(R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a diacylhydrazine group: Synthesis, biological evaluation, and SARs

Article abstract of DOI:10.3390/molecules24244440

A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a diacylhydrazine moiety were designed and synthesized. Their structures were confirmed by melting points, 1H NMR, 13C NMR, and elemental analysis (EA). Their antifungal and insecticidal activities were evaluated. The antifungal activity result indicated that most title compounds against Cercospora arachidicola, Alternaria solani, Phytophthora capsici, and Physalospora piricola exhibited apparent antifungal activities at 50 mg/L, and better than chlorothalonil or carbendazim. The EC50 values of (R)-N'-benzoyl-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-5) against six tested phytopathogenic fungi were comparable to those of chlorothalonil. The CoMSIA model showed that a proper hydrophilic group in the R1 position, as well as a proper hydrophilic and electron-donating group in the R2 position, could improve the antifungal activity against Physalospora piricola, which contributed to the further optimization of the structures. Meanwhile, most title compounds displayed good insecticidal activities, especially compound (R)-N'-(4-nitrobenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-3). The insecticidal mechanism results indicated that compound III-3 can serve as e_ective insect Ca2+ level modulators by disrupting the cellular calcium homeostasis in Mythimna separata.

Full text of DOI:10.3390/molecules24244440

Article
(R)-2-Phenyl-4,5-Dihydrothiazole-4-Carboxamide
Derivatives Containing a Diacylhydrazine Group:
Synthesis, Biological Evaluation, and SARs
1
2
1
1,
Feng-Yun Li , Jing-Bo Liu , Jia-Ning Gong and Gen Li *
1
College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine,
Tianjin 300193, China; lifengyun0518@163.com (F.-Y.L.); gongjianing991208@163.com (J.-N.G.)
College of Horticulture and Landscape Architecture, Tianjin Agricultural University,
2
Tianjin 300384, China; liujingbo0626@163.com
* Correspondence: ligen0725@163.com; Tel.: +86-1382-0392-565
Received: 5 October 2019; Accepted: 2 December 2019; Published: 4 December 2019
Abstract: A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a
diacylhydrazine moiety were designed and synthesized. Their structures were confirmed by
1
13
melting points, H NMR, C NMR, and elemental analysis (EA). Their antifungal and insecticidal
activities were evaluated. The antifungal activity result indicated that most title compounds against
Cercospora arachidicola, Alternaria solani, Phytophthora capsici, and Physalospora piricola exhibited
apparent antifungal activities at 50 mg/L, and better than chlorothalonil or carbendazim. The EC50
values of (R)-N’-benzoyl-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-5) against six
tested phytopathogenic fungi were comparable to those of chlorothalonil. The CoMSIA model
1
showed that a proper hydrophilic group in the R position, as well as a proper hydrophilic and
2
electron-donating group in the R position, could improve the antifungal activity against
Physalospora piricola, which contributed to the further optimization of the structures. Meanwhile,
most title compounds displayed good insecticidal activities, especially compound (R)-N’-(4-
nitrobenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-3). The insecticidal
2+
mechanism results indicated that compound III-3 can serve as effective insect Ca level modulators
by disrupting the cellular calcium homeostasis in Mythimna separata.
Keywords: (R)-2-Phenyl-4,5-dihydrothiazole-4-carboxamide; diacylhydrazine; biological activity;
CoMSIA model; insecticidal mechanism.
1. Introduction
By 2050, the global population is projected to grow to over 9 billion, with the associated demand
for increasing food production [1,2]. Plant diseases mainly caused by fungi, viruses, oomycetes, and
bacteria have caused severe losses to the yield of crops in the world per year. The control of plant
diseases in agriculture is very important. Some efficient measures have been taken to resolve the
above problem, and it is well known that the invention and use of agrochemicals play an important
role in reducing crop loss caused by plant diseases. However, many fungal, virus, oomycete, and
bacteria species have developed resistance to some of the currently available agrochemicals due to
long-term use of traditional pesticides with a single mode of action [3–6]. Moreover, the studies found
that a large-scale outburst of drug resistance can be fast accelerated within a relatively short period
once resistant populations emerge, which will further increase the difficulty in solving the severe
problem and the potential risks on food production [7,8]. Therefore scientists have been dedicated to
developing novel agrochemicals with innovative skeletons, novel mechanisms of action, and eco-
friendly characteristics.
Molecules 2019, 24, 4440; doi:10.3390/molecules24244440
www.mdpi.com/journal/molecules

Molecules 2019, 24, 4440
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In drug design processes, one of the most effective and promising ways to discover biological
active structures is based on existing pharmacological skeletons from natural products with various
bioactivities [9–11]. (R)-2-(2-Hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid, as a natural
product representative of 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives, has been
confirmed to possess anticancer activity for L1210 cell lines in vitro [12]. In the past years, researchers
have reported many 2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives with a variety of
biological activities in medicinal chemistry, including antibiotic [13], anti-HIV [14], and anticancer
activities [15]. However, few researches about the application in plant disease prevention have been
reported. Due to low toxicity, good biodegradability, and compatibility, natural products (NPs) have
been broadly used as a source of inspiration for many commercial synthetic organic fungicides,
herbicides, and insecticides, such as coumoxystrobin [16], glufosinate–ammonium [17], berberine
[18–20], and rotenone [21,22]. Moreover, natural products have also frequently served as lead
compounds in developing novel synthetic pesticides, which possess better efficacies than natural
products [23]. Recently, our research group found that some (R)-2-aryl-4,5-dihydrothiazole-4-
carboxylic acid derivatives containing amide and ester moieties displayed remarkable and broad-
spectrum antifungal activities [24,25], indicating that (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid
derivatives could be used as new potential lead structures for the development of antifungal agents.
It is well known that the nitrogen of acylhydrazine as an electron-rich group can easily form
hydrogen bonds with various enzymes in organisms to display various biological activities, such as
fungicidal [26], insecticidal [27,28], herbicidal [29], antivirus [30], antimicrobacterial [31],
antitrypanosomal [32], antitumor [33], and antioxidant activities [34]. Introducing acylhydrazine
structure into bioactive molecules is a significant method in improving the bioactivities to develop
new potent pesticidal candidates with novel modes of action by binding to different target receptors.
Inspired by the descriptions above, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide
derivatives containing a diacylhydrazine moiety (Figure 1) were designed and synthesized, and their
1
13
structures were confirmed by melting points, H NMR, C NMR, and elemental analysis (EA). Their
biological activities were investigated accordingly. The preliminary structure activity relationship
(SAR) was analyzed as well, and the preliminary insecticidal mechanism was explored with the
calcium imaging technique.
Figure 1. Design strategy of the title compounds.

Molecules 2019, 24, 4440
2. Results and Discussion
2.1. Chemistry
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The synthetic routes of the title compounds are shown in Scheme 1. Intermediates 2 were
prepared by treated benzoyl chloride derivatives 1 with tert-butylcarbazate [35]. After that,
intermediates 3 were obtained by treating intermediates 2 with 4 mol/L hydrochloride in methanol
in good yields. Intermediates 6 were synthesized by treating L-cysteine 5 with benzonitrile
derivatives 4 in the presence of sodium bicarbonate and sodium hydroxide in the mixture of
methanol and water, according to our previous report with some improvement [25]. Initial attempts
to synthesize the title compounds I–III by coupling intermediates 3 and 6 with N-(3-
dimethylaminopropyl)-N’-ethylcarbodiimide
hydrochloride
(EDCI)
and
1-hydroxy-1H-
benzotriazole (HOBT) as coupling reagents in the presence of triethylamine (Et3N) as acid binding
reagent, however, yielded very low title compounds. Then, with the improvement of reaction
conditions, N,N-diisopropylethylamine (DIPEA) was used as the acid binding reagent, and title
compounds I–III were obtained in moderate yields. The structures of title compounds were
1
13
confirmed by H NMR, C NMR, and elemental analysis (EA).
Scheme 1. Synthetic route of title compounds I–III.
2.2. Biological Activity and Structure Activity Relationships
2.2.1. Antifungal Activity and 3D-QSAR
To explore the relationship between activities of title compounds with different types of functional
1
2
1
2
groups R and R on the benzene ring, compounds with R (H, CH3, NO2) and R (H, CH3, NO2, OCH3, Cl)
were designed and synthesized. Title compounds I–III against six phytopathogenic fungi were evaluated
by the mycelium growth rate test according to the literature [36]. As shown in Table 1, most of the
compounds against Cercospora arachidicola, Alternaria solani, Phytophthora capsici, and Physalospora piricola
displayed obvious antifungal activities (in vitro) at the concentration of 50 mg/L, and better than the
control chlorothalonil or carbendazim. Furthermore, it is worthy to note that compounds I-1 and I-5
1
exhibited broad-spectrum antifungal activities. On the whole, when the group R was the same, the group
2
R on the benzene ring exerted different effects on antifungal activity following the order Cl and H > CH3
2
2
> OCH3 and NO2. For example, I-1 (R = H) and I-5 (R = Cl) against Phytophthora capsici exhibited 71.5%
2
2
2
and 72.4% antifungal activities, respectively, whereas I-2 (R = CH3), I-3 (R = OCH3), and I-4 (R = NO2)
displayed 64.2%, 52.7%, and 50.2% antifungal activities, respectively. Meanwhile, when the group R was
the same, the sequence of the antifungal activities of these compounds with R was H > CH3 and NO2.
From Table 1, the antifungal activities of compounds I (R = H) were better than those of II (R = OCH3)
2
1
1
1

Molecules 2019, 24, 4440
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1
1
2
and III (R = NO2). These results clearly indicate that the groups R = H and R = Cl or H on the benzene
ring had a positive effect on the antifungal activities. Meanwhile, the antifungal activities of compounds
I-1, II-1, and III-1 were better than that of 6a, indicating that introducing diacylhydrazine moiety could
improve the antifungal activity.
The EC50 values of compound I-5 against six phytopathogenic fungi were further tested and are
displayed in Table 2. From it, the EC50 values of compound I-5 were comparable to those of chlorothalonil.
Moreover, the EC50 value of compound I-5 against Physalospora piricola was lower than that of
chlorothalonil, indicating that compound I-5 against Physalospora piricola exhibited better antifungal
activity compared with chlorothalonil.
Table 1. Antifungal activity of the title compounds I−III.
Antifungal activity, inhibition rate (%, 50 mg/L)
1
2
Compd.
R
R
1
CA
AS
PC
FG
50.5
42.4
35.3
35.8
52.3
35.6
35.2
18.7
23.6
36.3
26.2
14.9
9.8
PP
SS
I-1
I-2
I-3
I-4
I-5
II-1
II-2
II-3
II-4
II-5
III-1
III-2
III-3
III-4
III-5
6a
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
NO2
NO2
NO2
NO2
NO2
--
H
CH3
NO2
OCH3
Cl
61.2
55.1
48.3
50.8
64.5
48.5
35.7
28.2
33.5
47.1
49.9
36.2
33.8
36.3
51.6
24.8
60.3
12.1
56.7
43.8
37.3
37.4
60.4
42.2
40.3
34.2
40.1
53.4
55.6
50.3
30.2
47.3
54.4
25.9
71.5
38.3
71.5
64.2
52.7
50.2
72.4
63.6
57.1
44.3
43.9
65.8
60.5
50.3
42.6
45.8
60.6
33.7
87.6
31.4
75.2
72.5
61.9
63.2
84.3
73.8
71.6
54.3
50.4
76.7
67.3
63.4
51.1
52.5
69.2
43.5
82.5
45.6
50.7
46.9
35.8
19.5
49.8
45.2
30.8
34.8
13.4
43.6
36.7
30.2
27.7
14.9
33.4
10.3
42.0
97.7
H
CH3
NO2
OCH3
Cl
H
CH3
NO2
OCH3
Cl
13.0
35.7
8.3
40.5
99.1
H
chlorothalonil
carbendazim
1 CA: Cercospora arachidicola; AS: Alternaria solani; PC: Phytophthora capsici; FG: Fusarium graminearum;
PP: Physalospora piricola; SS: Sclerotinia sclerotiorum.
Table 2. Antifungal activity of the title compounds I−III.
Compd.
I-5
Fungus
Cercospora arachidicola
Alternaria solani
Phytophthora capsici
Fusarium graminearum
Physalospora piricola
Sclerotinia sclerotiorum
EC50
15.6
21.5
9.3
8.5
6.1
Compd.
chlorothalonil
Fungus
Cercospora arachidicola
Alternaria solani
Phytophthora capsici
Fusarium graminearum
Physalospora piricola
Sclerotinia sclerotiorum
EC50
15.5
17.9
5.0
8.1
6.6
2.4
1.3
In order to elucidate the substitution effect on antifungal activity against Physalospora piricola of
the title compounds, a brief 3D-QASR analysis was carried out using Sybyl 6.9 software based on
pEC50 in Table 3 (Figure 2). The obtained 3D-QASR model was in agreement with the statistically
2
2
recommended values (q > 0.5, r > 0.8). To better reveal the 3D-QSAR results, I-5 was used as the
template molecule by virtue of the best antifungal activity. Steric, hydrophobic, electrostatic, H-bond
donor, and H-bond acceptor fields were used to build the CoMSIA model, and the sequence of the
relative contribution of them to the 3D-QASR model was electrostatic (47.5%) > hydrophobic (34.5%)
> H-bond acceptor (12.6%) > steric (5.4%) > H-bond donor (0%), which suggests that the antifungal
activity was mainly determined by electrostatic and hydrophobic fields.

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Table 3. EC50 (mg/L) and pEC50 of compounds I–III, chlorothalonil, and carbendazim against
Phytophthora piricola.
a
b
a
b
Compd.
EC50
9.6
12.3
16.2
19.0
6.1
pEC50
2.02
1.91
1.79
1.72
2.21
2.01
1.90
1.70
1.67
pEC50
2.13
1.94
1.78
1.74
2.24
1.97
1.99
1.68
1.60
Compd.
II-5
III-1
EC50
9.7
pEC50
2.01
1.82
1.78
1.67
1.69
1.95
-
pEC50
c
I-1
I-2
1.97
1.87
1.84
1.76
1.64
2.02
-
15.2
16.7
21.2
20.5
11.3
6.6
c
I-3
I-4
I-5
II-1
III-2
c
III-3
III-4
III-5
Chlorothalonil
Carbendazim
9.8
c
II-2
II-3
12.5
20.1
21.3
32.3
-
-
c
II-4
a Observed antifungal activity (pEC50); b calculated antifungal activity (pEC50); c the test set molecules.
Figure 2. Alignment of compounds I–III.
The CoMSIA contour maps in Figure 3 show how the electrostatic and hydrophobic fields contribute
to the antifungal activities. As for the electrostatic CoMSIA contour map (Figure 3), the red contours are
mainly located near the R2 group, indicating that placing proper electron-donating groups at this position
is favorable to antifungal activities, which is in agreement with the antifungal activities in the sequence of
2
the R group H and Cl > CH3 > OCH3 and NO2. As shown in the hydrophobic CoMSIA contour map
1
2
(Figure 3), around the R and R groups, the white contours mean that placing proper hydrophilic groups
at the positions could improve the antifungal activity, whereas there are almost no yellow contours
around the positions, indicating that placing hydrophobic groups is detrimental to activity, which is in
agreement with the antifungal activity. The results of the CoMSIA contour maps suggest that a proper
1
hydrophilic group in the R position, as well as a proper hydrophilic and electron-donating group in the
2
R position, could improve the antifungal activity against Physalospora piricola, which contributes to the
further optimization of the structures.
Figure 3. The contour map of the electrostatic field (a) and the hydrophobic field (b).

Molecules 2019, 24, 4440
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2.2.2. Insecticidal Activity Against Mythimna separata and Calcium Imaging
The insecticidal activities of title compounds I–III against Mythimna separata were tested and are
shown in Table 4. Title compounds I–III against Mythimna separata were determined in the
greenhouse according to the reported method [37]. As shown in Table 4, most of them confirm good
1
2
insecticidal activities at the concentration of 50 mg/L. Especially, compound III-3 (R = NO2, R = NO2)
showed more effective insecticidal activity than those of other compounds at 10 mg/L, which reveals
1
2
that the groups R = NO2 and R = NO2 on the benzene ring play an important role in the insecticidal
activities.
Table 4. Insecticidal activities of title compounds and chlorantraniliprole against Mythimna separata.
larvicidal activity (%) at concn of (mg/L)
larvicidal activity (%) at concn of (mg/L)
Compd.
Compd.
200 mg/L
100
50 mg/L
83
10 mg/L
50
200 mg/L
100
50 mg/L
83
10 mg/L
23
I-1
I-2
II-4
II-5
100
77
43
100
90
53
I-3
I-4
I-5
II-1
II-2
II-3
100
100
100
100
100
100
100
77
87
83
100
100
67
33
57
43
47
57
III-1
III-2
III-3
III-4
III-5
100
100
100
100
100
100
100
100
100
87
77
100
53
57
77
43
37
100
1
Chlo
1 Chlo: Chlorantraniliprole.
To explore the insecticidal mechanism of target compounds, influences of III-3 on calcium
channels in the central neurons isolated from the third instar of Mythimna separata were studied with
the calcium imaging technique after neuron loading with fluo-3 AM. As shown in Figure 4, compared
with the initial value when the central neurons treated with 20 ppm III-3 and chlorantraniliprole, the
2+
peaks of [Ca ]i increased to some extent (III-3: 105.2 ± 0.65, n = 7; chlorantraniliprole: 107.5 ± 0.78, n
= 7), respectively. The results indicate that III-3 can release stored calcium ions, likely from the
endoplasmic reticulum (ER) of Mythimna separata neurons. Combined with our previous work,
ryanodine receptors could be the biochemical target of III-3, and further research will be needed.
Figure 4. The change of [Ca2+]i versus recording time when the central neurons treated with 20 ppm
III-3 and chlorantraniliprole in the absence of extracellular calcium.

Molecules 2019, 24, 4440
3. Materials and Methods
3.1. Materials
7 of 12
1
13
H NMR and C NMR were recorded on a Bruker AV400 spectrometer (400 MHz) using CDCl3
or DMSO-d6 as solvent. Chemical shift values (δ) were reported in parts per million (ppm) with
tetramethylsilane (TMS) as the internal standard. Melting points were determined on an X-4
binocular microscope melting point apparatus (Beijing Tech Instruments Co., Beijing, China) and
uncorrected. Elemental analyses were performed on a Vario EL elemental analyzer (Elementar Co.,
Germany). Column chromatography purification was carried out using silica gel (200–300 mesh).
Reagents were all analytically or chemically pure. All solvents and liquid reagents were dried by
standard methods in advance and distilled before use. Intermediate compounds 3a–c and 6a–e were
synthesized in Scheme 1 according to the literature [25,35].
3.2. General Synthetic Procedure for Title Compounds I–III
To a solution of (R)-2-Aryl-4,5-dihydrothiazole-4-carboxylic acid 6 (0.5 mmol), 1-hydroxy-1H-
benzotriazole (HOBt, 0.072 g, 0.53 mmol) and N-(3-dimethylaminopropyl) -N’-ethylcarbodiimide
hydrochloride (EDCI, 0.115 g, 0.6 mmol) were subsequently added to dry dichloromethane (10 mL)
at 0 °C. After stirring at room temperature for 0.5 h, benzohydrazide hydrochloride 3 (0.5 mmol) and
N,N-diisopropylethylamine (DIPEA) (0.142 g, 1.1 mmol) were subsequently added at 0 °C. The
reaction was warmed to room temperature and stirred for 4 h, and then solvent was removed under
reduced pressure, and the residue was purified by silica gel column eluted with petroleum ether and
13
ethyl acetate (V:V = 1:2) to give the title compounds I–III. 1H NMR and C NMR of compounds I-III
are available in Supplementary Materials.
(R)-N’-benzoyl-2-phenyl-4,5-dihydrothiazole-4-carbohydrazide (I-1): White solid, yield 64.3%, m.p. 182–
1
183 °C. H-NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H, CONH), 10.20 (s, 1H, CONH), 7.92 (d, J = 7.4
Hz, 2H, Ph-H), 7.90 (d, J = 8.3 Hz, 2H, Ph-H), 7.60 (t, J = 7.4 Hz, 1H, Ph-H), 7.58 (t, J = 7.7 Hz, 1H, Ph-
H), 7.54 (t, J = 7.5 Hz, 2H, Ph-H), 7.52 (t, J = 7.9 Hz, 2H, Ph-H), 5.40 (t, J = 9.1 Hz, 1H, CH), 3.85–3.78
13
(m, 1H, 1/2CH2), 3.67–3.62 (m, 1H, 1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 169.48, 168.57, 165.34,
132.40, 132.29, 131.82, 128.76, 128.47, 128.34, 127.40, 126.54, 78.09, 34.91. Elem. anal. calcd. for
20
C17H15N3O2S (%): C, 62.75; H, 4.65; N, 12.91. Found: C, 62.79; H, 4.69; N, 12.93. [α] D = +16.2 (c 1,
MeOH).
(R)-N’-benzoyl-2-(p-tolyl)-4,5-dihydrothiazole-4-carbohydrazide (I-2): White solid, yield 66.1%, m.p. 187–
1
188 °C. H-NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H, CONH), 10.16 (s, 1H, CONH), 7.90 (d, J = 7.4
Hz, 2H, Ph-H), 7.79 (d, J = 8.1 Hz, 2H, Ph-H), 7.59 (t, J = 7.3 Hz, 1H, Ph-H), 7.51 (t, J = 7.5 Hz, 2H, Ph-
H), 7.33 (d, J = 8.0 Hz, 2H, Ph-H), 5.36 (t, J = 9.2 Hz, 1H, CH), 3.79–3.74 (m, 1H, 1/2CH2), 3.63–3.58 (m,
13
1H, 1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 169.58, 168.36, 165.35, 141.87, 132.38, 131.84, 129.69,
129.29, 128.47, 128.33, 127.39, 78.02, 34.81, 21.03. Elem. anal. calcd. for C18H17N3O2S (%): C, 63.70; H,
20
5.05; N, 12.38. Found: C, 63.75; H, 5.08; N, 12.42. [α] D = +14.3 (c 1, MeOH).
(R)-N’-benzoyl-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-3): White solid, yield 60.2%,
1
m.p. 190–191 °C. H-NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H, CONH), 10.19 (s, 1H, CONH), 7.94 –
7.89 (m, 4H, Ph-H), 7.62–7.58 (m, 3H, Ph-H), 7.54–7.50 (m, 2H, Ph-H), 5.41 (t, J = 9.2 Hz, 1H, CH), 3.85–
13
3.80 (m, 1H, 1/2CH2), 3.69–3.64 (m, 1H, 1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 169.38, 167.50,
165.35, 153.52, 132.37, 131.85, 131.08, 130.09, 128.88, 128.48, 127.39, 78.09, 35.25. Elem. anal. calcd. for
20
C17H14N4O4S (%): C, 55.13; H, 3.81; N, 15.13. Found: C, 55.15; H, 3.86; N, 15.14. [α] D = +19.8 (c 2,
MeOH).
(R)-N’-benzoyl-2-(4-methoxyphenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-4): White solid, yield 62.6%, m.p.
1
180–181 °C. H-NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H, CONH), 10.15 (s, 1H, CONH), 7.91 (d, J = 7.4
Hz, 2H, Ph-H), 7.85 (d, J = 8.2 Hz, 2H, Ph-H), 7.60 (t, J = 6.9 Hz, 1H, Ph-H), 7.52 (t, J = 7.2 Hz, 2H, Ph-H),
7.06 (d, J = 8.2 Hz, 2H, Ph-H), 5.34 (t, J = 9.0 Hz, 1H, CH), 3.84 (s, 3H, OCH3), 3.79–3.74 (m, 1H, 1/2CH2),

Molecules 2019, 24, 4440
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13
3.63–3.58 (m, 1H, 1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 169.69, 167.69, 165.32, 161.95, 132.40, 131.83,
130.17, 128.47, 127.40, 124.96, 114.04, 77.97, 55.43, 34.92. Elem. anal. calcd. for C18H17N3O3S (%): C, 60.83; H,
20
4.82; N, 11.82. Found: C, 60.85; H, 4.84; N, 11.86. [α] D = +10.5 (c 0.5, MeOH).
(R)-N’-benzoyl-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-5): White solid, yield 58.3%,
1
m.p. 176–177 °C. H-NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H, CONH), 10.16 (s, 1H, CONH), 7.89 (d,
J = 7.3 Hz, 2H, Ph-H), 7.84 (d, J = 7.4 Hz, 2H, Ph-H), 7.73 (d, J = 7.8 Hz, 2H, Ph-H), 7.58 (t, J = 6.7 Hz,
1H, Ph-H), 7.53–7.49 (m, 2H, Ph-H), 5.39 (t, J = 9.1 Hz, 1H, CH), 3.84–3.79 (m, 1H, 1/2CH2), 3.66–3.63
13
(m, 1H, 1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 169.83, 168.13, 165.82, 132.88, 132.33, 132.30, 131.92,
130.74, 128.97, 127.89, 125.95, 78.61, 35.73. Elem. anal. calcd. for C17H14ClN3O2S (%): C, 56.74; H, 3.92;
20
N, 11.68. Found: C, 56.77; H, 3.95; N, 11.65. [α] D = +13.7 (c 1, MeOH).
(R)-N’-(4-methoxybenzoyl)-2-phenyl-4,5-dihydrothiazole-4-carbohydrazide (II-1): White solid, yield 62.1%,
1
m.p. 197–198 °C. H-NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H, CONH), 10.10 (s, 1H, CONH), 7.89 –
7.86 (m, 4H, Ph-H), 7.57 (t, J = 6.8 Hz, 1H, Ph-H), 7.51 (t, J = 7.2 Hz, 2H, Ph-H), 7.03 (d, J = 7.6 Hz, 2H,
Ph-H), 5.36 (t, J = 9.0 Hz, 1H, CH), 3.82 (s, 3H, OCH3), 3.80–3.75 (m, 1H, 1/2CH2), 3.64–3.59 (m, 1H,
13
1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 170.00, 169.01, 165.32, 162.49, 132.80, 132.29, 129.80, 129.25,
128.83, 125.03, 114.19, 78.59, 55.87, 35.40. Elem. anal. calcd. for C18H17N3O3S (%): C, 60.83; H, 4.82; N,
20
11.82. Found: C, 60.86; H, 4.87; N, 11.85. [α] D = +16.9 (c 1, MeOH).
(R)-N’-(4-methoxybenzoyl)-2-(p-tolyl)-4,5-dihydrothiazole-4-carbohydrazide (II-2): White solid, yield 57.5%,
1
m.p. 213–214 °C. H-NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H, CONH), 10.09 (s, 1H, CONH), 7.88 (d, J =
7.4 Hz, 2H, Ph-H), 7.78 (d, J = 8.3 Hz, 2H, Ph-H), 7.32 (d, J = 8.2 Hz, 2H, Ph-H), 7.04 (d, J = 7.3 Hz, 2H, Ph-
H), 5.34 (t, J = 9.2 Hz, 1H, CH), 3.83 (s, 3H, OCH3), 3.79–3.73 (m, 1H, 1/2CH2), 3.63–3.58 (m, 1H, 1/2CH2),
13
2.38 (s, 3H, CH3). C-NMR (101 MHz, DMSO-d6) δ 169.58, 168.27, 164.82, 161.99, 141.84, 129.71, 129.28,
128.32, 124.54, 113.69, 78.03, 55.37, 34.82, 21.03. Elem. anal. calcd. for C19H19N3O3S (%): C, 61.77; H, 5.18; N,
20
11.37. Found: C, 61.82; H, 5.18; N, 11.39. [α] D = +14.8 (c 1, MeOH).
(R)-N’-(4-methoxybenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (II-3): White solid, yield
1
60.5%, m.p. 202–203 °C. H-NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H, CONH), 10.17 (s, 1H, CONH), 8.35
(d, J = 7.7 Hz, 2H, Ph-H), 8.14 (d, J = 7.4 Hz, 2H, Ph-H), 7.87 (d, J = 7.6 Hz, 2H, Ph-H), 7.03 (d, J = 7.7 Hz, 2H,
Ph-H), 5.45 (t, J = 9.2 Hz, 1H, CH), 3.89–3.84 (m, 1H, 1/2CH2), 3.82 (s, 3H, OCH3), 3.73–3.68 (m, 1H, 1/2CH2).
13
C-NMR (101 MHz, DMSO-d6) δ 169.69, 167.76, 165.46, 162.52, 149.67, 138.07, 130.11, 129.81, 124.91, 124.46,
114.21, 78.73, 55.86, 36.02. Elem. anal. calcd. for C18H16N4O5S (%): C, 53.99; H, 4.03; N, 13.99. Found: C,
20
54.02; H, 4.05; N, 14.03. [α] D = +16.7 (c 1, MeOH).
(R)-N’-(4-methoxybenzoyl)-2-(4-methoxyphenyl)-4,5-dihydrothiazole-4-carbohydrazide (II-4): White solid, yield
1
62.2%, m.p. 197–198 °C. H-NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H, CONH), 10.07 (s, 1H, CONH), 7.88
(d, J = 7.6 Hz, 2H, Ph-H), 7.84 (d, J = 7.4 Hz, 2H, Ph-H), 7.06 (d, J = 7.7 Hz, 2H, Ph-H), 7.04 (d, J = 7.3 Hz, 2H,
Ph-H), 5.32 (t, J = 9.2 Hz, 1H, CH), 3.83 (s, 6H, OCH3), 3.77–3.72 (m, 1H, 1/2CH2), 3.61–3.56 (m, 1H, 1/2CH2).
13
C-NMR (101 MHz, DMSO-d6) δ 170.21, 168.12, 165.31, 162.47, 162.43, 130.65, 129.80, 125.45, 125.02, 114.52,
114.18, 78.45, 55.92, 55.86, 35.41. Elem. anal. calcd. for C19H19N3O4S (%): C, 59.21; H, 4.97; N, 10.90. Found:
20
C, 59.24; H, 4.99; N, 10.94. [α] D = +15.1 (c 1, MeOH).
(R)-N’-(4-methoxybenzoyl)-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (II-5): White solid,
1
yield 68.1%, m.p. 203–205 °C. H-NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H, CONH), 10.10 (s, 1H,
CONH), 7.86 (d, J = 7.3Hz, 2H, Ph-H), 7.83 (d, J = 7.7 Hz, 2H, Ph-H), 7.73 (d, J = 7.8 Hz, 2H, Ph-H), 7.03
(d, J = 7.3 Hz, 2H, Ph-H), 5.36 (t, J = 8.9 Hz, 1H, CH), 3.82 (s, 3H, OCH3), 3.82–3.77 (m, 1H, 1/2CH2),
13
3.67–3.62 (m, 1H, 1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 169.94, 168.22, 165.44, 162.50, 132.30,
131.88, 130.73, 129.81, 125.95, 124.93, 114.20, 78.56, 55.86. Elem. anal. calcd. for C18H16ClN3O3S (%): C,
20
55.45; H, 4.14; N, 10.78. Found: C, 55.47; H, 4.17; N, 10.82. [α] D = +19.5 (c 2, MeOH).
(R)-N’-(4-nitrobenzoyl)-2-phenyl-4,5-dihydrothiazole-4-carbohydrazide (III-1): White solid, yield 63.4%,
1
m.p. 211–212 °C. H-NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H, CONH), 10.17 (s, 1H, CONH), 7.88 (d,
J = 7.8 Hz, 2H, Ph-H), 7.83 (d, J = 7.4 Hz, 2H, Ph-H), 7.73 (d, J = 7.6 Hz, 2H, Ph-H), 7.57 (d, J = 7.5 Hz,
1H, Ph-H),7.52–7.48 (m, 2H, Ph-H), 5.38 (t, J = 8.9 Hz, 1H, CH), 3.83–3.78 (m, 1H, 1/2CH2), 3.67–3.62

Molecules 2019, 24, 4440
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13
(m, 1H, 1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 169.90, 168.27, 165.95, 132.82, 132.39, 132.31, 131.90,
130.74, 129.00, 127.88, 125.96, 78.57, 35.72. Elem. anal. calcd. for C17H14N4O4S (%): C, 55.13; H, 3.81; N,
20
15.13. Found: C, 55.17; H, 3.84; N, 15.15. [α] D = +16.5 (c 1, MeOH).
(R)-N’-(4-nitrobenzoyl)-2-(p-tolyl)-4,5-dihydrothiazole-4-carbohydrazide (III-2): White solid, yield 58.8%, m.p.
1
1
216–218 °C. H-NMR (400 MHz, DMSO-d6) δ: H-NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H, CONH), 10.20
(s, 1H, CONH), 7.90 (d, J = 7.7 Hz, 2H, Ph-H), 7.78 (d, J = 7.3 Hz, 2H, Ph-H), 7.60 (d, J = 7.8 Hz, 2H, Ph-H),
7.33 (d, J = 7.4 Hz, 2H, Ph-H), 5.35 (t, J = 8.9 Hz, 1H, CH), 3.79–3.74 (m, 1H, 1/2CH2), 3.63–3.58 (m, 1H,
13
1/2CH2), 2.37 (s, 3H, CH3). C-NMR (101 MHz, DMSO-d6) δ 170.11, 168.99, 164.95, 142.41, 137.22, 131.58,
130.14, 129.82, 129.78, 129.13, 128.81, 78.45, 35.29, 21.51. Elem. anal. calcd. for C18H16N4O4S (%): C, 56.24; H,
20
4.20; N, 14.57. Found: C, 56.27; H, 4.23; N, 14.62. [α] D = +11.7 (c 1, MeOH).
(R)-N’-(4-nitrobenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-3): White solid, yield
1
62.7%, m.p. 225–226 °C. H-NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H, CONH), 10.28 (s, 1H, CONH),
8.35 (d, J = 7.8 Hz, 2H, Ph-H), 8.14 (d, J = 7.4 Hz, 2H, Ph-H), 7.79 (d, J = 7.7 Hz, 2H, Ph-H), 7.59 (d, J =
7.4 Hz, 2H, Ph-H), 5.47 (t, J = 9.1 Hz, 1H, CH), 3.90–3.85 (m, 1H, 1/2CH2), 3.73–3.68 (m, 1H, 1/2CH2).
13
C-NMR (101 MHz, DMSO-d6) δ 169.64, 167.85, 164.98, 149.69, 138.06, 137.26, 131.54, 130.11, 129.82,
129.14, 124.46, 78.70, 36.01. Elem. anal. calcd. for C17H13N5O6S (%): C, 49.16; H, 3.15; N, 16.86. Found:
20
C, 49.18; H, 3.18; N, 16.89. [α] D = +19.3 (c 1, MeOH).
(R)-N’-(4-nitrobenzoyl)-2-(4-methoxyphenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-4): White solid, yield
1
62.4%, m.p. 201–202 °C. H-NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H, CONH), 10.16 (s, 1H, CONH), 7.90
(d, J = 7.8 Hz, 2H, Ph-H), 7.83 (d, J = 7.4 Hz, 2H, Ph-H), 7.60 (d, J = 7.7 Hz, 2H, Ph-H), 7.05 (d, J = 7.4 Hz, 2H,
Ph-H), 5.32 (t, J = 8.6 Hz, 1H, CH), 3.83 (s, 3H, OCH3), 3.77–3.72 (m, 1H, 1/2CH2), 3.61–3.56 (m, 1H, 1/2CH2).
13
C-NMR (101 MHz, DMSO-d6) δ 170.15, 168.21, 164.81, 162.46, 137.18, 131.65, 130.65, 129.82, 129.12, 125.44,
114.54, 78.44, 55.93, 35.39. Elem. anal. calcd. for C18H16N4O5S (%): C, 53.99; H, 4.03; N, 13.99. Found: C,
20
54.03; H, 4.07; N, 14.02. [α] D = +12.6 (c 1, MeOH).
(R)-N’-(4-nitrobenzoyl)-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-5): White solid,
1
yield 58.1%, m.p. 201–202 °C. H-NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H, CONH), 10.18 (s, 1H,
CONH), 7.90 (d, J = 7.6 Hz, 2H, Ph-H), 7.83 (d, J = 7.4 Hz, 2H, Ph-H), 7.73 (d, J = 7.7 Hz, 2H, Ph-H),
7.58 (d, J = 7.4 Hz, 2H, Ph-H), 5.38 (t, J = 8.9 Hz, 1H, CH), 3.84–3.78 (m, 1H, 1/2CH2), 3.67–3.62 (m, 1H,
13
1/2CH2). C-NMR (101 MHz, DMSO-d6) δ 169.80, 168.17, 164.83, 137.20, 132.30, 131.91, 131.62, 130.73,
129.81, 129.13, 125.95, 78.58, 35.71. Elem. anal. calcd. for C17H13ClN4O4S (%): C, 50.44; H, 3.24; N, 13.84.
20
Found: C, 50.46; H, 3.28; N, 13.87. [α] D = +14.7 (c 1, MeOH).
3.3. Biological Assay
3.3.1. Fungicidal Activity
The fungicidal activity of compounds I–III was tested with the mycelium growth inhibition in vitro
against Cercospora arachidicola, Physalospora piricola, Alternaria solani, Fusarium graminearum, Phytophthora
capsici, and Sclerotinia sclerotiorum. Chlorothalonil and carbendazim were used as the controls. The relative
inhibition ratio (%) was determined through the mycelium growth rate method [36], and calculated using
the formula: Relative inhibition rate (%) = (D1 − D2) / D1 × 100%, D1 and D2 are the average diameter of
circle mycelia during the blank assay and test assay, respectively. The fungicidal activities of title
compounds I–III at 50 mg/L are shown in Table 1. The EC50 values of title compound I-5 against the six
tested fungi are shown in Table 2. The EC50 values of title compounds I–III, chlorothalonil, and
carbendazim against Phytophthora piricola are shown in Table 3.
3.3.2. Insecticidal Activity Against Mythimna separata
The insecticidal activity of I–III and chlorantraniliprole were tested by the reported method [37],
and the result is shown in Table 4.

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3.3.3. D-QSAR Calculation Methods
The CoMSIA studies were carried out using a SYBYL v6.9 software from Tripos Inc (St. Louis, MO,
USA). All molecules were built with the SKETCH option in SYBYL under default settings. CoMSIA
contour maps were generated with partial least-squares coefficients [38]. The partial least-squares was
carried out to establish a linear relationship. Cross-validation was performed by using the “leave-one-
2
out” method to obtain the cross-validated coefficient q and optimal number of components. The non-
2
2
cross-validated correlation coefficient r and cross-validated coefficient q could estimate the predictive
capability and modeling, respectively.
3.5. Calcium Imaging Experiment
Effects of III-3 on calcium channels in the central neurons isolated from the third instar of Mythimna
separata were studied by calcium imaging techniques as described in the literature [37].
4. Conclusions
A
series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing
a
diacylhydrazine moiety were designed and synthesized, and their chemical structures were identified by
1
13
melting points, H-NMR, C-NMR, and elemental analysis (EA). All of the title compounds I–III were
evaluated for antifungal and insecticidal activities. The antifungal activity evaluation revealed that most
of them against Cercospora arachidicola, Alternaria solani, Phytophthora capsici, and Physalospora piricola at 50
mg/L displayed obvious antifungal activities, and were more efficient than chlorothalonil or carbendazim.
Especially, compounds I-1 and I-5 against the six tested phytopathogenic fungi exhibited broad-spectrum
antifungal activities. Furthermore, the EC50 values of compound I-5 were equivalent to those of
chlorothalonil. Compound I-5 can be used as a novel lead structure for antiphytopathogenic fungus agent
1
2
development. The structure activity relationship indicated that the groups R = H and R = Cl or H on the
benzene ring had a positive effect on the antifungal activities. Moreover, the CoMSIA model suggested
1
that a proper hydrophilic group in the R position, as well as a proper hydrophilic and electron-donating
2
group in the R position, could improve the antifungal activity against Physalospora piricola, which
contributed to the further optimization of the structures. The insecticidal activities result showed that most
of them displayed remarkable insecticidal activities at 50 mg/L, in particular, compound III-3. The calcium
2+
imaging experiment results indicated that compound III-3 can serve as effective insect Ca level
modulators by disrupting the cellular calcium homeostasis in Mythimna separata.
Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1. 1H NMR and 13C NMR of
compounds I-III can be accessed online.
Author Contributions: Synthesis, biological experiment, 3D-QSRA, and writing—original draft preparation, F.-Y.L.;
calcium imaging experiment, J.-B.L.; part insecticidal assay, J.-N.G.; responsible for the correspondence of the
manuscript, G.L. All authors discussed, edited, and approved the final version of the manuscript.
Funding: This research was funded by the National Natural Science Foundation of China (No. 21907076 and No.
31901908), the China Postdoctoral Science Foundation (No. 2018M641666), and the Natural Science Foundation of
Tianjin (No. 19JCQNJC04600).
Acknowledgments: The authors are thankful to the College of Chinese Materia Medica, Tianjin University of
Traditional Chinese Medicine, and the College of Horticulture and Landscape Architecture, Tianjin Agricultural
University.
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of the compounds I–III are available from the authors.
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