Synthesis, biological activities and 3D-QSAR studies of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety

Article abstract of DOI:10.1016/j.cclet.2018.11.001

A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety were synthesized and characterized on the basis of NMR and elemental analysis (EA). The crystal structure of (R)-N-(2-methyl-1-(methylthio)propan-2-yl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carboxamide (13d) was determined to show R configuration. The bioasssy results indicated that most title compounds displayed good and broad spectrum antifungal activities against several phytopathogenic fungi. The structure activity relationships were discussed. Based on the antifungal activity of title compounds against Phytophthora capsici, a CoMSIA calculation was performed to establish a 3D-QSAR model, which revealed that electrostatic and hydrophobic fields were the two most significant factors for antifungal activity. According to the established 3D-QSAR model, structure optimization was carried out to find (R)-N-((R)-1-(methylthio)propan-2-yl)-2-(p-tolyl)-4,5-dihydrothiazole-4-carboxamide (15h) with excellent activity against Phytophthora capsici, thus emerging as a new lead compound for novel antiphytopathogenic fungus agent development.

Full text of DOI:10.1016/j.cclet.2018.11.001

Accepted Manuscript
Title: Synthesis, biological activities and 3D-QSAR studies of
(R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives
containing a sulfur ether moiety
Authors: Jingbo Liu, Fengyun Li, Yuanhong Wang, Haoxuan
Zhang, Jingyue Dong, Pengwei Sun, Yuxin Li
PII:
DOI:
Reference:
S1001-8417(18)30428-5
https://doi.org/10.1016/j.cclet.2018.11.001
CCLET 4705
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
23 September 2018
28 October 2018
1 November 2018
Please cite this article as: Liu J, Li F, Wang Y, Zhang H, Dong J, Sun P, Li Y, Synthesis,
biological activities and 3D-QSAR studies of (R)-2-phenyl-4,5-dihydrothiazole-4-
carboxamide derivatives containing a sulfur ether moiety, Chinese Chemical Letters
(2018), https://doi.org/10.1016/j.cclet.2018.11.001
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Communication
Synthesis, biological activities and 3D-QSAR studies of (R)-2-phenyl-4,5-
dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety
Jingbo Liua, Fengyun Lib, Yuanhong Wanga, Haoxuan Zhanga, Jingyue Dongc, Pengwei Sunc, Yuxin Lic,*
a College of Horticulture and Landscape Architecture, Tianjin Agricultural University, Tianjin 300384, China
b College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
c State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin), College of Chemistry, Nankai University, Tianjin 300071, China
* Corresponding author.
E-mail address: liyx128@nankai.edu.cn (Y. Li).
Graphical Abstract
A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety were designed, synthesized,
and tested for their antifungal activities against several phytopathogenic fungi. The established CoMSIA model could predict the
antifungal activity.
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether
moiety were synthesized and characterized on the basis of NMR and elemental analysis (EA). The
Received in revised form
Accepted
Available online
crystal
structure
of
(R)-N-(2-methyl-1-(methylthio)propan-2-yl)-2-(4-nitrophenyl)-4,5-
dihydrothiazole-4-carboxamide (13d) was determined to show R configuration. The bioasssy
results indicated that most title compounds displayed good and broad spectrum antifungal
activities against several phytopathogenic fungi. The structure activity relationships were
discussed. Based on the antifungal activity of title compounds against Phytophthora capsici, a
CoMSIA calculation was performed to establish a 3D-QSAR model, which revealed that
electrostatic and hydrophobic fields were the two most significant factors for antifungal activity.
According to the established 3D-QSAR model, structure optimization was carried out to find (R)-
N-((R)-1-(methylthio)propan-2-yl)-2-(p-tolyl)-4,5-dihydrothiazole-4-carboxamide (15h) with
excellent activity against Phytophthora capsici, thus emerging as a new lead compound for novel
antiphytopathogenic fungus agent development.
Keywords:
(R)-2-Phenyl-4,5-dihydrothiazole-4-carboxamide
Sulfur ether
Antifungal activity
SARs
CoMSIA model
Plant diseases, mainly caused by fungi, bacteria, viruses and oomycetes, have resulted in severe losses to agriculture, even emerged
threat to global food security, and affected our health [1]. Although some efficient measures have been taken to resolve the above problem,
it is well known that agrochemicals in reducing crop loss caused by plant diseases play an important role and cannot be ignored [2,3].
Natural products found in nature and produced by living organisms have low toxicity, good compatibility, and biodegradability, so
they have been widely used in the fields of medicine and agrochemistry, such as Eribulin [4], Paclitaxel [5], Artemisinin [6-8], and
Rotenone [9]. Furthermore, natural products are also often used as pesticide precursor compounds in discovering new synthetic pesticides
[10-13], which display better efficacies than those of natural products. (−)-(R)-Dihydroaeruginoic acid (Fig. S1 in Supporting
information), as a natural product, had been found to exhibit in vitro antiproliferative activity for L1210 cell lines [14]. Pyochelin (Fig.
S1 in Supporting information was produced by Gramnegative bacteria (Burkholderia cepacia and Pseudomonas aeruginosa), and
possessed a unique microbial siderophore activity [15]. Subsequently, a variety of 2-aryl-4,5-dihydrothiazole-4-carboxylic acid
analogues were reported, and displayed anticancer reactivity [16,17], anti-HIV [18], and antibiotic activity [19]. However, there are few
reports about the application of these analogues in plant disease prevention. Recently, our research group firstly reported the synthesis

and antifungal activity of a series of (R)-2-aryl-4,5-dihydrothiazole-4-carboxylic acid derivatives containing piperazine, piperidine, and
pyrimidine moieties, and some compounds exhibited good and broad spectrum antifungal activities [20].
Up to now, more than 30% of agrochemicals contain at least one sulfur atom and they have played an important role in the field of
modern crop protection [21]. The introduction of sulfur into a biologically active molecule is still an important way in modifying the
biological activities to discover novel agrochemical candidate with new modes of action by binding to a target receptor and blocking
metabolic deactivation [22,23]. Inspired by the above findings, herein we reported a series of (R)-2-phenyl-4,5-dihydrothiazole-4-
carboxamide derivatives containing a sulfur ether moiety. The bioactivities of the title compounds were evaluated, and the structure-
activity relationship of these compounds is studied. In addition, a CoMSIA model is built to optimize the substituents (R) on the benzene
ring.
The synthetic routes are depicted in Scheme S1 (Supporting information) and Scheme 1. Intermediates 3, 6, and 9 were synthesized
according to the literature [24] with some modifications. 2-Ammoniopropyl sulfates (2, 5, and 8) were obtained in 75%−85% yields by
reactions of 2-aminopropan-1-ol (1, 4, and 7) and chloronic sulfonic acid with anhydrous 1,2-dimethoxyethane as the solvent below 0
oC, which further reacted with sodium methyl mercaptan (20%) to afford intermediates 3, 6, and 9 in 75%−83% yields. The key
intermediates 12a−h were synthesized referring to our previously reported method [20] with some improvement in Scheme 1.
Subsequently, treatment of 12a−h with 1-(methylthio)propan-2-amines (3, 6, and 9) in the presence of N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride (EDCI), 1-hydroxy-1H-benzotriazole (HOBT) and N,N-diisopropylethylamine (DIPEA) afforded the
desired products 13−15. They were identified by NMR and elemental analysis (EA). Moreover, the structure of compound 13d was
confirmed through single crystal X-ray diffraction analysis. (Fig. S2 in Supporting information, CCDC: 1839896).
Scheme 1. Synthetic routes of title compounds 13−15.
The antifungal activities (in vitro) of title compounds 13−15 against six plant pathogenic fungi are displayed in Table 1. From it, all
of the title compounds exhibited good (>50%) antifungal activities against Physalospora piricola and Phytophthora capsici, and more
effective than the control carbendazim at the concentration of 50 mg/L. Furthermore, 13a, 13h, 15a, and 15h showed broad spectrum
antifungal activities. For six plant pathogenic fungi mentioned above, a preliminary structure activity relationship study indicated that
the antifungal activity can be affected by the different type of functional groups (R) on benzene ring and the configuration of 1-
(methylthio)propan-2-amine moiety. It could be concluded that the proper electron donating groups (R = EDG) on benzene ring result in
an enhancement of the antifungal activity, however, obviously decreased by electron withdrawing groups (R = EWG). For instance, the
antifungal activities of title compounds 13g, 13h, 14g, 15g, and 15h (R = OCH3 or CH3) were superior to the compounds 13d, 13e, 14d
14e, 15d and 15e (R = NO2 or CF3). Meanwhile, the configuration of 1-(methylthio) propan-2-amine moiety displayed the sequence of
antifungal activity as CR ≥ Cachiral ≈ CS. The EC50 values of compounds 13−15 against Phytophthora capsici were further tested and shown
in Table 2, and much lower than that of carbendazim. Moreover, the EC50 value of compound 15h (6.7 mg/L) was comparable to that of
chlorothalonil (5.1 mg/L).
Table 1
Biological activity of the title compounds 13−15.
Compd.
Antifungal activity, inhibition rate (%, 50 mg/L)
Insecticidal
activity,
(%, 100 mg/L)
Cercospora
arachidicola
45.2
36.6
17.2
28.3
34.5
31.8
39.6
Physalospora
piricola
75.2
63.5
64.6
50.3
55.5
63.2
70.2
Alternaria
solani
60.8
45.3
37.6
10.4
40.2
42.5
49.8
Fusarium
graminearum
57.4
33.5
44.9
36.8
27.1
25.3
49.2
Phytophthora
capsici
80.1
68.3
70.1
54.8
55.4
71.2
77.1
Sclerotinia
sclerotiorum
51.4
52.3
33.7
21.4
35.7
34.6
49.4
Plutella xylostella
13a
13b
13c
13d
13e
13f
13g
13ha
14a
63
50
63
77
87
33
33
53
53
47.8
43.3
76.3
70.4
52.8
46.7
45.4
47.3
87.3
77.5
51.2
47.5

14b
14c
14d
14e
37.1
29.6
16.2
27.3
38.5
49.2
58.3
47.1
39.0
37.6
39.1
47.6
52.9
64.6
63.8
10.6
NT
56.7
64.7
51.2
51.7
57.3
72.8
75.5
57.0
66.4
57.5
58.8
63.0
76.3
77.5
84.6
47.8
NT
33.7
25.6
10.7
19.7
33.8
50.4
53.7
42.4
36.7
18.4
29.7
33.8
55.9
65.8
72.3
40.7
NT
34.6
37.5
13.7
37.4
39.2
55.7
56.2
45.8
30.5
25.7
42.0
52.9
63.7
63.7
41.8
100
70.7
70.8
56.4
56.9
70.1
74.3
86.4
73.2
71.7
60.9
58.1
73.4
81.2
89.2
88.7
32.4
NT
41.2
26.8
7.9
57
33
57
63
33
27
63
57
53
67
77
47
53
47
NT
NT
100
13.4
32.7
48.3
50.3
57.6
29.3
11.0
31.4
45.5
46.4
50.2
42.5
98.5
NT
14f
14g
15a
15b
15c
15d
15e
15f
15g
15ha
CK-1
CK-2
CK-3
NT
CK-1: Chlorothalonil; CK-2: Carbendazim; CK-3: Chlorotraniliprole; NT: not tested.
aSynthesized after the CoMSIA model analysis.
The insecticidal activities of title compounds 13−15 against Plutella xylostella were tested and summarized in Table 1. Most of
compounds exhibited apparent insecticidal activities at 100 mg/L. The insecticidal activities of compounds (13d, 13e, 14d, 14e, 15d,
15e) with electron withdrawing groups (R = EWG) were better than those of compounds (13g, 14g, 15g) with electron donating groups
(R = EDG).
In order to give more information of SAR, a 3D-QSAR model was established based on the EC50 data of title compounds against
Phytophthora capsici shown in Table 2. Among 21 compounds, four compounds (13c, 13g, 14e and 15d) were chosen randomly as the
test set of the 3D-QSAR model. Due to the lowest EC50 value, 15a was used as the template molecule, and the superimposition of training
set compounds had shown in Fig. S3 (Supporting information). A correlation coefficient of r2 = 0.977, and a cross validated coefficient
of q2 = 0.876 were obtained as the best 3D-QSAR model. The standard error of estimate, optimal number of components, and F value
was 0.022, 9, and 132.682, respectively. The final 3D-QSAR model was satisfactory with respect to both the predictive ability and
statistical significance of the training set and test set. Steric, electrostatic, hydrophobic, H-bond acceptor, and H-bond donor fields were
used to build the CoMSIA model, and the order of the relative contribution of them to the full model is hydrophobic (37.5%) >
electrostatic (36.6%) > H-bond acceptor (18.5%) > steric (7.4%) > H-bond donor (0%). These results revealed that the hydrophobic and
electrostatic fields were the two most important factors to the antifungal activities.
Table 2
EC50 of compound 13−15 aganist Phytophthora capsici (mg/L)
Compd.
13a
13b
13c
13d
13e
EC50
Compd.
14f
14g
15a
15b
15c
15d
15e
15f
15g
15h
Chlorothalonil
Carbendazim
EC50
19.95
18.07
13.65
20.04
20.81
23.77
22.44
19.23
15.52
6.7
15.49
20.65
21.38
24.38
23.01
19.63
17.06
10.7
15.85
21.18
21.88
24.89
23.33
13f
13g
13h
14a
14b
14c
5.1
>50
14d
14e
As shown in Table S1 (Supporting information), the pEC50 data training set and test set compounds were predicted by the CoMSIA
model, and Fig. S4 (Supporting information) displayed the correlations, which indicated that the CoMSIA model established could
predict the antifungal activity.
The CoMSIA contour maps were showed in Fig. 1 to observe how hydrophobic and electrostatic fields contribute to antifungal
activities. Fig. 1a is the contour of the CoMSIA hydrophobic field. The black contours around the R group of phenyl ring reveal the areas
where the hydrophobic groups are favorable for the antifungal activity. The electrostatic CoMSIA contour map is shown in Fig. 1b. The
black contours around the R group of the phenyl ring indicate that the increase of negative charge will play a favourable role on antifungal
activity, which suggests that proper electron-donating groups at this position could improve the antifungal activity. This is consistent
with experimental data (13d, 13e, 14d, 14e, 15d, 15e vs. 13g, 14g, 15g). Analysis of the CoMSIA contour maps indicates that a proper
hydrophobic and electron-donating group in the R group of phenyl ring could increase the antifungal activity against Phytophthora
capsici, which provides useful information for the further optimization of the structures.

Fig. 1. The contour map of the hydrophobic field (a) and electrostatic field (b).
On the basis of the SAR and CoMSIA model, in order to improve the antifungal activity, we rationally designed and synthesized 2
compounds 13h (R = CH3) and 15h (R = CH3). As shown in Tables 1 and 2, the antifungal activities of 13h and 15h are increased to
some extent compared to other title compounds, and this is consistent with the prediction of the CoMSIA model, indicating that the
CoMSIA model displayed good predictability.
In conclusion, a series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a sulfur ether moiety were
synthesized and their chemical structures were identified. All the title compounds were evaluated for fungicidal and insecticidal activities,
and most of them exhibited excellent and broad spectrum antifungal activities against Physalospora piricola and Phytophthora capsici,
and more effective than the control carbendazim at 50 mg/L dosage. The preliminary SAR of the title compound was studied. The proper
electron donating groups (R = EDG) on benzene ring and the configuration of CR in 1-(methylthio)propan-2-amine moiety played an
important role in the antifungal activity. The built 3D-QSAR model revealed that electrostatic and hydrophobic fields were the two most
significant factors for antifungal activity. According to the CoMSIA model, structure optimization was carried out to find compound 15h
with excellent activity against Phytophthora capsici, thus emerging as a new lead compound for novel antiphytopathogenic fungus agent
development, which indicated that the CoMSIA model established could predict the antifungal activity.
Acknowledgments
This study was financially supported by the Scientific Project of Tianjin Municipal Education Commission (No. 2018KJ008), Tianjin
Natural Science Foundation (No. 16JCYBJC29400).
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