Synthesis, in vitro antibacterial and antifungal evaluation of novel 1,3,4-oxadiazole thioether derivatives bearing the 6-fluoroquinazolinylpiperidinyl moiety

Article abstract of DOI:10.1016/j.cclet.2019.06.037

A series of structurally novel 1,3,4-oxadiazole thioether derivatives (6a–6z) containing a 6-fluoroquinazolinylpiperidinyl moiety were designed and synthesized using pharmacophore hybrid approach, and their structures were fully characterized by ¹H NMR, ¹³C NMR and HRMS spectra. Among them, the structure of compound 6d was further corroborated via single-crystal X-ray diffraction analysis. In vitro antibacterial bioassays showed that compounds 6a, 6g, 6u and 6v possessed EC₅₀ values of 30.4, 30.6, 27.5 and 26.0 μg/mL against phytopathogenic bacterium Xanthomonas oryzae pv. oryzae, respectively, which were significantly superior to that of commercially-available bactericide Bismerthiazol (85.1 μg/mL). Moreover, in vitro antifungal bioassays indicated that seven compounds demonstrated broad-spectrum fungicidal acitivties against six types of phytopathogenic fungi at 50 μg/mL. The present work showed the potential of 1,3,4-oxadiazole thioether derivatives carrying a 6-fluoroquinazolinylpiperidinyl moiety as effective antimicrobial agents for crop protection, deserving further investigations in the future.

Full text of DOI:10.1016/j.cclet.2019.06.037

Accepted Manuscript
Title: Synthesis, in vitro antibacterial and antifungal
evaluation of novel 1,3,4-oxadiazole thioether derivatives
bearing the 6-fluoroquinazolinylpiperidinyl moiety
Authors: Jun Shi, Na Luo, Muhan Ding, Xiaoping Bao
PII:
DOI:
Reference:
S1001-8417(19)30366-3
https://doi.org/10.1016/j.cclet.2019.06.037
CCLET 5068
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Revised date:
Accepted date:
14 May 2019
15 June 2019
19 June 2019
Please cite this article as: Shi J, Luo N, Ding M, Bao X, Synthesis, in vitro
antibacterial and antifungal evaluation of novel 1,3,4-oxadiazole thioether derivatives
bearing the 6-fluoroquinazolinylpiperidinyl moiety, Chinese Chemical Letters (2019),
https://doi.org/10.1016/j.cclet.2019.06.037
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Communication
Synthesis, in vitro antibacterial and antifungal evaluation of novel 1,3,4-oxadiazole
thioether derivatives bearing the 6-fluoroquinazolinylpiperidinyl moiety
Jun Shi, Na Luo, Muhan Ding, Xiaoping Bao*
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025, China
Graphical abstract
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of structurally novel 1,3,4-oxadiazole thioether derivatives (6a6z) containing a 6-
fluoroquinazolinylpiperidinyl moiety were designed and synthesized using pharmacophore
hybrid approach, and their structures were fully characterized by 1H NMR, 13C NMR and
HRMS spectra. Among them, the structure of compound 6d was further corroborated via
single-crystal X-ray diffraction analysis. In vitro antibacterial bioassays showed that
compounds 6a, 6g, 6u and 6v possessed EC50 values of 30.4, 30.6, 27.5 and 26.0 μg/mL against
phytopathogenic bacterium Xanthomonas oryzae pv. oryzae, respectively, which were
significantly superior to that of commercially-available bactericide Bismerthiazol (85.1
μg/mL). Moreover, in vitro antifungal bioassays indicated that seven compounds demonstrated
broad-spectrum fungicidal acitivties against six types of phytopathogenic fungi at 50 μg/mL.
The present work showed the potential of 1,3,4-oxadiazole thioether derivatives carrying a 6-
fluoroquinazolinylpiperidinyl moiety as effective antimicrobial agents for crop protection,
deserving further investigations in the future.
Available online
Keywords:
1
,3,4-Oxadiazole thioether
Fluoroquinazolinylpiperidinyl
Synthesis
Antibacterial activity
Antifungal activity
Twenty-six 6-fluoroquinazolinylpiperidinyl-containing 1,3,4-oxadiazole thioether derivatives were designed and synthesized as
agricultural antimicrobial agents. The structure of compound 6d was confirmed by single-crystal X-ray diffraction analysis. Compounds
6
a, 6g, 6u and 6v exhibited higher antibacterial efficacy against Xoo than commercial bactericide Bismerthiazol.
Plant diseases have long been recognized as a serious threat to global agricultural production. Among them, phytopathogenic bacteria
and fungi are difficult to control and cause enormous crop yield losses per year [1,2]. For instance, Xanthomonas oryzae pv. oryzae (Xoo)
is a pathogen responsible for rice bacterial leaf blight, which can reduce rice yield by up to 50% under certain conditions [3]. On the
other hand, it is well-known that fungal diseases remain the biggest threat to global agricultural industry at all times [2]. Compared with
other methods, chemical control has some unique advantages, including high effectiveness, low cost and convenient application.
However, some severe problems had emerged due to long-term unreasonable utilization of the existing antimicrobial agents, such as
*
Corresponding author.
E-mail address: baoxp_1980@aliyun.com (X. Bao).

growing germicide resistances, decreasing control effects and environmental pollution [4,5]. Therefore, the search of new and more
efficient agricultural germicides is still an urgent task in the field of crop protection.
Previous studies had shown that 1,3,4-oxadiazole thioether derivatives possessed a wide range of pesticidal activities, including
antibacterial [68], nematicidal [9], antifungal [10], and anti-TMV activities [11]. Generally speaking, the presence of thioether group
in bioactive molecules was believed to increase the hydrophilicity and provide an additional hydrogen-bond accepting site for ligand-
protein binding, which were favorable for improving the pesticide-likeness [12,13]. On the other hand, quinazoline ring was one of the
most significant nitrogen-containing heterocycles, occupying an important position in medicine and pesticide chemistry [14]. Some
quinazoline-based drugs and pesticides have been on the market for many years, like anticancer drugs Gefitinib and Vandetanib, acaricide
Fenazaquin and sympatholytic drug Prazosin (Fig. 1). As is known, the method of pharmacophore hybridization [15,16] is quite practical
for the discovery of new drugs/pesticides as it can provide multiple interacton sites within a single molecule to interact with relevant
proteins of pathogenic microorganisms. Tiodazosin (Fig. 1), a potent competitive postsynaptic -adrenergic receptor antagonist, is just
an excellent example of the delicate combination of 1,3,4-oxadiazole thioether group and quinazoline backbone via a piperazinyl carbonyl
linkage.
In our previous work [4], a series of 1,2,4-triazole thioether derivatives containing both quinazolinylpiperidinyl moiety and acetamide
group were synthesized and some compounds exhibited better antibacterial activities against Xoo in vitro, relative to control agent
Bismerthiazol. Unfortunately, nearly all the compounds failed to display notable fungicidal activity against tested phytopathogenic fungi
at 50 μg/mL. In fact, antimicrobial capabilities of this class of compounds were less satisfied on the whole. As we all know, the
introduction of fluoro group into bioactive molecules can improve the lipophilicity, bioavailability and metabolic stability [1721]. Based
on the aforementioned considerations as well as our prior work [4], we thus designed a series of 1,3,4-oxadiazole thioether derivatives
containing the 6-fluoroquinazolinylpiperidinyl moiety using pharmacophore hybridization method (with the capacity to overcome the
resistance, reducing the toxicity and improve the pharmacokinetic properties) [22] and also took account of the following points: (a)
replacing the 1,2,4-triazole ring by its bioisosteric 1,3,4-oxadiazole ring; (b) introducing a fluoro group into the quinazoline backbone;
(c) simplifying the final structure by removing the amide group (Fig. 2).
Fig. 1. Some representative bioactive molecules containing either the 1,3,4-oxadiazole thioether group or a quinazoline moiety.

Fig. 2. Design strategy of target compounds in this work.
Scheme 1. Synthesis of target compounds 6a6z. Reagents and conditions: (a) HCONH
2
, reflux, 7 h; (b) SOCl
2
, DMF, reflux, 5 h; (c) methyl 4-
piperidinecarboxylate, 1,4-dioxane, reflux, 7 h; (d) hydrazine hydrate, MeOH, r.t., overnight; (e) i) NaOH, EtOH, CS
2
, r.t. 15 min then reflux 8 h; ii) 10% HCl,
2 3 3
pH 5.5; (f) RX, K CO , CH CN, r.t., 8-12 h.
Synthetic procedures for target compounds 6a6z were depicted in Scheme 1. First, 4-chloro-6-fluoroquinazoline 2 [23] was reacted
with methyl 4-piperidinecarboxylate in 1,4-dioxane solution to afford ester 3, which was then subjected to hydrazinolysis for the
preparation of hydrazide 4. Next, hydrazide 4 was treated with CS
2
under basic conditions and then acidified to furnish oxadiazole-thiol
5
. Finally, target compounds 6a6z were readily obtained in 55%95% yield by reaction of thiol 5 with various halogenated
1
2 3 3
hydrocarbons in K CO /CH CN system at room temperature. The structures of target compounds 6a6z were fully characterized by H
1
3
NMR, C NMR and HRMS spectra. Detailed synthetic procedures, characterization data and spectral copies of intermediates 35 and
target compounds 6a6z are available in Supporting information. Fortunately, a single crystal of compound 6d suitable for X-ray
diffraction analysis (Fig. 3) was obtained by slow evaporation of a DMF solution of 6d at room temperature.
Fig. 3. Crystal structure of compound 6d (CCDC 1913061).
In vitro inhibition activities of target compounds 6a−6z and intermediates 35 against three pathogenic bacteria Xoo, Rs (Ralstonia
solanacearum) and Xac (Xanthomonas axonopodis pv. citri) were assessed based on the turbidimetric method [4,24], with commercially-
available agrobactericides Bismerthiazol (BMT) and Thiodiazole-copper (TDC) as positive control agents. As listed in Table 1, some of
the target compounds demonstrated significantly better antibacterial efficacy towards the pathogens under the tested concentrations,
relative to control agents. For example, compounds 6a, 6g, 6h, 6n, 6u and 6v showed the inhibition ratios of 96.8%, 90.9%, 85.1%,
8
5.5%, 91.8% and 92.9% against Xoo at 100 μg/mL, respectively, which were considerably superior to that of control BMT (58.4%).
Unfortunately, only two compounds within the series (namely compounds 6u and 6v) were found to possess a comparable inhibition
activity against Xac at 100 μg/mL, in comparison to control BMT (62.0%). As far as the bacterium Rs was concerned, compounds 6g,
6
h, 6n and 6u had more potent inhibition efficacies of 74.7%, 76.0%, 72.8% and 81.6% at 100 μg/mL, respectively, compared with
control agents BMT (46.1%) and TDC (32.3%).
In consideration of outstanding antibacterial activites exhibited by most of the target compounds against Xoo, EC50 values (half-
maximal effective concentration) of all the target compounds were further determined. As summarized in Table 1, more than half of the
target compounds had a clearly lower EC50 value than control BMT. It was noteworthy that compounds 6a, 6g, 6h, 6i, 6k, 6l, 6n, 6u and
6
v possessed EC50 values of 30.4, 30.6, 36.5, 37.1, 39.4, 41.1, 36.1, 27.5 and 26.0 μg/mL, respectively, over two times more potent than
control BMT (85.1 μg/mL). A preliminary structure-activity relationship analysis demonstrated the following findings: (a) The
introduction of strong electron-withdrawing groups in the benzene ring of benzyl group was detrimental to antibacterial activity, like -
CF , -NO and -OCF groups; (b) The presence of a cyano group at the 2- or 3-position of the benzyl group (compounds 6u and 6v) was
3 2 3
found to be most beneficial to bactericidal activity against Xoo, which may be attributed to the formation of an additional hydrogen bond
between cyano group (being a strong hydrogen-bond acceptor) and relevant bacterial protein [25]; (c) The presence of a mono-halogen

substituent (such as -F and -Cl) on the phenyl ring was helpful to antibacterial activity on the whole, in comparison with other substituents;
d) The existence of sterically bulky tert-butyl group (6e), strong electron-withdrawing -OCF (6x) or 3-NO (6s) groups or ethyl thioether
unit (6z) in the target compounds led to the weakest antibacterial effect.
(
3
2
In vitro antifungal activities of target compounds 6a6z and intermediates 35 were also evaluated using the mycelial growth rate
method [4,5], against six types of phytopathogenic fungi. As shown in Table 2, some of the target compounds displayed a pronounced
fungicidal effect against certain fungi at 50 μg/mL. For example, compounds 6a, 6c, 6d, 6g, 6h, 6j, 6m, 6n, 6q, 6y and 6z exhibited a
significant antifungal activity towards G. zeae, slightly higher or similar to that of control Hymexazol (53.6%). Concerning the fungus
C. gloeosporioides, only compounds 6a and 6h were found to exhibit comparable antifungal activities to control Hymexazol (71.8%). It
should be noted that seven compounds (including 6a, 6c, 6g, 6h, 6m, 6n and 6z) possessed broad-spectrum fungicidal activities against
all six fungi, having an inhibition ratio of >50% in nearly every case.
Table 1
Antibacterial activities of target compounds 6a−6z and intermediates 3, 4 as well as 5 against phytopathogenic bacteria Xoo, Xac and Rs.
Compd. Xoo
Inhibition ratio (%)
00μg/mL
Xac
Rs
a
a
a
Regression equation
r
EC50
(μg/mL)
Inhibition ratio (%)
100 μg/mL 50 μg/mL
Inhibition ratio (%)
100 μg/mL 50 μg/mL
1
50 μg/mL
14.2 ± 1.9
17.1 ± 0.6
21.2 ± 2.2
65.6 ± 1.4
41.3 ± 3.4
33.4 ± 1.8
53.3 ± 2.4
18.2 ± 0.7
19.9 ± 4.8
60.6 ± 3.9
53.0 ± 1.5
52.4 ± 2.1
37.2 ± 4.6
53.6 ± 1.4
57.6 ± 2.6
39.5 ± 2.9
57.8 ± 2.0
40.5 ± 1.4
25.0 ± 1.6
34.4 ± 1.8
29.0 ± 3.1
14.6 ± 3.3
16.3 ± 2.0
61.7 ± 2.7
68.6 ± 2.4
18.6 ± 3.0
12.3 ± 1.6
38.6 ± 2.2
15.6 ± 2.3
35.5 ± 1.7
3
4
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
30.7 ± 1.6
28.3 ± 1.4
43.4 ± 1.0
96.8 ± 0.2
63.4 ± 3.6
54.9 ± 3.3
70.8 ± 1.8
31.0 ± 4.2
37.8 ± 2.5
90.9 ± 2.3
85.1 ± 3.5
81.5 ± 1.3
57.1 ± 1.8
80.5 ± 2.7
74.7 ± 3.0
62.3 ± 2.0
85.5 ± 3.9
54.7 ± 3.9
37.1 ± 2.3
44.7 ± 4.6
43.9 ± 4.0
22.3 ± 2.9
43.4 ± 2.7
91.8 ± 2.1
92.9 ± 3.6
38.3 ± 1.0
25.8 ± 3.8
67.6 ± 2.5
23.4 ± 3.2
58.4 ± 2.2
--
--
--
--
--
--
--
--
--
23.9 ± 0.9
16.4 ± 1.7
21.8 ± 2.0
35.8 ± 3.2
14.8 ± 2.5
38.4 ± 0.6
18.6 ± 0.2
7.6 ± 1.9
10.6 ± 1.3
9.3 ± 2.4
16.5 ± 1.2
21.6 ± 1.3
5.4 ± 1.4
18.3 ± 1.3
7.2 ± 2.4
6.4 ± 3.5
6.4 ± 2.8
22.4 ± 2.5
20.3 ± 2.9
13.7 ± 0.7
9.0 ± 2.4
17.8 ± 1.7
16.3 ± 2.3
2.6 ± 0.5
19.1 ± 1.1
3.8 ± 1.0
2.4 ± 2.5
4.6 ± 2.2
14.6 ± 4.1
7.0 ± 3.6
2.0 ± 2.4
30.4 ± 2.0
37.9 ± 2.6
6.4 ± 1.6
6.1 ± 1.4
23.4 ± 3.1
19.0 ± 1.6
28.7 ± 0.9
17.1 ± 3.6
23.4 ± 2.0
25.7 ± 1.8
50.0 ± 3.9
19.5 ± 5.7
12.8 ± 2.6
42.7 ± 1.3
10.8 ± 3.3
21.4 ± 2.1
74.7 ± 0.9
76.0 ± 2.7
59.4 ± 2.0
48.6 ± 5.0
47.4 ± 2.5
54.4 ± 4.0
46.7 ± 1.4
72.8 ± 1.7
38.5 ± 4.2
17.3 ± 5.7
33.5 ± 4.6
22.0 ± 2.1
2.4 ± 1.9
11.9 ± 5.3
81.6 ± 2.5
59.1 ± 2.7
42.0 ± 1.2
12.5 ± 4.9
39.4 ± 0.9
30.2 ± 2.0
46.1 ± 1.6
32.3 ± 3.9
9.8 ± 2.3
16.1 ± 1.2
15.5 ± 2.1
22.1 ± 2.4
7.8 ± 3.5
6.4 ± 5.3
23.1 ± 4.6
5.0 ± 3.7
10.6 ± 4.1
41.2 ± 0.9
55.4 ± 2.9
26.7 ± 2.7
20.3 ± 4.2
23.2 ± 3.9
42.8 ± 4.3
20.8 ± 6.6
48.8 ± 1.6
24.7 ± 4.4
7.2 ± 5.7
18.7 ± 5.4
7.1 ± 4.6
1.1 ± 2.5
7.1 ± 4.8
54.9 ± 4.0
44.9 ± 5.5
25.2 ± 5.9
9.8 ± 4.5
24.8 ± 1.6
26.9 ± 2.2
36.9 ± 4.8
23.6 ± 2.4
a
b
c
d
e
y = 2.7085x + 0.9825
y = 1.7089x + 1.9594
y = 1.4324x + 2.2107
y = 1.7623x + 2.0284
y = 0.9886x + 2.5081
y = 1.3549x + 1.9345
y = 2.1665x + 1.7826
y = 2.0453x + 1.8040
y = 1.9648x + 1.9164
y = 1.5037x + 2.2127
y = 1.8808x + 1.9995
y = 1.7419x + 2.1897
y = 1.4215x + 2.3019
y = 2.0647x + 1.7851
y = 1.3587x + 2.4589
y = 1.2077x + 2.2092
y = 1.2503x + 2.3077
y = 1.2646x + 2.3341
y = 0.8778x + 2.4234
y = 1.1709x + 2.2939
y = 2.2407x + 1.7743
y = 2.3508x + 1.6742
y = 1.3643x + 1.9461
y = 1.0166x + 2.1887
y = 1.5722x + 2.2044
y = 0.9823x + 2.3156
y = 1.5404x + 2.0271
--
0.9909
0.9974
0.9947
0.9893
0.9839
0.9870
0.9843
0.9845
0.9827
0.9873
0.9885
0.9914
0.9896
0.9808
0.9718
0.9923
0.9873
0.9912
0.9689
0.9523
0.9888
0.9849
0.9980
0.9742
0.9792
0.9832
0.9808
--
30.4 ± 0.7
60.2 ± 4.3
88.6 ± 4.6
48.6 ± 3.2
331.4 ± 4.7
183.0 ± 2.5
30.6 ± 1.1
36.5 ± 2.5
37.1 ± 0.7
71.4 ± 5.2
39.4 ± 3.3
41.1 ± 4.6
79.1 ± 1.6
36.1 ± 0.8
74.2 ± 0.5
204.6 ± 7.0
142.3 ± 4.2
128.3 ± 6.0
861.6 ± 3.2
204.7 ± 6.0
27.5 ± 0.8
26.0 ± 0.3
173.1 ± 8.4
582.6 ± 8.8
60.0 ± 4.0
540.6 ± 7.7
85.1 ± 1.7
--
f
8.8 ± 2.1
g
h
i
j
k
l
m
n
o
p
q
r
50.7 ± 0.4
43.4 ± 1.5
36.8 ± 3.0
13.1 ± 1.2
36.4 ± 2.6
40.3 ± 2.0
4.5 ± 0.7
47.7 ± 3.7
13.3 ± 0.9
10.8 ± 1.3
21.7 ± 2.6
32.3 ± 2.9
9.5 ± 2.9
s
t
3.9 ± 2.4
u
v
w
x
y
z
62.9 ± 2.7
66.1 ± 3.3
9.1 ± 2.3
7.8 ± 3.8
42.1 ± 2.3
33.6 ± 2.0
62.0 ± 1.5
b
BMT
TDC
b
c
c
c
c
NT
NT
NT
NT
a
b
c
The average of three trials.
Commercial bactericides Bismerthiazol (BMT) and Thiodiazole-copper (TDC) were used as positive control agents.
NT: not tested.
Table 2
Antifungal activities of target compounds 6a-6z and intermediates 3, 4 and 5 at 50 μg/mL.
a
Compd.
Inhibition ratio (%)
GZ
18.6 ± 1.1 14.1 ± 2.1 15.0 ± 1.5 27.9 ± 2.6 13.1 ± 0.7 9.0 ± 0.8
9.6 ± 1.9 8.8 ± 2.1 2.8 ± 0.9 4.3 ± 0.9
27.6 ± 2.2 9.8 ± 1.2 23.0 ± 1.3 6.5 ± 1.0 12.9 ± 1.2 10.5 ± 2.5
CG
PI
VD
SS
CM
3
4
5
0
0
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
55.7 ± 0.8 64.9 ± 1.0 65.8 ± 2.4 68.6 ± 0.7 63.0 ± 2.3 52.2 ± 2.6
21.1 ± 0.2 28.9 ± 1.3 38.9 ± 1.0 13.2 ± 1.5 33.2 ± 1.1 10.4 ± 0.9
51.9 ± 2.3 52.1 ± 1.9 55.0 ± 1.7 70.0 ± 1.3 54.1 ± 1.0 47.8 ± 3.9
61.6 ± 0.6 51.8 ± 1.3 58.4 ± 2.1 48.8 ± 2.8 54.8 ± 0.7 29.7 ± 1.3
31.9 ± 2.2 16.0 ± 2.5 26.2 ± 0.3 17.0 ± 3.2 14.4 ± 1.1 4.8 ± 2.1
1.6 ± 1.6
16.4 ± 1.5 11.4 ± 1.0 2.8 ± 0.9
20.1 ± 1.0 3.0 ± 1.0
56.7 ± 2.8 50.8 ± 2.6 53.0 ± 1.7 71.6 ± 1.1 51.4 ± 0.6 43.9 ± 0.5
56.2 ± 2.0 68.7 ± 0.8 56.8 ± 1.5 76.4 ± 1.5 66.1 ± 1.1 55.4 ± 2.4
29.8 ± 1.7 46.6 ± 0.3 44.4 ± 0.9 51.0 ± 0.9 39.1 ± 1.1 33.7 ± 1.5
47.8 ± 2.2 49.6 ± 0.6 56.0 ± 1.1 65.9 ± 1.0 43.1 ± 1.6 38.2 ± 8.3
21.1 ± 1.8 37.9 ± 0.4 43.8 ± 1.3 65.4 ± 2.1 32.2 ± 2.0 42.2 ± 1.4
22.4 ± 1.2 46.9 ± 1.1 45.7 ± 1.4 63.8 ± 0.3 28.9 ± 1.2 46.1 ± 2.8
59.5 ± 1.5 43.2 ± 2.1 50.9 ± 1.9 62.3 ± 1.1 46.0 ± 0.9 47.5 ± 1.9
53.3 ± 0.9 50.9 ± 0.9 49.6 ± 1.2 65.0 ± 1.6 35.6 ± 2.0 47.9 ± 1.1
46.8 ± 2.0 40.1 ± 2.8 53.9 ± 0.7 63.0 ± 1.9 32.3 ± 4.2 17.2 ± 3.4
20.5 ± 2.0 24.4 ± 0.5 35.8 ± 1.9 32.1 ± 1.1 19.3 ± 1.0 16.5 ± 2.4

6
6
6
6
6
6
6
6
6
6
q
r
s
56.5 ± 1.9 17.3 ± 2.8 51.8 ± 0.7 23.8 ± 1.4 54.7 ± 0.5 25.6 ± 1.4
12.4 ± 1.6 21.6 ± 1.1 20.1 ± 1.1 28.1 ± 1.3 15.6 ± 1.4 19.5 ± 0.9
2.9 ± 2.0
9.6 ± 0.9
6.8 ± 2.1
18.9 ± 1.9 8.4 ± 2.8
7.8 ± 1.6
7.5 ± 1.2
11.0 ± 2.0
t
15.2 ± 1.3 23.9 ± 2.2 28.1 ± 2.2 6.8 ± 1.1
u
v
w
x
y
z
43.5 ± 1.2 32.7 ± 2.8 42.5 ± 0.9 73.7 ± 1.4 31.2 ± 0.9 33.4 ± 1.3
9.9 ± 1.0 17.3 ± 2.1 12.8 ± 0.8 34.1 ± 2.6 9.5 ± 0.4 17.3 ± 1.5
22.9 ± 1.5 15.2 ± 1.3 23.9 ± 2.2 15.2 ± 1.3 12.5 ± 2.0 13.9 ± 1.0
21.1 ± 1.8 44.6 ± 1.9 35.2 ± 2.9 48.1 ± 1.9 32.5 ± 0.8 39.4 ± 4.6
50.3 ± 0.5 37.8 ± 1.6 25.5 ± 2.8 32.1 ± 2.1 34.2 ± 3.3 34.5 ± 5.5
55.1 ± 1.7 52.6 ± 0.9 36.0 ± 1.3 79.1 ± 3.0 48.5 ± 0.4 51.3 ± 2.9
53.6 ± 1.4 71.8 ± 1.4 67.5 ± 0.8 86.2 ± 2.3 73.8 ± 2.6 59.8 ± 2.2
b
Hymexazol
GZ: Gibberella zeae; CG: Colletotrichum gloeosporioides; PI: Phytophthora infestans; VD: Verticillium dahlia; SS: Sclerotinia sclerotiorum; CM: Cytospora
mandshurica.
a
The average of three trials.
The commercial agrofungicide Hymexazol was utilized as a positive control agent.
b
In summary, a series of novel 6-fluoroquinazolinylpiperidinyl-containig 1,3,4-oxadiazole thioether derivatives were evaluated as
agricultural antimicrobial agents. In vitro antibacterial bioassays indicated that compounds 6a, 6g, 6u and 6v had significantly higher
inhibiton activity against phytopathogenic bacterium Xoo, relative to commercially-available bactericide Bismerthiazol. Additionally, in
vitro antifungal assays showed that seven compounds demonstrated broad-spectrum fungicidal activities against tested phytopathogenic
fungi at 50 μg/mL. The present work demonstrated the potential of fluoroquinazolinylpiperidinyl-containing 1,3,4-oxadiazole thioether
derivatives as effective antimicrobial agents for crop protection, deserving more considerations in future studies.
Acknowledgments
This work was financially supported by Young Top-Notch Talent Support Program of Guizhou Provincial Education Department (No.
2
018038), Guizhou Provincial High-Level Overseas Talents Innovation and Enterpreneurship Program (No. 201809) and Breeding
Program of Guizhou University (No. 20185781).
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