Synthesis, Antifungal Activity, and SAR Study of Some New 6-Perfluoropropanyl Quinoline Derivatives

Article abstract of DOI:10.1002/jhet.3031

A series of novel quinoline derivatives containing perfluoropropanyl moiety were designed and synthesized. The bioassay results showed that some of them exhibited good control efficacy against Pyricularia oryae. The fungicidal activity was affected by the substituted position in the molecule. It was found that the compound 3n possessed highest control effect against P.?oryae at different concentration. It is better than that of control Tebufloquin.

Full text of DOI:10.1002/jhet.3031

Month 2017
Synthesis, Antifungal Activity, and SAR Study of Some New
-Perfluoropropanyl Quinoline Derivatives
6
a,b
b
a
a
a
a
Yue-Ming Fang, Rui-Rui Zhang, Zhong-Hua Shen, Hong-Ke Wu, Cheng-Xia Tan, Jian-Quan Weng,
b
a
Tian-Ming Xu, * and Xing-Hai Liu *
a
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
b
Zhejiang Base of National Southern Pesticide Research Centre, Zhejiang Research Institute of Chemical Industry,
Hangzhou 310023, China
*
E-mail: xhliu@zjut.edu.cn; xutianming@sinochem.com
Received April 10, 2017
DOI 10.1002/jhet.3031
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel quinoline derivatives containing perfluoropropanyl moiety were designed and synthe-
sized. The bioassay results showed that some of them exhibited good control efficacy against Pyricularia
oryae. The fungicidal activity was affected by the substituted position in the molecule. It was found that
the compound 3n possessed highest control effect against P. oryae at different concentration. It is better than
that of control Tebufloquin.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
medicinal chemistry, pesticidal chemistry, and materials
chemistry. Quinoline is one of the most common skeleton
in many natural production and has many important
physiological activities, such as anti-tubercular agents [8],
anti-cancer [9], antioxidant activity [10], aromatase
inhibitors [11], multi-trypanosomatid activity [12],
trypanocidal activities [13], and antibacterial activity [14].
Therefore, the synthesis of novel quinolone derivatives
has attracted by many organic chemists.
In line with our continued efforts to synthesize novel lead
compounds for pesticide discover [15–25], the fungicide
Tebufloquin was selected as a lead compound, the t-Bu
group was replaced by perfluoropropanyl group and the
fluorine atom was replaced by methyl group. Then the
ether group was replaced by ester carbonate. Our original
strategy is depicted in Scheme 1. Surprisingly, the
designed compounds not only exhibited excellent control
efficacy than the fungicide Tebufloquin against P. oryae.
Recent years, the pesticide-resistance problem had
become series all over the world [1,2], especially for
fungicides. Rice is an oldest and major food crop in asian
country. Pyricularia oryae, commonly known as fire
blast, blast hanging head, and pinch neck blast in China,
is the world’s important rice disease caused by P. oryae.
P. oryae can decrease the yield of rice. Sometimes, the re-
duction can reach 40% to 50%, even more. Tricyclazole, an
effective fungicide developed by Eli Lilly and Company, is
always used to control P. oryae for many years. Many ref-
erences reported that P. oryae had resistant when using the
fungicide tricyclazole. It is urgent to develop novel envi-
ronmentally friendly and high active compounds with dif-
ferent mode of action in order to overcome the resistance
of fungals [3]. Tebufloquin 1 is a novel structural heterocy-
clic compound that provides outstanding control over
P. oryae with novel mode of actions. Meiji Seika Kaisha
[
4] reported that Tebufloquin is highly active against
P. oryae.
Quinoline derivatives are an important class of
EXPERIMENTAL
heterocyclic aromatic compounds, which name is derived
from the anti-malaria drug quinine. In modern synthesis
chemistry, quinoline compounds had been applied in
many fields [5–7], such as coordination chemistry,
Instrument and materials.
Melting points were
measured on a Taike X-4 apparatus (Beijing, China)
1
and uncorrected. H NMR data were determined by
Bruker AV-400 instrument (Billerica, MA). The elemental
analysis data were measured by a Perkin-Elmer 240C
organometallic
chemistry,
asymmetric
synthesis,
©
2017 Wiley Periodicals, Inc.

Y.-M. Fang, R.-R. Zhang, Z.-H. Shen, H.-K. Wu, C.-X. Tan, J.-Q. Weng, T.-M. Xu, and X.-H. Liu Vol 000
Scheme 1. The design strategy of title compounds. [Color figure can be
viewed at wileyonlinelibrary.com]
Synthesis of target compounds 3a–3p. To a solution of
,3,8-trimethyl-6-(perfluoropropan-2-yl)quinolin-4-ol (0.5 g,
.4 mmol) and potassium carbonate (0.084 g, 1.4 mmol) in
2
1
acetone (50 mL), the substituted benzyl carbonochloridate
1.4 mmol) was dropwised, TLC monitored. After the
(
reaction is completed, the mixture was filtered and
evaporated. The target compound was purified by
chromatography on a silica gel using petroleum ether and
ethyl acetate (V(EA):V(PE) = 1:8) as the eluent to afford the
compounds 3a–3p. The synthetic route was shown in
Scheme 2.
2
,3,8-Trimethyl-6-(perfluoropropan-2-yl)quinolin-4-yl
elemental analyzer (Waltham, MA). All the TLC or
chemical reagents are purchased (analytical grade).
1
acetate 3a. White solid, yield 60.5%, H NMR (400 MHz,
CDCl ) δ: 2.26(s, 3H), 2.50 (s, 3H), 2.75 (s, 3H), 2.82
s, 3H), 7.61 (s, 1H), 7.82 (s, 1H); ESI–MS: 398
M + H] ; Elemental anal. calculated for C H F NO
%): C, 51.39; H, 3.55; N, 3.53; found: C, 51.44; H, 3.45;
N, 3.66.
3
General procedure. Synthesis of intermediate 1. To a
solution of o-methylaniline (180 g, 1.68 mol) in methyl
tert-butyl ether solution (800 mL) and water (800 mL),
the mixture of tetrabutylammonium hydrogen sulfate
(
[
(
+
17
14
7
2
(50.5 g, 1.68 mol), sodium bicarbonate (125.16 g,
2
,3,8-Trimethyl-6-(perfluoropropan-2-yl)quinolin-4-yl
1
.68 mol), and hydrosulfite (259.42 g, 1.68 mol) was
1
but-3-ynoate 3b.
White solid, yield 67.2%, H NMR
added dropwisely at 25°C. Then the 1,1,1,2,3,3,3-
heptafluoro-2-iodopropane (497.28 g, 1.68 mol) was
dropwised slowly at 0°C, TLC monitored. After the
reaction is completed, subsequently, the reaction mixture
was diluted with water (200 mL); the organic layer was
seperated. Then the residue solution was extracted several
times with ethyl acetate (200 mL). The combined organic
phases were washed with brine, dried over magnesium
sulfate, and evaporated to afford the red brown oil
(
2
(
400 MHz, CDCl ) δ: 1.05 (t, 3H), 1.79–1.88 (m, 2H),
3
.35 (s, 3H), 2.78 (s, 3H), 2.85 (s, 3H), 4.32 (t, 2H), 7.66
+
s, 1H), 7.95 (s, 1H); ESI–MS: 436 [M + H] ; Elemental
anal. calculated for C H F NO (%): C, 55.18; H, 3.70;
N, 3.22; found: C, 55.23; H, 3.86; N, 3.12.
20
16
7
2
8-Ethyl-2,3-dimethyl-6-(perfluoropropan-2-yl)quinolin-4-
yl(2-methoxyethyl)carbonate 3c. White solid, yield 54.3%,
1
H NMR (400 MHz, CDCl ) δ: 2.34 (s, 3H), 2.76 (s, 3H),
3
2.83 (s, 3H), 3.81 (t, 2H), 4.58 (t, 2H), 7.64 (s, 1H), 7.93 (s,
1
for C H F NO (%): C, 50.96; H, 4.28; N, 2.97; found:
+
(
328.02 g, yield 71%) without further purified. The 2-
H); ESI–MS: 472 [M + H] ; Elemental anal. calculated
ethyl-4-(perfluoropropan-2-yl)aniline was synthesized
20 20 7 4
according to this procedure with the yield 95%.
Synthesis of intermediate 2a. In a 500 mL three-neck
bottom, the 2-methyl-4-(perfluoropropan-2-yl)aniline
C, 51.01; H, 4.32; N, 2.89.
Butyl (8-ethyl-2,3-dimethyl-6-(perfluoropropan-2-yl)quinolin-
4-yl) carbonate 3d. White solid, yield 58.0%, H NMR
1
(
(
100 g, 0.364 mol), ethyl 2-substituted-3-oxobutanoate
0.364 mol), and polyphosphoricacid (75.5 g) were stirred
(400 MHz, CDCl ) δ: 0.99 (t, 3H), 1.37 (t, 3H), 1.43–1.50
(m, 2H), 1.75–1.79 (m, 2H), 2.33 (s, 3H), 2.75 (s, 3H),
3
at 150°C, TLC monitored. After the reaction is completed,
the mixture was poured into the water (400 mL); lots of
solid was given and dried, yield 93.1%. The intermediate
3.31 (q, 2H), 4.35 (t, 2H), 7.70 (s, 1H), 7.92 (s, 1H); ESI–
MS: 470 [M + H] ; Elemental anal. calculated for
+
C H F NO (%): C, 53.73; H, 4.72; N, 2.98; found: C,
21
22
7
3
2
b, 2c, and 2d were synthesized according this method.
53.98; H, 4.65; N, 3.01.
Scheme 2. The synthetic route of title compounds.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Quinolines with Antifungal Activities
Ethyl (8-ethyl-2,3-dimethyl-6-(perfluoropropan-2-yl)quinolin-
5.37–5.49 (m, 2H), 6.02 (m, 1H), 7.62 (s, 1H), 7.91 (s,
1
+
4
(
-yl) carbonate 3e.
White solid, yield 61.3%, H NMR
1
H); ESI–MS: 482 [M + H] ; Elemental anal. calculated
400 MHz, CDCl ) δ: 1.37 (t, 3H), 1.43 (t, 3H), 2.33 (s,
3
for C H F NO (%): C, 54.89; H, 4.61; N, 2.91; found:
22
22
7
3
3
7
H), 2.75 (s, 3H), 3.32 (q, 2H), 4.39 (q, 2H), 7.63 (s, 1H),
.92 (s, 1H); ESI–MS: 442 [M + H] ; Elemental anal.
C, 54.88; H, 4.58; N, 3.02.
2-Ethyl-3,8-dimethyl-6-(perfluoropropan-2-yl)-4-
phenoxyquinoline 3m. White solid, yield 61.5%, H NMR
+
1
calculated for C H F NO (%): C, 51.71; H, 4.11; N,
1
9
18
7
3
(
400 MHz, CDCl ) δ: 1.42 (t, 3H), 2.29 (s, 3H), 2.84 (s,
3
.17; found: C, 51.65; H, 4.15; N, 3.24.
3
8
-Ethyl-2,3-dimethyl-6-(perfluoropropan-2-yl)quinolin-4-
3H), 3.02 (q, 2H), 5.34 (s, 2H), 7.40–7.89 (m, 7H); ESI–
MS: 446 [M + H] ; Elemental anal. calculated for
C H F NO (%): C, 59.33; H, 4.07; N, 3.14; found: C,
22 18 7
+
yl(trichloromethyl) carbonate 3f. White solid, yield 44.7%,
H NMR (400 MHz, CDCl ) δ: 1.37 (t, 3H), 2.56 (s, 3H),
1
3
2
.76 (s, 3H), 3.32 (q, 2H), 7.65 (s, 1H), 8.32 (s, 1H); ESI–
59.44; H, 3.99; N, 3.21.
+
MS: 531 [M + H] ; Elemental anal. calculated for
C H Cl F NO (%): C, 40.74; H, 2.47; N, 2.64; found:
C, 40.87; H, 2.45; N, 2.66.
2-Ethyl-3,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-4-
1
ylacetate 3n.
White solid, yield 42.2%, H NMR
18
13
3
7
3
(
400 MHz, CDCl ) δ: 1.21 (t, 3H), 2.52 (s, 3H), 2.73 (q,
3
2
H), 2.81 (s, 3H), 2.83 (s, 3H), 7.62 (s, 1H), 7.76 (s,
2
-Ethyl-3,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-4- 1
+
ylisopropylcarbonate 3g.
White solid, yield 49.2%, H
1H); ESI–MS: 412 [M + H] ; Elemental anal. calculated
NMR (400 MHz, CDCl ) δ: 1.35–1.45 (m, 9H), 2.85 (s,
for C18
H F NO (%): C, 52.56; H, 3.92; N, 3.41; found:
16 7 2
3
3
H), 3.03 (q, 2H), 4.99–5.06 (m, 1H), 7.64 (s, 1H), 7.91
C, 52.67; H, 3.98; N, 3.66.
+
2
-Chloroethyl (2-ethyl-3,8-dimethyl-6-(perfluoropropan-2-yl)
(s, 1H); ESI–MS: 456 [M + H] ; Elemental anal.
1
quinolin-4-yl) carbonate 3o. White solid, yield 47.2%, H
calculated for C H F NO (%): C, 52.75; H, 4.43; N,
2
0
20
7
3
NMR (400 MHz, CDCl ) δ: 1.23 (t, 3H), 2.78–2.83 (m,
3
3
.08; found: C, 52.67; H, 4.45; N, 3.05.
8
H), 3.82 (t, 2H), 4.59 (t, 3H), 7.65 (s, 1H), 7.88 (s, 1H);
Allyl(2-ethyl-3,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
+
1
ESI–MS: 476 [M + H] ; Elemental anal. calculated for
C H ClF NO (%): C, 47.96; H, 3.60; N, 2.94; found:
4
-yl)carbonate 3h. White solid, yield 56.0%, H NMR
(400 MHz, CDCl ) δ: 1.43 (t, 3H), 2.34 (s, 3H), 2.85 (s,
19 17
7
3
3
C, 48.04; H, 3.45; N, 2.87.
Butyl(2-ethyl-3,8-dimethyl-6-(perfluoropropan-2-yl)quinolin-
4-yl)carbonate 3p. White solid, yield 61.5%, H NMR
3
5
4
H), 3.03 (q, 2H), 4.80 (d, 2H), 5.37–5.49 (m, 2H),
.98–6.07 (m, 1H), 7.64 (s, 1H), 7.93 (s, 1H); ESI–MS:
1
+
54 [M
+
H] ; Elemental anal. calculated for
(
400 MHz, CDCl ) δ: 1.02 (t, 3H), 1.23 (t, 3H),
3
C H F NO (%): C, 52.99; H, 4.00; N, 3.09; found: C,
20
18
7
3
1
.78–1.81 (m, 2H), 2.77–2.83 (m, 8H), 4.30 (t, 2H),
53.06; H, 3.95; N, 3.24.
+
7
.64 (s, 1H), 7.87 (s, 1H); ESI–MS: 470 [M + H] ;
8
-Ethyl-3-methyl-6-(perfluoropropan-2-yl)-2-
Elemental anal. calculated for C H ClF NO (%): C,
53.73; H, 4.72; N, 2.98; found: C, 53.87; H, 4.77; N,
phenylquinolin-4-ylpropylcarbonate 3i. White solid, yield
19 17
7
3
1
5
1
2
1.8%, H NMR (400 MHz, CDCl ) δ: 1.06 (t, 3H),
.39 (t, 3H), 1.80–1.89 (m, 2H), 2.38 (s, 3H), 3.34 (q,
H), 4.34 (t, 2H), 7.48–8.01 (m, 7H); ESI–MS: 518
3
3
.01.
Bioassay for P. oryae.
The antifungal activity was
+
tested according to our previous work [15]. Greenhouse-
grown rice and cucumber seedlings with four leaves were
used as the host plants. They were sprayed with the test
solution and then placed in a drying hood at room
temperature. Three replicates were used for each
treatment. Tested compounds and commercial fungicides
tebufloquin were sprayed with a hand sprayer on the
surface of the leaves (5 mL per plant) at different
concentrations. After 24 hr, inoculations of P. oryae were
[M + H] ; Elemental anal. calculated for C H F NO
2
5
22
7
3
(%): C, 58.03; H, 4.29; N, 2.71; found: C, 58.21; H,
4
.44; N, 2.97.
8
-Ethyl-3-methyl-6-(perfluoropropan-2-yl)-2-
phenylquinolin-4-yl phenyl carbonate 3j. White solid, yield
1
4
7.6%, H NMR (400 MHz, CDCl ) δ: 1.40 (t, 3H), 2.48
3
(
[
(
s, 3H), 3.36 (q, 2H), 7.28–8.12 (m, 12H); ESI–MS: 552
M + H] ; Elemental anal. calculated for C H F NO
%): C, 60.98; H, 3.66; N, 2.54; found: C, 61.04; H,
+
2
8
20
7
3
carried out by spraying fungal spore suspensions with
3
.45; N, 2.49.
5
2
× 10 spore/mL, homogenized with an IKA T10 basic
Ethyl (8-ethyl-2-isopropyl-3-methyl-6-(perfluoropropan-2-yl)
1
quinolin-4-yl) carbonate 3k. White solid, yield 49.3%, H
NMR (400 MHz, CDCl ) δ: 1.37–1.46 (m, 12H), 2.38 (s,
ULTRA-TURRAX homogenizer (Guangzhou, China).
Each kind of inoculum was sprayed at the volume of
5 mL/plant. After inoculation, the plants were maintained
at 18–30°C [mean temperature of 24°C and about 80%
relative humidity]. The fungicidal activity was evaluated
when the nontreated plant (blank) fully developed
symptoms. The area of inoculated treated leaves covered
by disease symptoms was assessed and compared with
that of nontreated ones to determine the average disease
index after 7 days. The relative fungicidal efficacy of
3
3
H), 3.32 (q, 2H), 3.41–3.47 (m, 1H), 4.39 (q, 2H), 7.62
+
(s, 1H), 7.91 (s, 1H); ESI–MS: 470 [M + H] ; Elemental
anal. calculated for C H F NO (%): C, 53.73; H, 4.72;
N, 2.98; found: C, 53.98; H, 4.75; N, 3.03.
2
1
22
7
3
Allyl (8-ethyl-2-isopropyl-3-methyl-6-(perfluoropropan-2-yl)
1
quinolin-4-yl) carbonate 3l. White solid, yield 47.6%, H
NMR (400 MHz, CDCl ) δ: 1.35–1.39 (m, 9H), 2.38 (s,
3
3
H), 3.30–3.34 (q, 2H), 3.45 (m, 1H), 4.80 (d, 2H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y.-M. Fang, R.-R. Zhang, Z.-H. Shen, H.-K. Wu, C.-X. Tan, J.-Q. Weng, T.-M. Xu, and X.-H. Liu Vol 000
compounds compared with the blank assay was calculated
via the following equation:
RESULTS AND DISCUSSION
The synthetic route is showed in Scheme 2. Generally,
perfluoropropanyl substituted aniline was synthesized
using substituted aniline and FITS reagent as starting
materials. In this paper, 1,1,1,2,3,3,3-heptafluoro-2-
iodopropane was used as FITS reagent due to it can form
positive ion easily under the initiator Na S O .
relative control efficacyð%Þ ¼ ðCK ꢀ PTÞ=CKꢁ100%;
where CK is the average disease index of the blank assay
and PT is the average disease index after treatment during
testing. All experiments were replicated three times.
2
2 4
Table 1
The in vivo protection and curative efficacy against Pyricularia oryae at different concentration.
1
3
2
3
4
No.
R
R
R
R
Concentration (mg/L)
100
Protection efficacy (%)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
CH
COCH
3
2
CH
3
CH
CH
CH
CH
CH
CH
Et
3
3
3
3
3
3
100
65
45
100
65
35
95
70
55
90
65
0
5
1
0
0
Et
COCH
CCH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
100
5
1
0
0
Et
COOCH
COOCH
COOCH
2
2
2
CH
2
2
3
OCH
3
100
5
1
0
0
d
e
Et
CH
CH
CH
2
CH
3
100
5
1
0
0
Et
100
100
75
30
80
65
30
100
60
25
90
70
25
100
85
45
100
70
35
95
70
50
100
90
75
100
75
45
100
99
85
100
95
80
100
85
70
100
70
0
5
1
0
0
f
Et
COOCCl
3
100
5
1
0
0
g
h
i
CH
CH
Et
3
COOCH(CH
3
)
2
100
5
1
0
0
3
COOCH
COOCH
COOAr
COOCH
COOCH
COOCH
2
CH = CH
2
Et
100
5
1
0
0
2
CH
2
CH
3
Ph
100
5
1
0
0
j
Et
Ph
100
5
1
0
0
k
l
Et
2
2
2
CH
3
CH(CH
CH(CH
Et
3
)
2
2
100
5
1
0
0
Et
CH = CH
2
3
)
100
5
1
0
0
m
n
o
p
CH
CH
CH
CH
3
3
3
3
Ph
100
5
1
0
0
COCH
3
Et
100
5
1
0
0
COOCH
2
2
CH
2
2
Cl
Et
100
5
1
0
0
COOCH
CH
CH
2
CH
3
Et
100
5
1
0
0
Tebufloquin
100
5
1
0
0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Quinolines with Antifungal Activities
Table 2
CLogP, total energy, energy gap, and frontier orbital energy.
100 mg/L, except compounds 3c (95%), 3d (90%), 3f
(85%), 3h (95%), and 3k (95%). On the other hand, all
of the compounds held good in vivo curative activity
DFT
3n
Tebufloquin
(
>85%) against P. oryae at 100 mg/L. The control
b
E
E
E
total/Hartree
ꢀ1598.85738245
ꢀ0.22205
ꢀ0.08253
0.13952
ꢀ1865.96608237
ꢀ0.22894
ꢀ0.07096
0.15798
Tebufloquin was studied at the same condition with the
values of 100% (protection activity).
HOMO/Hartree
LUMO/Hartree
a
ΔE /Hartree
On the basis of the preliminary in vivo fungicidal
activity against P. oryae results, the title compounds were
selected for further bioassay at lower dose for fungicidal
activity against P. oryae. The subsequent results in
Table 1 showed that the most of tested compounds had
moderate protection activity against P. oryae with the
range of 65–85% inhibition at 50 mg/L. But the
compound 3l (90%), 3n (99%), and 3o (95%) possessed
good efficacy against P. oryae at 50 mg/L. The three
compounds exhibited higher protection activity than that
of control Tebufloquin (70%). At the concentration of
10 mg/L, the control Tebufloquin had no activity. But
most of title compounds exhibited good protection
activity efficacy, such as compounds 3l (75%), 3n (85%),
and 3o (80%), respectively. Among them, only
compound 3d had no inhibitory against P. oryae at
10 mg/L.
CLogP
5.53
4.81
a
ΔE = ELUMO ꢀ EHOMO.
b
ꢀ18
1
Hartree = 4.35974417 × 10
J = 27.2113845ev.
Many references reported the synthetic methods about
quinolone derivatives, such as Skraup method, Combes
method, Camps method, Niementowsld method,
Friedlander method, and Pfitzinger method. Comparing
these method, Combes method was selected, which
cyclized from the starting material 2-methyl-
-(perfluoropropan-2-yl)aniline and ethyl 2-methyl-3-
oxobutanoate under acid condition. At first, the target
compounds were synthesized using THF as solvent and
Et N as base, but the yield is low, and the target
4
3
compound is difficult to purity. Finally, we selected
acetone as solvent and K CO3 as base; the yield
In order to study their structure–active relationship, we
choose a high active compound 3n and lead compound
Tebufloquin as model compounds; the frontier orbital and
CLogP was calculated. The CLogP, energy of HOMO and
LUMO, total energy, and energy gap are listed in Table 2
According to the frontier molecular orbital theory,
HOMO has the priority to provide electrons, while
LUMO can accept electrons firstly. As we can see from
Figure 1, the LUMO and HOMO are different between
the high active compound 3n and lead compound
Tebufloquin, especially in the orient of electron transition
2
increased and can purity easily. All the compounds were
1
identified and characterized by H NMR, MS, and
elemental analysis. The appearance of signals at about
7
.6 and 7.9 ppm are assigned to CH of quinolone ring
due to the electronegativity of CF (CF ) . Meanwhile,
3
2
+
most of the title compounds exhibited the M + H peak
in the ESI–MS results.
The results of fungicidal activity against P. oryae in vivo
were shown in Table 1. Most of the compounds possessed
excellent in vivo activity (100%) against P. oryae at
Figure 1. Frontier molecular orbitals of compound 3n and Tebufloquin. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y.-M. Fang, R.-R. Zhang, Z.-H. Shen, H.-K. Wu, C.-X. Tan, J.-Q. Weng, T.-M. Xu, and X.-H. Liu Vol 000
and energy gap. For the HOMO, the electron of compound
n is mainly located on the ester carbonate group and ethyl
[2] Gobeil-Richard, M.; Tremblay, D. M.; Beaulieu, C.; Van der
Heyden, H.; Carisse, O. Pest Manag Sci 2016, 72, 566.
3
[3] Hidalgo, W.; Cano, M.; Arbelaez, M.; Zarrazola, E.; Gil, J.;
group and a little on the quinoline ring. On the opposite,
the electron of Tebufloquin is mainly located on the
quinoline ring and the fluorine atom, a little on the two
methyl group and ester carbonate group. For the LUMO,
the two compounds still are different. The electron of
compound 3n is evenly distributed among the ethyl
group, methyl group, and the quinoline ring. But the
electron of Tebufloquin is mainly located on the ester
carbonate group, methyl group, and a little quinolone
ring. Perhaps the reason of different fungicidal activity
between the compound 3n and Tebufloquin is electron
transition direction and energy gap. From the Table 1, we
assumed that the compound with higher energy gap and
lower total energy exhibited higher fungicidal activity.
The other fact is the CLogP. From Table 2, the CLogP is
different between the two compounds.
Schneider, B.; Otalvaro, F. Pest Manag Sci 2016, 72, 796.
[4] Matsumura, M.; Mitomi, M., Yabusaki, M.B., Japan Patent
2007112760. 2005.
[5] Perin, N.; Nhili, R.; Cindric, M.; Bertosa, B.; Vusak, D.;
Martin-Kleiner, I.; Laine, W.; Karminski-Zamola, G.; Kralj, M.; David-
Cordonnier, M. H.; Hranjec, M. Eur J Med Chem 2016, 122, 530.
[6] Ni, Y.; Xu, T. M.; Zhong, L. K.; Kong, X. Y.; Shi, J. J.; Liu,
X. H.; Kong, X. L.; Ji, W. J.; Tan, C. X. Chin J Org Chem 2015, 35,
2
2
218.
399.
[
[
7] Phaniband, M. A.; Dhumwad, S. D. J Coord Chem 2009, 62,
8] Jain, P. P.; Degani, M. S.; Raju, A.; Anantram, A.; Seervi, M.;
Sathaye, S.; Ray, M.; Rajan, M. G. R. Bioorg Med Chem Lett 2016, 26,
645.
[9] Kamath, P. R.; Sunil, D.; Ajees, A. A. Res Chem Intermed
016, 42, 5899.
10] Puskullu, M. O.; Shirinzadeh, H.; Nenni, M.; Gurer-Orhan, H.;
2
[
Suzen, S. J Enzyme Inhib Med Chem 2016, 31, 121.
[11] Ghodsi, R.; Azizi, E.; Ferlin, M. G.; Pezzi, V.; Zarghi, A. Lett
Drug Des Discov 2016, 13, 89.
[12] Di Pietro, O.; Vicente-Garcia, E.; Taylor, M. C.; Berenguer,
To explore higher active compounds with antifungal
activity, some new 6-perfluoropropanyl quinoline
derivatives were designed and synthesized via two steps
with yields ranging from 42% to 62%. Most of them
exhibited excellent in vivo antifungal activity against P.
oryzae at 100 mg/L. Among them, compounds 3n and 3o
are highly active at 10 mg/L. Furthermore, a density
functional theory study established the structure–activity
relationships of the synthesized compounds. It can be
found that the electron transit orient is different between
the high active compound and lead compound
Tebufloquin. Quinoline derivatives, which possess good
control effective against P. oryzae, may become new lead
compounds for the development of antifungals with
further structure modification.
D.; Viayna, E.; Lanzoni, A.; Sola, I.; Sayago, H.; Riera, C.; Fisa, R.;
Clos, M. V.; Perez, B.; Kelly, J. M.; Lavilla, R.; Munoz-Torrero, D. Eur
J Med Chem 2015, 105, 120.
[13] Coa, J. C.; Castrillon, W.; Cardona, W.; Carda, M.; Ospina, V.;
Munoz, J. A.; Velez, I. D.; Robledo, S. M. Eur J Med Chem 2015, 101,
746.
[14] Huang, X.; Bao, Y.; Zhu, S.; Zhang, X.; Lan, S.; Wang, T.
Bioorg Med Chem Lett 2015, 25, 3928.
[15] Liu, X.-H.; Wang, Q.; Sun, Z. H.; Wedge, D. E.; Becnel, J. J.;
Estep, A. S.; Tan, C. X.; Weng, J. Q. Pest Manag Sci 2017, 73, 953.
[16] Yan, S. L.; Yang, M. Y.; Sun, Z. H.; Min, L. J.; Tan, C. X.;
Weng, J. Q.; Wu, H. K.; Liu, X. H. Lett Drug Des Discov 2014, 11, 940.
[17] Zhai, Z. W.; Shi, Y. X.; Yang, M. Y.; Zhao, W.; Sun, Z. H.;
Weng, J. Q.; Tan, C. X.; Liu, X. H.; Li, B. J.; Zhang, Y. G. Lett Drug
Des Discov 2016, 13, 521.
[
18] Liu, X. H.; Tan, C. X.; Weng, J. Q. Phosphorus Sulfur Silicon
Relat Elem 2011, 186, 558.
19] Liu, X. H.; Sun, Z. H.; Yang, M. Y.; Tan, C. X.; Weng, J. Q.;
Zhang, Y. G.; Ma, Y. Chem Biol Drug Des 2014, 84, 342.
20] Zhang, L. J.; Yang, M. Y.; Sun, Z. H.; Tan, C. X.; Weng, J. Q.;
Wu, H. K.; Liu, X. H. Lett Drug Des Discov 2014, 11, 1107.
21] Liu, X. H.; Zhao, W.; Shen, Z. H.; Xing, J. H.; Yuan, J.; Yang,
G.; Xu, T. M.; Peng, W. L. Bioorg Med Chem Lett 2016, 26, 3626.
22] Zhao, W.; Xing, J. H.; Xu, T. M.; Peng, W. L.; Liu, X. H. Front
Chem Sci Eng 2017, 11, 363.
23] Liu, X. H.; Zhao, W.; Shen, Z. H.; Xing, J. H.; Xu, T. M.;
[
[
[
Acknowledgments. This work was supported financially by
Zhejiang Provincial Science Foundation of China (No.
LY16C140007).
[
[
Peng, W. L. Eur J Med Chem 2017, 125, 881.
[24] Zhao, W.; Shen, Z. H.; Xu, T. M.; Peng, W. L.; Liu, X.-H.
J Heterocycl Chem 2017, 54, 1751.
REFERENCES AND NOTES
[
1] Kramer, W.; Schirmer, U. Modern Crop Protection; Wiley-
[25] Zhao, W.; Shen, Z. H.; Xu, T. M.; Peng, W. L.; Liu, X. H. Lett
Drug Des Discov 2017, 14, 323.
VCH: Weinheim, Germany, 2007, pp. 1–30.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet