Synthesis and Antibacterial Evaluation of N-phenylacetamide Derivatives Containing 4-Arylthiazole Moieties

Article abstract of DOI:10.3390/molecules25081772

A series of new N-phenylacetamide derivatives containing 4-arylthiazole moieties was designed and synthesized by introducing the thiazole moiety into the amide scaffold. The structures of the target compounds were confirmed by ¹H-NMR, ¹³C-NMR and HRMS. Their in vitro antibacterial activities were evaluated against three kinds of bacteria-Xanthomonas oryzae pv. Oryzae (Xoo), Xanthomonas axonopodis pv. Citri (Xac) and X.oryzae pv. oryzicola (Xoc)-showing promising results. The minimum 50% effective concentration (EC₅₀) value of N-(4-((4-(4-fluoro-phenyl)thiazol-2-yl)amino)phenyl)acetamide (A₁) is 156.7 μM, which is superior to bismerthiazol (230.5 μM) and thiodiazole copper (545.2 μM). A scanning electron microscopy (SEM) investigation has confirmed that compound A₁ could cause cell membrane rupture of Xoo. In addition, the nematicidal activity of the compounds against Meloidogyne incognita (M. incognita) was also tested, and compound A₂₃ displayed excellent nematicidal activity, with mortality of 100% and 53.2% at 500 μg/mL and 100 μg/mL after 24 h of treatment, respectively. The preliminary structure-activity relationship (SAR) studies of these compounds are also briefly described. These results demonstrated that phenylacetamide derivatives may be considered as potential leads in the design of antibacterial agents.

Full text of DOI:10.3390/molecules25081772

molecules
Article
Synthesis and Antibacterial Evaluation of
N-phenylacetamide Derivatives Containing
4-Arylthiazole Moieties
Hui Lu, Xia Zhou * , Lei Wang and Linhong Jin *
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District,
Guiyang 550025, China; luhui2624904231@163.com (H.L.); wanglei880328@163.com (L.W.)
* Correspondence: zhouxia_j@126.com (X.Z.); linhong_j@126.com (L.J.); Tel.: +86-851-3620-521 (X.Z. & L.J.);
Fax: +86-851-3622-211 (X.Z. & L.J.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Andrea Penoni
Received: 4 April 2020; Accepted: 10 April 2020; Published: 12 April 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A series of new N-phenylacetamide derivatives containing 4-arylthiazole moieties
was designed and synthesized by introducing the thiazole moiety into the amide scaffold.
The structures of the target compounds were confirmed by 1H-NMR, 13C-NMR and HRMS.
Their in vitro antibacterial activities were evaluated against three kinds of bacteria—Xanthomonas
oryzae pv. Oryzae (Xoo), Xanthomonas axonopodis pv. Citri (Xac) and X.oryzae pv. oryzicola
(Xoc)—showing promising results. The minimum 50% effective concentration (EC50) value of
N-(4-((4-(4-fluoro-phenyl)thiazol-2-yl)amino)phenyl)acetamide (A1) is 156.7 µM, which is superior
to bismerthiazol (230.5 M) and thiodiazole copper (545.2 M). A scanning electron microscopy
µ
µ
(SEM) investigation has confirmed that compound A1 could cause cell membrane rupture of Xoo.
In addition, the nematicidal activity of the compounds against Meloidogyne incognita (M. incognita)
was also tested, and compound A23 displayed excellent nematicidal activity, with mortality of 100%
and 53.2% at 500 µg/mL and 100 µg/mL after 24 h of treatment, respectively. The preliminary
structure-activity relationship (SAR) studies of these compounds are also briefly described. These
results demonstrated that phenylacetamide derivatives may be considered as potential leads in the
design of antibacterial agents.
Keywords: synthesis; thiazole; nematicidal activity; antibacterial activity; structure-activity
relationship
1. Introduction
Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola parasitizing rice can cause
serious degradation of rice quality and yield [
1]. Xanthomonas axonopodis pv. citri mainly harms citrus
fruits while causing a plant bacterial disease, citrus canker [
2]. In recent decades, the long-term
use of traditional bactericides has resulted in their large accumulation in the soil and resistance of
pathogenic bacteria, reducing control capability. For example, bismerthiazol, one of the most widely
used bactericides, has indicated low efficiency of 25.5% at a high dosage of 200 µg/mL [3]. Therefore,
it is necessary to develop highly efficient and environmentally friendly bactericides to protect crops.
Thiazole-containing aromatic heterocycles are reported to bind to certain proteins and receptors of
bacteria and exhibit a wide range of biological activities such as insecticidal [
herbicidal [ ], antiviral [10] and fungicidal ones [11 12]. In addition, compounds with an amide
structure have revealed various activities as antimicrobial [13 15] and nematicidal [16 17] agents.
4,5], bactericidal [6–8],
9
,
–
,
Based on the reported good performance of derivatives containing thiazole or amide groups, splicing
them to get new antibacterial structures was presumed to be a reasonable and promising approach.
Molecules 2020, 25, 1772; doi:10.3390/molecules25081772
www.mdpi.com/journal/molecules

Molecules 2020, 25, 1772
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Attracted by these facts, we have carried out the preparation of a series of novel N-phenylacetamide
derivatives A1 36 and the subsequent evaluation of their biological activities against Xoo, Xac and
–
A
Xoc. Their preliminary structure-activity relationships are discussed. Additionally, the nematicidal
activity of all target compounds against M. incognita were also checked.
2. Results and Discussion
2.1. Chemistry
As shown, compounds N-substituted-2-amino-4-arylthiazoles A1
Scheme 1. Starting from p-phenylenediamine (PPD), the synthesis involves firstly aniline protection,
amide formation and deprotection to afford the 4-amino-N-phenylacetamide intermediates which
were then turned into isothiocyanates and converted to thioureas . Finally, were condensed
with different -halocarbonyl compounds to give the target derivatives. The steps for each reaction
–A36 were synthesized following
2
3
4
4
α
described in Scheme 1 were elaborated as follows.
Specifically, the protection of PPD in first step utilized a N-tert-butyloxycarbonylation
strategy [18
(DCM), PPD was converted into the corresponding N-BOC-amine [20]. The mono-N-BOC protected
derivative (NH2-Ph-NH-BOC) was purified by column chromatography to remove the di-N-BOC
(BOC-NH-Ph-NH-BOC) side product. Then was reacted with an acyl chloride (RCOCl) to
produce the corresponding amide RCONH-Ph-NH-BOC, which was then acidified to produce the
4-amino-N-phenylacetamides . Thereafter, were converted to the corresponding isothiocyanates
–20]. By reacting with 0.5 equiv. of di-tert-butyl dicarbonate (BOC2O) in dichloromethane
1
1
2
2
3
via dithiocarbamates (generated by adding CS2 to Et3N) promoted by BOC2O and a catalytic amount of
4-dimethylaminopyridine (DMAP) [21]. BOC2O here, as reported, may desulfurize the corresponding
dithiocarbamates during the isothiocyanate formation [21
prepared from isothiocyanates upon reaction with ammonia [23
condensed with diverse -bromophenylethanones [24
,
22]. Then, various aryl thioureas
4
4
were
were
3
,24]. Finally, thioureas
α
,
25], synthesized separately via reaction of
acetophenones with Br2 in DCM [24], to afford the 2-amino-1,3-thiazole heterocyclic skeleton, and the
targeted compound N-phenylacetamide derivatives containing thiazole moieties were thus obtained.
The structures of all target compounds were confirmed by 1H-NMR, 13C-NMR and HRMS. Among
them, it was unexpectedly found that compounds A4, A7, A11, A12 have been previously reported [25].
Scheme 1. Synthetic routes for the target compounds A1–A36
.

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2.2. In Vitro Antibacterial Activity
The in vitro antibacterial activities of the target compounds against three phytopathogenic
bacterial (Xoo, Xac and Xoc) were initially evaluated at the concentrations of 200 g/mL and 100 g/mL,
µ
µ
respectively. As a comparison, the commercial bactericides bismerthiazol and thiodiazole copper
served as positive controls (see preliminary screening results in the Supplementary Materials).
Compounds that performed well in the initial tests were further tested to determine their EC50
values, with the results shown in Table 1. The EC50 values of compounds A1
,
A4
M, which were significantly better than that of thiodiazole copper (545.2
4 had the best inhibitory effect on Xoc with an EC50 value of 194.9 M, which was
M) and thiodiazole copper (607.5 M). Compound
M) showed the best antibacterial activity against Xac, which was better than that of the
commercial bactericide thiodiazole copper (476.52 µM).
,
A6 against Xoo
are 156.7, 179.2, 144.7
Moreover, compound
µ
µM).
A
µ
slightly better than that of bismerthiazol (254.96
A4 (281.2
µ
µ
µ
Table 1. EC50 (µM) values of some target compounds against Xoo, Xac and Xoc a.
EC50 (µM) c
Compound
Xoo
Xac
Xoc
A1
A3
A4
A6
A11
A13
A25
156.7±7.4
260.9±9.0
179.2±6.2
144.7±3.2
152.0±7.8
561.6±6.8
281.2±9.4
347.3±5.6
250.7±8.0
361.4±9.3
194.9±8.0
248.5±12.1
512.1±13.4 812.3±11.0 280.6±16.4
541.4±15.3 660.4±10.1
918.8±19.0 1186±11.9 716.5±19.0
392.8±6.3
Bismerthiazol b
230.5±7.5
162.7±3.9
254.9±8.2
Thiodiazole copper b 545.2±13.7 476.5±19.9 607.5±3.78
a
The statistic analysis was conducted by the ANOVA method under conditions of assumed equal variances
b
(p > 0.05) and not assumed equal variances (p < 0.05). The commercial antibacterial agents bismerthiazol and
thiodiazole-copper were used as positive controls. The corresponding regression equation and R value for this
c
EC50 are provided in the Supplementary Materials.
2.3. Structure-Activity Relationship Analyses
With the results indicated in Table 1, a preliminary structure-activity relationship of the target
compounds can be discussed. It can be observed that the type and position of the substituent R on
the benzene ring had an important effect on the bactericidal activity of the target compounds. First of
all, the type and position of F, Cl, Br, and CF3 at the 4-position of the benzene ring can increase the
bactericidal activity of the compound, and the 3-position is not conducive to improving the bactericidal
activity. For example, the order of the inhibitory effect of the target compound on Xoo bacteria follows
the order A1 A2
>
, A4 > A5, confirming the above conclusion. In addition, the activity trend A1 (4-F)
>
A
4 (4-Cl) > A7 (4-Br) reveals that a 4-F substituted benzene ring is the most helpful for conferring
antibacterial activity. Secondly, comparing different types of groups at the same position on the
benzene ring, the corresponding compounds with 4-R electron-withdrawing substituents have a higher
bactericidal activity against Xoo, Xac and Xoc than 4-R electron-donating substituents such as A1 (4-F)
>
A4 (4-Cl) > A11 (4-CH3). The type of amide-linked sidechain could also have a significant impact on
the bactericidal activity of the corresponding target compounds.
2.4. Scanning Electron Microscopy Studies
Due to its outstanding activity shown in Table 1, compounds
A1 was further examined by SEM
analysis to study the effect on Xoo. It can be observed that the cell membrane was damaged by the
compound and the normal physiological functions of the cell would thus be affected. More importantly,
this adverse effect becomes more severe with increasing compound concentration. For example, the
surface of cells without compound treatment is smooth and the cell membrane is intact (Figure 1A).

Molecules 2020, 25, 1772
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At the concentration of 100
µg/mL, a small part of the cell morphology appears abnormal (Figure 1B).
When the concentration was increased to 200 µg/mL, most of the cell surfaces were deformed, with
few surviving cells (Figure 1C). In summary, the inhibitory effect of compound A1 on Xoo was further
clarified by the SEM images.
Figure 1. SEM images for Xoo after incubated using different concentrations of compound A1
(A) 0 µg/mL; (B) 50 µg/mL and (C) 100 µg/mL. Scale for A, B and C is 5 µm.
,
2.5. Nematicidal Biological Activities
The nematicidal activity results of the target compounds are summarized in Table 2. Unfortunately,
most of the compounds showed poor activities against M. incognita, although compound 23, with its
mortality rates of 100% at 500 g/mL and 51.3% at 100 g/mL which are comparable to the commercial
nematicide avermectin (100% at 500 g/mL and 71.8% at 100 g/mL) in 24 h after treatment stuck out.
A
µ
µ
µ
µ
Table 2. Mortality (%) of the target compounds against M. incognita a.
500 µg/mL
100 µg/mL
Compound
R’/R
24 h
72 h
24 h
72 h
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
A14
A15
A16
A17
A18
A19
A20
A21
A22
A23
A24
A25
A26
A27
A28
4-F/CH3
3-F/CH3
3,4-diF/CH3
4-Cl/CH3
3-Cl/CH3
3,4-diCl/CH3
4-Br/CH3
3-Br/CH3
4- CF3/CH3
3-CF3/CH3
4-CH3/CH3
26.6
11.9
20.2
14.7
8.7
11.9
14.1
11.9
23.7
11.5
14.7
21.2
6.1
6.7
15.1
7.4
7.4
21.5
5.1
15.4
17.3
‘13.1
100
29.5
6.1
6.7
15.4
19.9
26.9
13.1
23.7
21.8
17.3
20.5
21.2
14.4
29.2
17.6
21.8
23.4
11.5
9.9
14.1
14.4
10.0
23.1
2.9
16.7
18.3
15.4
100
9.3
0
6.4
5.1
0
9.9
5.4
9.0
5.1
0
4.8
5.8
7.1
14.1
8
5.1
3.5
0.6
1.0
2.6
3.8
1.0
3.8
0
1.3
4.2
3.8
51.3
7.7
0.6
1.0
5.4
5.8
7.1
8
8.3
17.3
8.7
5.1
5.4
2.6
3.2
2.9
6.7
2.3
4.8
0
1.9
5.3
7.1
53.2
9.3
2.6
5.2
7.7
6.1
H/CH3
4-F/CH2CH3
3-F/CH2CH3
3,4-diF/CH2CH3
4-Cl/CH2CH3
3-Cl/CH2CH3
3,4-diCl/CH2CH3
4-Br/CH2CH3
3-Br/CH2CH3
4- CF3/CH2CH3
3- CF3/CH2CH3
4-CH3/CH2CH3
H/CH2CH3
30.1
11.5
10.0
21.2
20.8
4-F/CH(CH3)2
3-F/CH(CH3)2
3,4-diF/CH(CH3)2
4-Cl/CH(CH3)2

Molecules 2020, 25, 1772
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Table 2. Cont.
500 µg/mL
100 µg/mL
24 h 72 h
Compound
R’/R
24 h
72 h
A29
A30
A31
A32
A33
A34
A35
A36
3-Cl/CH(CH3)2
4-CF3/CH(CH3)2
3-CF3/CH(CH3)2
3,4-diCl/CH(CH3)2
4-Br/CH(CH3)2
3-Br/CH(CH3)2
4-CH3/CH(CH3)2
H/CH(CH3)2
7.4
22.1
17.6
17.0
16.0
29.8
19.6
18.6
100
0
15.5
26
0
10.3
0
0
12.8
0
17.6
17.3
24.7
30.4
20.8
19.9
100
0
0
0
7.4
9.9
8
8.7
71.8
0
8.3
10.9
9.3
9.3
79.3
0
Avermectin b
CK c
a
c
b
Averages of three replicates. The commercial nematicide avermectin was used for a comparison of activity.
Control sample.
3. Experimental
3.1. Chemicals and Instruments
All reagents used for reactions were purchased from a commercial source (Aladdin Chemistry
Co., Shanghai, China) and were of analytical grade with no further purification. Basic alumina
oxide (200 to 300 mesh, Aladdin Chemistry Co.) was applied for purification of target compounds
by column chromatography. Melting points of the target compounds were recorded on an XT-4B
binocular microscope (Beijing Tech Instrument Co., Beijing, China). NMR spectra were obtained on a
400 MHz spectrometer (Bruker BioSpin AG, Fällanden, Switzerland) using TMS as internal standard
and DMSO-d6 as solvent. HRMS data were recorded on a Thermo Scientific Q Exactive system (Thermo
Fisher Scientific, Waltham, MA, USA). Single crystal structure data were collected using a single crystal
diffractometer (Gemini E, Oxford Instruments, Oxford, UK). SEM analysis was carried out with a FEI
Nova NanoSEM 450 (FEI Company, Hillsboro, OR, USA).
3.2. General Synthetic Procedure for the Target Compounds
3.2.1. Synthesis of Intermediate 1
p-Phenylenediamine (PPD, 9.25 mmol, 1.0 equiv.) was dissolved in dry dichloromethane (50mL),
degassed under N2 (g) and cooled in an ice bath. BOC2O (4.62 mmol, 0.50 equiv.) was added dropwise
to the p-phenylenediamine solution using a disposable syringe. After the addition, the mixture was
reacted at room temperature (R.T.) for 5 h, monitored by thin layer chromatography (TLC). After
the reaction was complete, the mixture was purified by flash column chromatography (petroleum
ether:ethyl acetate, 3:1) to obtain yellow solid compound intermediate 1 in a yield of 63%.
3.2.2. Synthesis of Intermediates 2
A mixture of 1
(1.0 equiv.) and an acid chloride (1.10 equiv.) in DCM (40mL) was stirred at 0 ◦C
for 1 h. Then, excess 4 M HCl was added and stirred at R.T. for 10 min. The reaction progress was
monitored by TLC. After completion of the reaction, a saturated Na2CO3 solution was added to adjust
to 7.0 the pH of mixture which was then extracted with DCM (50 mL
concentrated to give intermediate 2 as white solids in yields of 69–75%.
×
3). The organic phase was
3.2.3. Synthesis of Intermediates 3
A mixture of intermediate
2 (12.64 mmol, 1.0 equiv.), triethylamine (Et3N, 13.87 mmol, 1.10 equiv.)
and carbon disulfide (CS2, 126.40 mmol, 10.0 equiv) in ethanol (50 mL) was stirred at R.T. for 2 h, then
cooled down to 0 ◦C to add DMAP (0.38 mmol, 0.03 equiv.) and BOC2O (12.51 mmol, 0.99 equiv.). The

Molecules 2020, 25, 1772
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mixture was stirred for about 2 h◦at room temperature till the reactants were completely consumed.
The mixture was cooled to
of 75–81%.
−
10 C overnight then filtered to give the isothiocyanates 3 in yields
3.2.4. Synthesis of the Intermediates 4
The mixture of (12.64 mmol, 1.0 equiv.) with excess ammonia solution in ethanol (30 mL)
3
was stirred at R.T. The reaction was monitored by TLC using petroleum ether:ethyl acetate (1:1).
The mixture was filtered through a Celite pad to afford the thioureas 4 in approximately 100% yield.
3.2.5. Synthesis of the α-Bromophenylethanone Intermediates
Br2 (2.2 mmol, 1.10 equiv.) was added slowly to a DCM solution of substituted acetophenone
(2.0 mmol, 1.0 equiv.) and the mixture was stirred at R.T. for 5 h, after which the reaction mixture was
tpoured into distilled water and extracted with DCM three times. The organic phases were combined
and the solvent removed under reduced pressure to obtain the
65–83%.
α-bromophenylethanones in yields of
3.2.6. Synthesis of the Target Compounds A
A mixture of α-bromophenylethanone (2.05 mmol, 1.0 equiv.) and intermediate 4 (2.25 mmol,
1.10 equiv.) was dissolved in ethanol (20 mL) and then heated at reflux for 5 h. Upon completion of the
reaction the liquid was filtered and the solid formed was washed with saturated potassium carbonate
solution. The crude product was purified by column chromatography on basic alumina to give the
various target compounds in yields ranging from 55% to 94%, respectively.
N-(4-((4-(4-F◦luorophenyl)thiazol-2-yl)amino)phenyl)acetamide (
A1): yellow solid; yield 57%; mp:
10.19 (s, 1H), 9.85 (s, 1H), 7.96 (m, 2H, Ar-H), 7.63 (d, J = 8.9 Hz,
1
201.0–202.0 C; H-NMR
δ
2H, Ar-H), 7.54 (d, J = 8.9 Hz, 2H, Ar-H), 7.27 (d, J = 8.5 Hz, 2H, Ar-H), 7.24 (s, 1H, thiazole-H), 2.03 (s,
3H, CH3). 13C-NMR
δ 168.29, 163.84, 163.28, 160.85, 149.48, 137.11, 133.80, 131.65 (d, J = 2.9 Hz), 128.14
(d, J = 8.1 Hz), 120.35, 117.76, 116.05, 115.83, 102.72, 24.35. HRMS (ESI): m/z [M + H]+ calculated for
C17H15FN3OS: 328.09144; found: 328.09097.
N-(4-((4-(3-Fluorophenyl)thiazol-2-yl)amino)phenyl)acetamide (
A
2): yellow solid; yield 82%; mp:
10.16 (s, 1H, NH), 9.81 (s, 1H,NH), 7.91 (d, J = 8.6 Hz, 2H, Ar-H),
7.59 (d, J = 9.0 Hz, 2H, Ar-H), 7.51 (d, J = 9.0 Hz, 2H, Ar-H), 7.45 (d, J = 8.6 Hz, 2H, Ar-H), 7.33 (s,
◦
1
162.4–163.2 C; H-NMR
δ
1H, thiazole-H), 1.99 (s, 3H, CH3). 13C-NMR
δ 168.26, 163.65, 150.60, 137.22 (d, J = 4.8 Hz), 133.71,
132.41, 129.67, 126.10, 120.35, 117.70, 102.07, 24.35, 21.33. HRMS (ESI): m/z [M + H]+ calculated for
C17H15FN3OS: 328.09144; found: 328.09094.
N-(4-(4-(3,4-Difluorophenyl)thiazol-2-ylamino)phenyl)acetamide (
A
3): yellow solid; yield 81%; mp:
10.21 (s, 1H), 9.85 (s, 1H), 7.91–7.87 (m, 1H, Ar-H), 7.77–7.72 (m, 1H,
Ar-H), 7.59 (d, J = 9.0 Hz, 2H, Ar-H), 7.52 (d, J = 9.0 Hz, 2H, Ar-H), 7.45 (d, J = 10.6 Hz, 1H, Ar-H), 7.36
◦
1
228.8–229.3 C; H-NMR
δ
(s, 1H, thiazole-H), 2.00 (s, 3H, CH3). 13C-NMR
δ 168.2, 163.98, 148.82, 137.29, 136.99, 133.94, 131.35,
130.62, 128.56, 125.16, 122.56, 120.37, 117.91, 104.64, 24.35. HRMS (ESI): m/z [M + H]+ calculated for
C17H14F2N3OS: 346.08202; found: 346.08136.
N-(4-(4-(4-Chlorophenyl)thiazol-2-ylamino)phenyl)acetamide (
A
4): yellow solid; yield 87%; mp:
10.16 (s, 1H, NH), 9.81 (s, 1H, NH), 7.93–7.88 (m, 2H, Ar-H), 7.59 (d,
J = 9.0 Hz, 2H, Ar-H), 7.51 (d, J = 8.6 Hz, 2H, Ar-H), 7.45 (d, J = 8.6 Hz, 2H, Ar-H), 7.33 (s, 1H,
◦
1
210.5–211.2 C; H-NMR
δ
thiazole-H), 1.99 (s, 3H, CH3). 13C-NMR
δ 168.34, 163.98, 149.37, 137.12, 133.94, 132.43, 129.19, 127.93,
120.41, 117.89, 103.90, 24.42. HRMS (ESI): m/z [M + H]+ calculated for C17H15ClN3OS: 344.06189; found:
344.06134.
N-(4-(3-(4-Chlorophenyl)thiazol-2-ylamino)phenyl)acetamide (
A
5): yellow solid; yield 88%; mp:
◦
1
179.7–180.3 C; H-NMR
δ 10.22 (s, 1H, NH), 9.86 (s, 1H, NH), 7.78 (d, J = 7.9 Hz, 1H, Ar-H),

Molecules 2020, 25, 1772
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7.71 (d, J = 9.8 Hz, 1H, Ar-H), 7.65–7.59 (m, 2H, Ar-H), 7.55 (d, J = 9.0 Hz, 2H, Ar-H), 7.48 (d, J = 6.2 Hz,
1H, Ar-H), 7.44 (s, 1H, thiazole-H), 7.14 (d, J = 2.5 Hz, 1H, Ar-H), 2.03 (s, 3H, CH3). 13C-NMR
168.35,
δ
163.90, 148.71, 137.31, 137.03, 133.93, 131.37, 130.58, 128.51, 125.15, 122.55, 120.28, 117.79, 104.70, 24.34.
HRMS (ESI): m/z [M + H]+ calculated for C17H15ClN3OS: 344.06189; found: 344.06140.
N-(4-((4-(3,4-Dichlorophenyl)thiazol-2-yl)amino)phenyl)acetamide (
179.3–181.7 ◦C; 1H-NMR
10.55 (s, 1H, NH), 10.15 (s, 1H, NH), 8.14 (d, J = 2.0 Hz, 1H, Ar-H), 7.93 (m,
1H, Ar-H), 7.70 (d, J = 8.5 Hz, 1H, Ar-H), 7.67 (d, J = 9.1 Hz, 2H, Ar-H), 7.61 (d, J = 9.1 Hz, 2H, Ar-H),
A6): yellow solid; yield 93%; mp:
δ
7.54 (s, 1H, thiazole-H), 2.06 (s, 3H, CH3). 13C-NMR
δ 168.37, 164.00, 147.82, 136.97, 135.60, 133.99,
131.86, 131.37, 130.05, 127.58, 126.30, 120.26, 117.80, 105.37, 24.34. HRMS (ESI): m/z [M + H]+ calculated
for C17H14Cl2N3OS: 378.02291; found: 378.02249.
N-(4-((4-(4-Bromophenyl)thiazol-2-yl)amino)phenyl)acetamide (
209.6–210.4 ◦C; 1H-NMR
10.19 (s, 1H, NH), 9.83 (s, 1H, NH), 7.84 (m, 2H, Ar-H), 7.60 (d, J = 9.1 Hz,
2H, Ar-H), 7.58 (d, J = 4.4 Hz, 2H, Ar-H), 7.52 (d, J = 8.8 Hz, 2H, Ar-H), 7.33 (s, 1H, thiazole-H), 2.00 (s,
3H, CH3). 13C-NMR
168.36, 163.96, 149.40, 137.11, 134.27, 133.91, 132.10, 128.24, 121.04, 120.40, 117.87,
103.98, 24.43. HRMS (ESI): m/z [M + H]+ calculated for C17H15BrN3OS: 388.01137; found: 388.01102.
A7): white solid; yield 75%; mp:
δ
δ
N-(4-((4-(3-Bromophenyl)thiazol-2-yl)amino)phenyl)acetamide ( 8): yellow solid; yield 85%; mp:
10.38 (s, 1H, NH), 10.01 (s, 1H, NH), 8.04 (t, J = 1.8 Hz, 1H, Ar-H),
7.90 (d, J = 7.9 Hz, 1H, Ar-H), 7.62-7.57 (m, 2H, Ar-H), 7.56-7.52 (m, 2H, Ar-H), 7.46 (d, J = 6.9 Hz, 1H,
Ar-H), 7.42 (s, 1H, thiazole-H), 7.36 (t, J = 7.9 Hz, 1H, Ar-H), 2.00 (s, 3H,CH3). 13C-NMR
168.29,
A
◦
1
202.8–203.9 C; H-NMR
δ
δ
163.98, 148.82, 137.29, 136.99, 133.94, 131.35, 130.62, 128.56, 125.16, 122.56, 120.37, 117.91, 104.64, 24.35.
HRMS (ESI): m/z [M + H]+ calculated for C17H15BrN3OS: 388.01137; found: 388.01102.
N-(4-(4-(4-(Trifluoromethyl)phenyl)thiazol-2-ylamino)phenyl)acetamide (
253.2–254.2 ◦C; 1H-NMR
10.29 (s, 1H, NH), 9.89 (s, 1H, NH), 8.14 (d, J = 8.3 Hz, 2H, Ar-H), 7.73-7.79
(d, J = 7.8 Hz, 2H, Ar-H), 7.65 (m, 2H, Ar-H), 7.58 (d, J = 2.2 Hz, 2H, Ar-H), 7.56 (s, 1H, thiazole-H),
A9): yellow solid; yield 69%; mp:
δ
2.04 (s, 3H, CH3). 13C-NMR
δ 168.30, 164.01, 148.99, 138.67, 136.97, 133.93, 128.14, 127.82, 126.87,
126.38 (d, J = 59.5 Hz), 123.50, 120.30, 117.85, 105.87, 24.36. HRMS (ESI): m/z [M + H]+ calculated for
C18H15F3N3OS: 378.08824; found: 378.08765.
N-(4-((4-(3-(Trifluoromethyl)phenyl)thiazol-2-yl)amino)phenyl)acetamide (
179.3–180.7 ◦C; 1H-NMR
10.31 (s, 1H, NH), 9.93 (s, 1H,NH), 8.26 (d, J = 11.0 Hz, 2H, Ar-H), 7.69 (d,
J = 6.9 Hz, 2H, Ar-H), 7.67–7.62 (m, 2H, Ar-H), 7.60 (d, J = 9.1 Hz, 2H, Ar-H), 7.58 (s, 1H, thiazole-H),
2.07 (s, 3H, CH3). 13C-NMR
168.39, 164.18, 148.81, 136.98, 135.88, 133.98, 130.06 (d, J = 33.3Hz), 129.52,
A10): yellow solid; yield 87%; mp:
δ
δ
128.79, 126.09, 124.38 (d, J = 3.6 Hz), 123.38, 122.35 (d, J = 3.7 Hz), 120.38, 117.97, 104.95, 24.32. HRMS
(ESI): m/z [M + H]+ calculated for C17H15F3N3OS: 378.08824; found: 378.08765.
N-(4-(4-p-Tolylthiazol-2-ylamino)phenyl)acetamide (
1H-NMR
10.15 (s, 1H, NH), 9.85 (s, 1H, NH), 7.81 (d, J = 8.0 Hz, 2H, Ar-H), 7.63 (d, J = 8.9 Hz, 2H,
Ar-H), 7.54 (d, J = 8.9 Hz, 2H, Ar-H), 7.23 (d, J = 8.1 Hz, 2H, Ar-H), 7.21 (s, 1H), 2.33 (s, 3H, CH3), 2.03 (s,
3H, CH3). 13C-NMR
168.26, 163.66, 150.61, 137.23, 133.72, 132.41, 129.67, 126.10, 120.36, 117.71, 102.06,
24.35, 21.32; HRMS (ESI): m/z [M + H]+ calculated for C18H18N3OS: 324.11651; found: 324.11597.
A
11): yellow solid; yield 89%; mp: 207.2–208.1 ◦C;
δ
δ
N-(4-((4-Phenylthiazol-2-yl)amino)phenyl)acetamide (
12): yellow solid; yield 71%; mp: 174.7–175.2 ◦C;
1H-NMR
10.19 (s, 1H, NH), 9.88 (s, 1H, NH), 7.9–7.86 (m, 2H, Ar-H), 7.66 (d, J = 9.0 Hz, 2H, Ar-H),
7.57 (d, J = 9.0 Hz, 2H, Ar-H), 7.43 (t, J = 7.6 Hz, 2H, Ar-H), 7.31 (t, J = 7.3 Hz, 1H, Ar-H), 7.27 (s, 1H,
A
δ
thiazole-H), 2.04 (s, 3H, CH3). 13C-NMR
δ 168.38, 163.79, 150.57, 137.22, 135.03, 133.74, 129.11, 128.01,
126.15, 120.44, 117.76, 102.97, 24.32. HRMS (ESI): m/z [M + H]+ calculated for C17H16N3OS: 310.10086;
found: 310.10034.
N-(4-((4-(4-Fluorophenyl)thiazol-2-yl)amino)phenyl)propionamide (
186.5–187.4 ◦C; 1H-NMR
10.24 (s, 1H, NH), 9.80 (s, 1H, NH), 7.95 (s, 1H, thiazole-H), 7.93–7.87 (m,
1H, Ar-H), 7.64–7.60 (m, 2H, Ar-H),7.60–7.54 (m, 2H, Ar-H), 7.50–7.41 (m, 2H, Ar-H), 7.37 (dd, J = 5.9,
A13): white solid; yield 85%; mp:
δ

Molecules 2020, 25, 1772
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0.9 Hz, 1H), 2.31 (q, J = 7.6 Hz, 2H, CH2), 1.10 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
δ
172.03, 164.03,
148.82, 137.30, 136.93, 134.00, 131.34, 130.62, 128.58, 125.14, 122.55, 120.41, 117.95, 104.62, 29.91, 10.25.
HRMS (ESI): m/z [M + H]+ calculated for C18H17FN3OS: 342.10709; found: 342.10617.
N-(4-((4-(3-F◦luorophenyl)thiazol-2-yl)amino)phenyl)propionamide (
A14): white solid; yield 83%; mp:
10.18 (s, 1H, NH), 9.76 (s, 1H, NH), 7.74 (d, J = 7.8 Hz, 1H, Ar-H),
1
230.2–231.1 C; H-NMR
δ
7.67 (d, J = 10.6 Hz, 1H, Ar-H), 7.59 (d, J = 8.8 Hz, 2H, Ar-H), 7.54 (d, J = 8.9 Hz, 2H,Ar-H), 7.44 (dd,
J = 14.3, 7.8 Hz, 1H, Ar-H), 7.39 (s, 1H, thiazole-H), 7.11 (dd, J = 11.7, 5.4 Hz, 1H, Ar-H), 2.27 (q, J = 7.5
Hz, 2H, CH2), 1.06 (t, J = 7.5 Hz, 3H, CH3). 13C-NMR
δ 172.04, 164.21, 163.89, 161.80, 149.24, 137.40,
136.95, 133.91, 131.13, 122.23, 120.41, 117.86, 114.77, 112.48, 104.53, 29.90, 10.27. HRMS (ESI): m/z [M +
H]+ calculated for C18H17FN3OS: 342.10709; found: 342.10617.
N-(4-((4-(3,4-Difluorophenyl)thiazol-2-yl)amino)phenyl)propionamide (
230.4–230.8 ◦C; 1H-NMR
10.18 (s, 1H, NH), 9.75 (s, 1H, NH), 7.92-7.87 (m, 1H, Ar-H), 7.75 (dd, 1H,
J = 8.6, 4.3 Hz, Ar-H), 7.61-7.56 (m, 2H, Ar-H), 7.53 (dd, J = 9.2, 2.3 Hz, 2H, Ar- H), 7.46 (d, J = 10.6, 1H,
Ar-H), 7.37 (s, 1H, thiazole-H), 2.27 (q, J = 7.6 Hz, 2H, CH2), 1.05 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
A15): white solid; yield 69%; mp:
δ
δ
172.00, 164.00, 148.37, 136.89, 133.96, 122.92, 120.39, 118.24 (d, J = 17.2 Hz), 117.89, 114.87 (d, J = 18.4
Hz), 104.16, 29.90, 10.27. HRMS (ESI): m/z [M + H]+ calculated for C18H16F2N3OS: 360.09767; found:
360.09653.
N-(4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenyl)propionamide (
269.3–270.1 ◦C; 1H-NMR
10.24 (s, 1H, NH), 9.80 (s, 1H, NH), 7.97–7.84 (m, 2H, Ar-H), 7.62 (d, J = 9.2
Hz, 2H, Ar-H), 7.58 (d, J = 9.2 Hz, 2H, Ar-H), 7.50–7.42 (m, 2H, Ar-H), 7.33 (s, 1H, thiazole-H), 2.21 (q,
A16): white solid; yield 90%; mp:
δ
J = 7.6 Hz, 2H, CH2), 1.05 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
δ 172.07, 163.93, 149.32, 137.03, 133.94,
132.41, 129.20, 127.92, 120.38, 117.84, 103.90, 29.96, 10.36. HRMS (ESI): m/z [M + H]+ calculated for
C18H17ClN3OS: 358.07754; found: 358.07639.
N-(4-((4-(3-Chlorophenyl)thiazol-2-yl)amino)phenyl)propionamide (
A17): white solid; yield 82%; mp:
223.5–224.6 ◦C; 1H-NMR)
δ
10.24 (s, 1H, NH), 9.80 (s, 1H, NH), 7.95 (s, 1H, thiazole-H), 7.90 (d, J = 7.8
Hz, 1H, Ar-H), 7.62 (d, J = 9.2 Hz, 2H, Ar-H), 7.58 (d, J = 9.2 Hz, 2H, Ar-H), 7.52–7.42 (m, 2H, Ar-H),
7.37 (dd, J = 8.0, 1.1 Hz, 1H, Ar-H), 2.31 (q, J = 7.6 Hz, 2H, CH2), 1.10 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
δ
172.08, 164.05, 149.00, 137.05, 134.02, 131.13, 127.80, 125.74, 124.84, 120.46, 117.97, 104.70, 29.97, 10.34.
HRMS (ESI): m/z [M + H]+ calculated for C18H17ClN3OS: 358.07754; found: 358.07639.
N-(4-((4-(3,4-Dichlorophenyl)thiazol-2-yl)amino)phenyl)propionamide ( 18): white solid; yield 77%; mp:
A
258.1–259.0 ◦C; 1H-NMR
δ
10.27 (s, 1H, NH), 9.80 (s, 1H, NH), 8.10 (d, J = 2.0 Hz, 1H, Ar-H), 7.88
(dd, J = 8.4, 2.1 Hz, 1H, Ar-H), 7.66 (d, J = 8.5 Hz, 1H, Ar-H), 7.57 (d, J = 9.2 Hz, 2H, Ar-H), 7.54 (d,
J = 9.2 Hz, 2H, Ar-H), 7.50 (s, 1H, thiazole-H), 2.27 (q, J = 7.5 Hz, 2H, CH2), 1.05 (t, J = 7.6 Hz, 3H, CH3).
13C-NMR
δ 172.12, 164.15, 147.98, 136.92, 135.65, 134.11, 131.95, 131.44, 130.17, 127.68, 126.36, 120.41,
118.01, 105.37, 29.96, 10.34. HRMS (ESI): m/z [M + H]+ calculated for C18H16Cl2N3OS: 392.03856; found:
392.03856 392.03784.
N-(4-(4-(4-Bromophenyl)thiazol-2-ylamino)phenyl)propionamide (
219.5–220.8 ◦C; 1H-NMR
10.17 (s, 1H, NH), 9.75 (s, 1H, NH), 7.84 (d, J = 8.5 Hz, 2H,), 7.61–7.58 (m,
2H), 7.58 (d, J = 2.0 Hz, 2H, Ar-H), 7.53 (d, J = 9.0 Hz, 2H, Ar-H), 7.34 (s, 1H, thiazole-H), 2.27 (q,
A19): white solid; yield 65%; mp:
δ
J = 7.6 Hz, 2H, CH2), 1.05 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
δ 172.07, 163.99, 149.39, 137.03, 134.28,
133.97, 132.10, 128.24, 121.03, 120.41, 117.89, 103.98, 29.97, 10.34. HRMS (ESI): m/z [M + H]+ calculated
for C18H17BrN3OS: 402.02702; found: 402.02594.
N-(4-(4-(3-Bromophenyl)thiazol-2-ylamino)phenyl)propionamide (
A
20): white solid; yield 94%; mp:
◦
1
238.4–239.1 C; H-NMR
δ 10.21 (s, 1H, NH), 9.79 (s, 1H, NH), 8.08 (t, J = 1.7 Hz, 1H, Ar-H),
7.93 (d, J = 7.8 Hz, 1H, Ar-H), 7.61 (d, J = 9.2 Hz, 2H, Ar-H), 7.57 (d, J = 9.2 Hz, 2H, Ar-H), 7.50 (dd,
J = 8.0, 0.9 Hz, 1H, Ar-H), 7.45 (s, 1H, thiazole-H), 7.40 (t, J = 7.9 Hz, 1H, Ar-H), 2.31 (q, J = 7.5 Hz, 2H,
CH2), 1.09 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
δ 172.06, 164.02, 148.81, 137.29, 136.93, 133.98, 131.35,

Molecules 2020, 25, 1772
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130.62, 128.57, 125.13, 122.56, 120.41, 117.94, 104.62, 40.58, 40.37, 40.16, 39.95, 39.75, 39.54, 39.33, 29.91,
10.26. HRMS (ESI): m/z [M + H]+ calculated for C18H17BrN3OS: 402.02702; found: 402.02606.
N-(4-((4-(4-(Trifluoromethyl)phenyl)thiazol-2-yl)amino)phenyl)propionamide (
mp: 242.1–243.0 ◦C; 1H-NMR
10.23 (s, 1H, NH), 9.76 (s, 1H, NH), 8.22–8.16 (m, 2H, Ar-H), 7.64 (d,
J = 5.9 Hz, 2H, Ar-H), 7.60-7.55 (m, 2H, Ar-H), 7.54 (d, J = 2.9 Hz, 2H, Ar-H), 7.53 (s, 1H, thiazole-H),
2.27 (q, J = 7.5 Hz, 2H, CH2), 1.05 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
172.02, 164.18, 148.80, 136.87,
A21): white solid; yield 82%;
δ
δ
135.90, 134.07, 130.07 (d, 17.6 Hz), 126.10, 124.37, 123.39, 122.35, 120.3, 117.98, 104.97, 29.90, 10.25.
HRMS (ESI): m/z [M + H]+ calculated for C19H17F3N3OS: 392.10389; found: 392.10281.
N-(4-((4-(3-(Trifluoromethyl)phenyl)thiazol-2-yl)amino)phenyl)isobutyramide (
mp: 168.2–168.9 ◦C; 1H-NMR
10.24 (s, 1H, NH), 9.77 (s, 1H, NH), 8.21-8.17 (m, 2H, Ar-H), 7.64 (d,
J = 7.1 Hz, 2H), 7.58 (d, J = 9.1 Hz, 2H, Ar-H), 7.55 (d, J = 2.3 Hz, 2H, Ar-H), 7.53 (s, 1H, thiazole-H),
2.27 (q, J = 7.5 Hz, 2H, CH2), 1.05 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
172.02, 164.18, 148.80, 136.87,
A22): yellow solid; yield 86%;
δ
δ
135.90, 134.07, 130.33, 129.97, 126.10, 124.37, 123.39, 122.35, 120.35, 117.98, 104.97, 29.90, 10.25. HRMS
(ESI): m/z [M + H]+ calculated for C19H16F3N3OS: 392.10389; found: 392.10266.
N-(4-((4-(p-Tolyl)thiazol-2-yl)amino)phenyl)propionamide (
1H-NMR (400 MHz, DMSO-d6)
10.23 (s, 1H, NH), 9.85 (s, 1H, NH), 7.81 (d, J = 8.0 Hz, 2H, Ar-H),
A
23): white solid; yield 79%; mp: 286.4–287.5 ◦C;
δ
7.66 (d, J = 9.0 Hz, 2H, Ar-H), 7.59 (d, J = 9.0 Hz, 2H, Ar-H), 7.24 (d, J = 8.0 Hz, 2H, Ar-H), 7.21 (s, 1H,
Thiazole-H), 2.34 (d, J = 8.1 Hz, 3H, CH3), 2.30 (d, J = 7.5 Hz, 2H, CH2), 1.10 (t, J = 7.6 Hz, 3H, CH3).
13C-NMR (100 MHz, DMSO-d6)
δ 172.01, 163.67, 150.59, 137.19, 133.78, 132.42, 129.67, 126.09, 120.36,
117.70, 102.04, 29.91, 21.32, 10.30. HRMS (ESI): m/z [M + H]+ calculated for C19H20N3OS: 338.13216;
found: 338.13129.
N-(4-((4-Phenylthiazol-2-yl)amino)phenyl)propionamide (
1H-NMR
10.16 (s, 1H, NH), 9.76 (s, 1H, NH), 7.89 (dd, J = 8.2, 1.1 Hz, 2H, Ar-H), 7.61 (d, J = 9.0 Hz,
2H, Ar-H), 7.54 (d, J = 9.0 Hz, 2H, Ar-H), 7.39 (d, J = 7.7 Hz, 2H, Ar-H), 7.28 (dd, J = 10.5, 4.3 Hz, 1H,
Ar-H), 7.26 (s, 1H, thiazole-H), 2.28 (q, J = 7.5 Hz, 2H, CH2), 1.06 (t, J = 7.6 Hz, 3H, CH3). 13C-NMR
A
24): white solid; yield 87%; mp: 187.5–187.9 ◦C;
δ
δ
171.99, 163.78, 150.55, 137.11, 135.04, 133.82, 129.11, 128.00, 126.15, 120.39, 117.76, 102.98, 29.91, 10.28.
HRMS (ESI): m/z [M + H]+ calculated for C18H20N3OS: 324.11651; found: 324.11514.
N-(4-(4-(4-Fluorophenyl)thiazol-2-ylamino)phenyl)isobutyramide (
172.4–173.9 ◦C; 1H-NMR
10.16 (s, 1H, NH), 9.72 (s, 1H, NH), 7.92 (m, 2H, Ar-H), 7.62–7.57 (m, 2H,
Ar-H), 7.56–7.51 (m, 2H, Ar-H), 7.23 (d, J = 4.4 Hz, 2H, Ar-H), 7.20 (s, 1H, thiazole-H), 2.59–2.50 (m,
1H), 1.07 (d, J = 6.8 Hz, 6H, CH3). 13C-NMR
175.27, 163.94, 163.29, 160.86, 149.50, 137.08, 133.91,
A25): yellow solid; yield 74%; mp:
δ
δ
131.67 (d, J = 3.1 Hz), 128.13 (d, J = 8.0 Hz), 120.53, 117.81, 116.03, 115.81, 102.70, 56.51, 35.30, 20.04.
HRMS (ESI): m/z [M + H]+ calculated for C19H19FN3OS: 356.12274; found: 356.12180.
N-(4-((4-(3-Fluorophenyl)thiazol-2-yl)amino)phenyl)isobutyramide (
230.9–232.0 ◦C; 1H-NMR
10.18 (s, 1H, NH), 9.72 (s, 1H, NH), 7.74 (d, J = 7.9 Hz, 1H, Ar-H), 7.67 (d,
J = 9.8 Hz, 1H, Ar -H), 7.62–7.56 (m, 2H, Ar -H), 7.57–7.52 (m, 2H, Ar -H)„ 7.44 (m, 1H, Ar-H), 7.40
(s, 1H, thiazole-H), 7.10 (m, 1H, Ar-H), 2.54 (m, 1H, CH), 1.07 (d, J = 6.8 Hz, 6H, CH3). 13C-NMR
A26): yellow solid; yield 58%; mp:
δ
δ
175.24, 164.21, 163.91, 161.81, 149.25 (d, J = 2.8 Hz), 137.41 (d, J = 8.2 Hz), 136.98, 133.98, 131.13 (d,
J = 8.5 Hz), 122.23, 120.54, 117.87, 114.66 (d, J = 21.3 Hz), 112.72, 112.49, 104.52, 35.29, 20.05. HRMS
(ESI): m/z [M + H]+ calculated for C19H19FN3OS: 356. 12274; found: 356 12149.
N-(4-((4-(3,4-Difluorophenyl)thiazol-2-yl)amino)phenyl)isobutyramide (
A27): yellow solid; yield 69%; mp:
190.6–191.6 ◦C; 1H-NMR
δ
10.22 (s, 1H, NH), 9.76 (s, 1H, NH), 7.93 (dd, J = 11.2, 6.9 Hz, 1H, Ar-H), 7.78
(dd, J = 8.7, 4.3 Hz, 1H, Ar-H), 7.61 (d, J = 9.3 Hz, 2H, Ar-H), 7.57 (d, J = 9.3 Hz, 2H, Ar-H), 7.50 (d,
J = 8.6 Hz, 1H, Ar-H), 7.41 (s, 1H, thiazole-H), 2.59 (m, 1H, CH), 1.10 (d, J = 6.8 Hz, 6H, CH3). 13C-NMR
δ
175.31, 164.06, 151.24, 150.45, 148.87 (d, J = 12.7 Hz), 148.36, 148.06 (d, J = 12.7 Hz), 136.95, 133.99,
132.71, 122.89, 120.57, 118.22 (d, J = 17.1 Hz), 117.92, 114.86 (d, J = 18.3 Hz), 104.13, 35.29, 20.03. HRMS
(ESI): m/z [M + H]+ calculated for C19H18N3OF2S: 374.11332; found: 374.11191.

Molecules 2020, 25, 1772
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N-(4-((4-(4-Chlorophenyl)thiazol-2-yl)amino)phenyl)isobutyramide (
A
28): yellow solid; yield 91%; mp:
264.5–265.7 ◦C; 1H-NMR
δ 10.15 (s, 1H, NH), 9.72 (s,1H, NH), 7.88 (m, 2H, Ar-H) 7.65-7.57 (m, 2H,
Ar-H), 7.57–7.52 (m, 2H, Ar-H), 7.40 (m, 2H, Ar-H), 7.28 (d, J = 7.3 Hz, 1H, Ar-H), 7.26 (s, 1H, thiazole-H),
2.60–2.49 (m, 1H, CH), 1.11 (d, J = 6.8 Hz, 6H, CH3). 13C-NMR δ 175.28, 163.92, 149.22, 137.04, 133.92,
132.33, 129.12, 127.84, 120.43, 117.77, 103.83, 35.30, 20.07. HRMS (ESI): m/z [M + H]+ calculated for
C19H19ClN3OS: 372.09319; found: 372.09207.
N-(4-((4-(3-Chlorophenyl)thiazol-2-yl)amino)phenyl)isobutyramide (
234.4–235.7 ◦C; 1H-NMR
10.20 (s, 1H, NH), 9.73 (s, 1H, NH), 7.91 (t, J = 1.8 Hz, 1H, Ar-H), 7.86 (dd,
J = 7.8, 0.9 Hz, 1H, Ar-H), 7.61–7.56 (m, 2H, Ar-H), 7.56–7.52 (m, 2H, Ar-H), 7.46–7.39 (m, 2H, Ar-H),
7.33 (dd, J = 8.0, 1.1 Hz, 1H, thiazole-H), 2.55 (m, 1H,CH), 1.07 (d, J = 6.8 Hz, 6H,CH3). 13C-NMR
A29): yellow solid; yield 91%; mp:
δ
δ
175.25, 163.99, 148.93, 136.99, 133.98, 131.05, 127.73, 125.69, 124.76, 120.51, 117.90, 104.64, 35.30, 20.06.
HRMS (ESI): m/z [M + H]+ calculated for C19H19ClN3OS: 372.09319; found: 372.09204.
N-(4-((4-(3,4-Dichlorophenyl)thiazol-2-yl)amino)phenyl)isobutyramide (
251.4–252.7 ◦C; 1H-NMR
10.21 (s, 1H, NH), 9.72 (s, 1H, NH), 8.10 (d, J = 1.9 Hz, 1H, Ar-H), 7.88 (m,1H,
Ar-H), 7.65 (m, 1H, Ar-H), 7.55 (d, J = 9.7 Hz, Ar-H), 7.55–7.51 (m, 2H, Ar-H), 7.49 (s, 1H, thiazole-H),
A30): yellow solid; yield 71%; mp:
δ
2.54 (m, 1H, CH), 1.07 (d, J = 6.8 Hz, 6H). 13C-NMR
δ 175.25, 164.11, 147.93, 136.84, 135.57, 134.09,
131.89, 131.39, 130.13, 127.63, 126.30, 120.49, 117.96, 105.31, 35.29, 20.05. HRMS (ESI): m/z [M + H]+
calculated for C19H18Cl2N3OS: 406.05421; found: 406.05307.
N-(4-(4-(4-Bromophenyl)thiazol-2-ylamino)phenyl)isobutyramide (
A
31): white solid; yield 87%; mp:
10.19 (s, 1H, NH), 9.73 (s, 1H, NH), 7.92–7.82 (m, 2H, Ar-H), 7.66–7.60
(m, 4H, Ar-H), 7.57 (d, J = 9.2 Hz, 2H, Ar-H), 7.37 (s, 1H, thiazole-H), 2.65–2.53 (m, 1H, CH), 1.11 (d,
◦
1
190.6–191.6 C; H-NMR
δ
J = 6.8 Hz, 6H, CH3). 13C-NMR
δ 175.24, 163.98, 149.34, 137.00, 134.23, 133.97, 132.03, 128.17, 120.97,
120.50, 117.86, 103.91, 35.30, 20.05. HRMS (ESI): m/z [M + H]+ calculated for C19H19BrN3OS: 416.04267;
found: 416.04153.
N-(4-(4-(3-Bromophenyl)thiazol-2-ylamino)phenyl)isobutyramide (A32
)
:
white solid; yield 55%; mp:
◦
1
238.2–239.0 C; H-NMR
δ 10.17 (s, 1H, NH), 9.70 (s, 1H, NH), 8.05 (d, J = 1.8 Hz, 1H, Ar-H),
7.90 (dd, J = 6.6, 1.2 Hz, 1H, Ar-H), 7.56 (d, J = 6.4 Hz, 2H, Ar-H), 7.54 (d, J = 6.4 Hz, 2H, Ar-H),
7.53–7.44 (m, 1H, Ar-H), 7.42 (s, 1H, thiazole-H), 7.36 (t, J = 7.9 Hz, 1H, Ar-H), 2.60–2.50 (m, 1H,CH),
1.07 (d, J = 6.8 Hz, 6H, CH3). 13C-NMR
δ 175.25, 164.03, 148.81, 137.30, 136.94, 134.05, 131.35, 130.62,
128.58, 125.13, 122.56, 120.52, 117.94, 104.63, 35.30, 20.04. HRMS (ESI): m/z [M + H]+ calculated for
C19H19BrN3OS: 416.04267; found: 416.04153.
N-(4-((4-(4-(Trifluoromethyl)phenyl)thiazol-2-yl)amino)phenyl)isobutyramide (
mp: 198.8–199.5 ◦C; 1H-NMR
10.23 (s, 1H, NH), 9.73 (s, 1H, NH), 8.24–8.13 (m, 2H, Ar-H), 7.67–7.61
(m, 2H, Ar-H), 7.60–7.56 (m, 2H, Ar-H), 7.55 (d, J = 6.4 Hz, 2H, Ar-H), 7.54 (s, 1H, thiazole-H), 2.58–2.50
A33): white solid; yield 71%;
δ
(m, 1H, CH), 1.07 (d, J = 6.8 Hz, 6H, CH3). 13C-NMR
δ 175.32, 164.27, 148.86, 136.96, 135.97, 134.18,
130.40, 130.03, 125.89, 124.45, 122.46, 120.55, 118.04, 105.04, 35.37, 20.11. HRMS (ESI): m/z [M + H]+
calculated for C20H19F3N3OS: 406.11954; found: 406.11868.
N-(4-(4-(3-(Trifluoromethyl)phenyl)thiazol-2-ylamino)phenyl)isobutyramide (A34): yellow solid; yield 81%;
mp: 198.8–199.5 ◦C; 1H-NMR
δ
10.21 (s, 1H), 9.71 (s, 1H), 8.19 (s, 2H, Ar-H), 7.64 (d, J = 6.7 Hz, 2H,
Ar-H), 7.58 (m, 2H, Ar-H), 7.53 (s, 1H, thiazole-H), 2.59–2.50 (m, 1H, CH), 1.07 (d, J = 6.8 Hz, 6H, CH3).
13C-NMR
δ 175.32, 164.30, 148.88, 136.98, 135.99, 134.20, 130.38, 130.19, 129.98, 125.90, 124.45, 123.73,
122.45, 120.58, 118.07, 105.02, 35.37, 20.10. HRMS (ESI): m/z [M + H]+ calculated for C20H19F3N3OS:
406.11954; found: 406.11826.
N-(4-((4-(p-Tolyl)thiazol-2-yl)amino)phenyl)isobutyramide
(
A
35): yellow solid; yield 73%; mp:
10.12 (s, 1H, NH), 9.71 (s, 1H, NH), 7.77 (d, J = 8.1 Hz, 2H, Ar-H),
7.58 (d, J = 9.1 Hz, 2H, Ar-H), 7.53 (d, J = 9.1 Hz, 2H, Ar-H), 7.20 (d, J = 8.0 Hz, 2H, Ar-H), 7.18 (s, 1H,
thiazole-H), 2.62–2.50 (m, 1H, CH), 2.29 (s, 3H, CH3), 1.07 (d, J = 6.8 Hz, 6H, CH3). 13C-NMR
175.20,
◦
1
245.2–246.4 C; H-NMR
δ
δ

Molecules 2020, 25, 1772
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163.70, 150.60, 137.20, 133.82, 132.41, 129.67, 126.09, 120.49, 117.72, 102.06, 35.28, 21.32, 20.07. HRMS
(ESI): m/z [M + H]+ calculated for C20H22N3OS: 352.14781; found: 352.14685.
N-(4-((4-Phenylthiazol-2-yl)amino)phenyl)isobutyramide (
1H-NMR
10.15 (s, 1H, NH), 9.72 (s, 1H, NH), 7.88 (d, J = 7.2 Hz, 2H, Ar-H), 7.60 (d, J = 9.0 Hz, 2H,
Ar-H), 7.55 (d, J = 9.0 Hz, 2H, Ar-H), 7.39 (t, J = 7.7 Hz, 2H, Ar-H), 7.28 (d, J = 7.3 Hz, 1H, Ar-H), 7.26 (s,
A
36): white solid; yield 84%; mp: 239.6–241.0 ◦C;
δ
1H, Thiazole-H), 2.59–2.50 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H, CH3). 13C-NMR
δ 175.23, 150.54, 137.13,
135.04, 133.87, 129.11, 128.00, 126.15, 120.51, 117.76, 102.98, 35.29, 20.06. HRMS (ESI): m/z [M + H]+
calculated for C19H20N3OS: 338.13216; found: 338.13101.
3.3. X-ray Diffraction Analysis
To further confirm the three-dimensional structure of the target compounds, crystals (1.9 mm
×
0.5 mm
diffraction. Cell dimensions and intensities were measured at 298 K on a Bruker Smart Apex CCD
diffractometer with MoK radiation ( = 0.71073 Å). The structure was solved by direct method
×
1.6 mm) of A4 (Figure 2) were obtained by slow evaporation and analyzed by X-ray
α
λ
with the SHELXS-97 program. The results show that crystals of A4 is monoclinic system, which is
characterized by no higher-order symmetry axis. A total of 2709 reflections were measured, of which
1714 were unique in the range of 2.19 <
θ
< 25.02◦ (h,
−
14 to 19; k,
−
6 to 5; l, 22 to 21). The two benzene
−
rings in the molecule are almost in the same plane. All of the non-H atoms were refined anisotropically
by full-matrix least-squares to give the final R = 0.0732 and WR = 0.1820. The completeness of the
crystal data is 99.9%. The crystal data of the compound A4 have been deposited at the Cambridge
Crystallographic Data Center under code CCDC 1,975,217 that contains all the above data.
Figure 2. Crystal structure of compound A4.
3.4. In Vitro Antibacterial Activity Bioassays
The in vitro antibacterial activity of target compounds against Xoo, Xac and Xoc was evaluated
using a turbidimeter test [26,27]. For comparison, the commercial antibacterial agents bismerthiazol
and thiodiazole copper was used as positive controls. DMSO in sterile water served as negative
control. Nutrient broth medium (NB, 1 g of yeast powder, 3 g of beef extract, 10 g of glucose, 5 g of
peptone and 1 L of distilled water, pH 7.0 to 7.2) in tubes was sterilized under high temperature and
pressure. The tested compounds were dissolved in 120
solution, and finally working solution concentrations of 200 and 100
of the solution containing compounds, bismerthiazol and thiadiazole copper was transferred into
µL DMSO then diluted with 0.1% Tween-20
µg/mL were obtained. 1 mL
tubes (15 × 150 mm) containing 4 mL nutrient broth (NB) medium. Approximately 40
µ
L of a◦ctivated
bacteria was introduced into each tube. Finally, the test tubes were incubated at 28
±
1 C with
continuous shaking at 180 rpm for 24–48h. The density value (OD595) of the solution in the tube
was monitored on the microplates when the OD595 of the negative control group was 0.6 to 0.8. The
inhibition rate was calculated using the following equation:
Inhibitory Rate (%) = (CK − T)/CK × 100%.
(1)
where “CK” represents the density value (OD595) of negative control group, and “T” implies the
density value (OD595) of the treated NB medium. The EC50 values against Xoo, Xac and Xoc of the
target compounds were tested at five gradient concentrations and computed from analysis using

Molecules 2020, 25, 1772
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the SPSS 17.0 software (IBM, New York, NY, USA). The experiments were repeated three times for
each compound.
3.5. Scanning Electron Microscopy
The cell surface was observed as previously described [28]. Xoo culture (OD595 = 1.0) was
centrifuged and washed with PBS (pH = 7.2), then resuspended in 1.0 mL of PBS buffer. Then, the cells
were treated with compound
A µg/mL and 100 µg/mL. The
1 for 10 h at 28 ◦C at concentrations of 50
untreated sample served as a negative control. Next, the compound solution was removed by washing
three times with PBS buffer. The Xoo cells were fixed with 2.5% glutaraldehyde at 4 ◦C overnight and
then dehydrated with 70%, and 90% ethanol, respectively.
3.6. Nematicidal Biological Activity In Vitro
The nematicidal activities of the compounds A1
assay [29 30]. The tested compounds were dissolved with DMSO and then diluted with 1% Tween-80
solution to prepare 500 and 100 g/mL solutions. Approximately 200 L of test solution was added
–A36 against M. incognita were tested by a typical
,
µ
µ
into a 48 well plate. Then a suspension that included approximately 200 living nematodes was added
into the above solution. Avermectin was used as positive control. The solution without compound was
used as a negative control. All experiments were repeated three times. The mortality of the nematodes
was seen under a stereoscopic binocular microscope after 24 and 72 h. The corrected mortality of
nematicide was calculated using the following equation:
Corrected Mortality (%) = (Mortality of Treatment − Mortality of Control)/(1 − Mortality of Control) × 100%
4. Conclusions
In summary, a series of new N-phenylacetamide derivatives containing 4-arylthiazole moieties was
designed and synthesized by introducing the thiazole moiety into the scaffolds of N-phenylacetamides.
The target compounds were evaluated for their in vitro antibacterial activities against Xoo, Xac and
Xoc. The bactericidal activity data show that most of the target compounds have moderate inhibitory
activities against the above pathogens, among which compounds A1 and A3 have good inhibitory
effects on Xoo and Xoc. The cell-rupturing effect of compound
A1 on Xoo was studied through SEM
analysis. In addition their nematocidal activity was also determined and the compound A23 exhibited
strong toxicity against M. incognita, comparable to that of avermectin.
Supplementary Materials: 1H-NMR, 13C-NMR and HRMS spectra for the target compounds are available online.
Author Contributions: Funding acquisition, L.J. and X.Z.; Investigation, H.L. and L.W.; Project administration
and supervision, X.Z.; Writing-original draft, H.L., manuscript review and edit, X.Z. All authors have read and
agreed to the published version of the manuscript.
Funding: This work was supported by the National Nature Science Foundation of China NSFC 21967006, and by
The Excellent Young Science and Technology Talent Cultivation Plan 201122, and by International Science and
Technology Cooperation Program of Guizhou province 2009700112.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds A1–A36 are available from the authors.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).