, D. W. Gray, A. H. Fairlamb,
D. Waterson, S. F. Campbell, P. Willis, K. D. Read, I. H.
Gilbert, ‘Discovery of a quinoline-4-carboxamide derivative
with a novel mechanism of action, multistage antimalarial
activity, and potent in vivo efficacy’, J. Med. Chem. 2016,
59, 9672–9685.
[21] B. Pallavi, P. Sharma, N. Baig, V. K. Madduluri, A. K. Sah, U.
Saumya, U. S. Dubey, P. Shukla, ‘Quinoline glycoconjugates
as potentially anticancer and anti-inflammatory agents: An
investigation involving synthesis, biological screening, and
docking’, ChemistrySelect 2020, 5, 9878–9882.
[30] R. Yang, W. H. Du, H. Yuan, T. H. Qin, R. X. He, Y. N. Ma, H. Y.
Du, ‘Synthesis and biological evaluation of 2-phenyl-4-
aminoquinolines as potential antifungal agents’, Mol.
Diversity 2020, 24, 1065–1075.
[22] S. Q. Shi, P. Xiao, K. M. Wang, Y. K. Gong, J. Nie, ‘Influence
of chemical structures of benzodioxole-based coinitiators
on the properties of the unfilled dental resin’, Acta
Biomater. 2010, 6, 3067–3071.
Received February 9, 2021
Accepted March 23, 2021
[23] R. M. Hassan, W. H. Abd-Allah, A. M. Salman, A. A. El-
Azzouny, M. N. Aboul-Enein, ‘Design, synthesis and anti-
www.cb.wiley.com
(8 of 8) e2100106
© 2021 Wiley-VHCA AG, Zurich, Switzerland