Synthesis and Antifungal Activity of Cuminic Acid Derivatives

Article abstract of DOI:10.1007/s10600-017-2212-z

A series of benzamide derivatives (compounds 1–29) was synthesized based on the lead compound cuminic acid. The crystal structure of compound 11 was characterized by single crystal X-ray diffraction. The antifungal activity of the synthesized compounds wa

Full text of DOI:10.1007/s10600-017-2212-z

DOI 10.1007/s10600-017-2212-z
Chemistry of Natural Compounds, Vol. 53, No. 6, November, 2017
SYNTHESIS AND ANTIFUNGAL ACTIVITY
OF CUMINIC ACID DERIVATIVES
Jian Yang, Yang Gao, Hui Liu,
and Xiaorong Tang*
A series of benzamide derivatives (compounds 1–29) was synthesized based on the lead compound cuminic
acid. The crystal structure of compound 11 was characterized by single crystal X-ray diffraction. The antifungal
activity of the synthesized compounds was determined against seven plant pathogenic fungi, namely
Rhizoctonia solani, Gibberella zeae, Helminthosporium maydis, Sclerotinia sclerotiorum, Botrytis cinerea,
Coniothyrium diplodiella, and Coniothyrium lagenarium. Preliminary results indicated that most of them
revealed significant antifungal activity. Among them, compound 22 showed the strongest activity and possessed
better antifungal activity against H. maydis, S. sclerotiorum, and B. cinerea than carbendazim.
Keywords: cuminic acid, synthesis, crystal structure, antifungal activity.
Cuminic acid (p-isopropylbenzoic acid) is a natural product found in the seed of Cuminum cyminum [1, 2]. It can also
be obtained by chemical synthesis. It has various biological activities, including insecticidal and antifungal activity [3–6].
At the same time, its structure is simple and synthesis is easy, so its structure may be further optimized and modified to
synthesize and discover more active compounds or lead compounds with new structures, which will lay a good foundation for
its application in the agricultural chemistry field.
Carboxylic acid amide fungicides have always played an important role in the history of pesticide science. Since the
first carboxylic acid amide fungicide carboxin was discovered in 1966 [7], numerous carboxylic acid amide fungicides with
novel structures have been successively reported [8–11]. At present, these carboxylic acid amide fungicides are mostly used to
control diseases caused by plant pathogenic fungi and bacteria [12–16]. They can inhibit the growth of pathogens and cause
their eventual death by interfering with the pathogenꢀs respiration [17]. In addition, carboxylic acid amide fungicides are
usually efficient, safe, and environmentally friendly [18, 19].
In the present study, a series of cuminic acid derivatives has been designed in accordance with its structural features
and synthesized using cuminic acid and its derivatives and amines as raw materials to find new fungicides or lead compounds
with high efficacy and low toxicity as well as safety to non-target organisms. In the meantime, their antifungal activities
against R. solani, G. zeae, H. maydis, S. sclerotiorum, B. cinerea, C. diplodiella, and C. lagenarium were evaluated in the
laboratory.
According to the method shown in Scheme 1, compounds 1–29 were successfully synthesized. Their structures were
1
13
confirmed by H NMR and C NMR. The results showed that their NMR spectra were in agreement with the proposed
structures. To date, all the compounds have not been reported except 3, 7, 11, 16, 19, 22, 23, and 24.
The molecular structure of compound 11 is shown by X-ray determination in Fig. 1. The crystal data and structure
refinement for compound 11 are displayed in Table 1. Its crystallographic information file is deposited at the Cambridge
Crystallographic Data Center (CCDC No. 1415261).
School of Science, Xihua University, 610039, Chengdu, P. R. China, e-mail: txrlaoshi_xhu@126.com.
Published in Khimiya Prirodnykh Soedinenii, No. 6, November–December, 2017, pp. 945–948. Original article submitted
January 25, 2016.
1112
0009-3130/17/5306-1112 02017 Springer Science+Business Media New York

TABLE 1. Crystal Data and Structure Refinement of Compound 11
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
C18H18N2OS
310.40
293.15
Monoclinic
P21/c
6.1288 (2)
18.8208 (8)
14.1610 (5)
90.00
99.544 (4)
90.00
Absorption coefficient/mm–1
F(000)
0.204
656.0
0.3 ꢁ 0.2 ꢁ 0.2
0.71073
6.22–52.74
6892
3299(0.0229)
Crystal size/mm3
°
Wavelength/A
ꢂ range for data collection/ꢃ
Reflections collected
Independent reflections (Rint)
Data/restraints/parameters
Good-of-fit on F2
°
A/A
°
B/A
°
C/A
3299/0/202
0.984
ꢄ/ꢃ
ꢅ/ꢃ
ꢇ/ꢃ
R1 = 0.0477, wR2 = 0.1044
R1 = 0.0767, wR2 = 0.1127
0.21/–0.21
Final R indexes [I 2ꢆ (I)]
Final R indexes (all data)
° 3
° –3
Volume/A
1610.85 (11)
4
Largest diff. peak/hole/e A
Z
Index ranges
–7 ꢈ h ꢈ 7, –23 ꢈ k ꢈ 15, –13 ꢈ l ꢈ 17
Dc/(g cm–3)
1.280
O
X
N
H
X-NH
2
O
O
R
1 - 24
1
1
OH
Cl
a
O
O
H N-Y-NH
2
Y
N
2
1'
1
4
R
N
4
R
N
H
H
4'
1a - 3a
4
R
R
25 - 29
Cl
CH
NO
2
S
3
S
S
S
S
S
CH
3
X =
N
N
N
N
N
1, 9, 17
2, 10, 18
3, 11, 19
4, 12, 20
5, 13, 21
6, 14, 22
O
Y =
25, 27, 29
26, 28
7, 15, 23
8, 16, 24
1 – 8, 25, 26: R = CH(CH ) ; 9 – 16, 27, 28: R = C(CH ) ; 17 – 24, 29: R = CF
3
3 2
3 3
a. SOCl , reflux
2
Scheme 1
C15
N1
C10
C7
S1
C8
C9
C6
C5
C11
C12
C16
C1
N2
C19
C14
O1
C13
C4
C3
C2
C17
Fig. 1. Molecular structure of compound 11.
Compared with the efficient fungicide carbendazim, the synthesized compounds were submitted to laboratorial bioassay
using R. solani, G. zeae, H. maydis, S. sclerotiorum, B. cinerea, C. diplodiella, and C. lagenarium as targets. The results are
presented in Table 2. Compound 22 possessed the best antifungal activity against the seven fungi, and its activity against
H. maydis, S. sclerotiorum, and B. cinerea was superior to carbendazim. Compounds 1 and 4 showed excellent activity against
R. solani, H. maydis, and B. cinerea, with their inhibition rate reaching above 90% at 100 mg/L and their activity against
H. maydis and B. cinerea exceeding carbendazim. Compounds 9, 12, 17, and 20 displayed good activity against R. solani,
H. maydis, and B. cinerea, and their inhibition rate reached above 80% at 100 mg/L. Similarly, the inhibition rate of compounds
15, 27, and 29 against H. maydis and B. cinerea also surpassed 80% at 100 mg/L. Compounds 11 and 16 revealed good activity
against B. cinerea.
1113

–1
a
TABLE 2. Antifungal Activity of Compounds 1–29 at 100 mg L (inhibition of growth , %)
Compound
R. solani
G. zeae
H. maydis
S. sclerotiorum
B. cinerea
C. diplodiella
C. lagenarium
1
91.8 ꢉ 2.1
66.8 ꢉ 2.4
92.7 ꢉ 1.1
86.3 ꢉ 2.3
93.4 ꢉ 1.9
83.8 ꢉ 2.5
24.7 ꢉ 2.6
2
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
44.7 1.3
19.6 1.7
47.4 1.5
36.8 2.0
53.7 1.8
33.3 1.4
11.4 1.6
3
4
5
36.9 ꢉ 1.8
90.7 ꢉ 2.1
36.1 ꢉ 2.6
31.5 ꢉ 1.5
62.3 ꢉ 1.9
28.1 ꢉ 2.2
44.3 ꢉ 2.1
93.1 ꢉ 1.8
44.1 ꢉ 1.6
36.1 ꢉ 2.2
88.2 ꢉ 0.7
33.4 ꢉ 1.4
48.2 ꢉ 2.6
98.6 ꢉ 1.3
47.8 ꢉ 1.9
35.8 ꢉ 2.3
80.4 ꢉ 2.4
31.8 ꢉ 1.8
19.2 ꢉ 1.3
24.9 ꢉ 2.2
18.2 ꢉ 1.2
6
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
29.3 2.3
18.4 2.7
35.7 2.1
21.1 1.8
43.1 2.4
19.3 1.4
14.6 1.5
7
31.3 ꢉ 2.1
15.8 ꢉ 1.8
33.4 ꢉ 2.0
26.3 ꢉ 2.4
37.8 ꢉ 2.5
23.3 ꢉ 2.3
13.9 ꢉ 1.9
8
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
42.5 1.8
34.6 1.6
44.3 1.9
38.1 1.5
49.4 0.7
35.6 1.1
–17.4 0.9
9
82.7 ꢉ 1.4
64.2 ꢉ 2.1
85.3 ꢉ 2.3
80.2 ꢉ 1.3
87.4 ꢉ 1.3
73.5 ꢉ 2.8
21.5 ꢉ 2.2
10
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
35.3 2.5
28.1 0.9
40.7 1.1
32.8 2.7
45.4 1.5
31.1 1.4
19.6 3.8
11
12
13
14
15
16
17
18
61.7 ꢉ 1.2
81.7 ꢉ 1.5
36.9 ꢉ 1.9
36.0 ꢉ 2.2
71.1 ꢉ 2.7
69.3 ꢉ 1.5
88.7 ꢉ 2.1
38.7 ꢉ 1.0
24.8 ꢉ 1.4
57.9 ꢉ 2.1
23.4 ꢉ 1.7
19.5 ꢉ 2.7
30.6 ꢉ 2.4
42.1 ꢉ 1.6
30.4 ꢉ 2.5
28.5 ꢉ 1.8
67.1 ꢉ1.7
84.2 ꢉ 2.6
41.9 ꢉ 2.2
40.3 ꢉ 2.7
84.3 ꢉ 2.5
73.5 ꢉ 2.8
89.7 ꢉ 0.9
42.6 ꢉ 1.6
42.5 ꢉ 1.1
78.9 ꢉ 1.9
31.1 ꢉ 2.6
30.3 ꢉ 2.3
64.7 ꢉ 2.0
58.8 ꢉ 2.4
72.1 ꢉ 2.3
33.1 ꢉ 2.8
88.3 ꢉ 1.9
90.4 ꢉ 2.2
47.3 ꢉ 1.5
45.3 ꢉ 2.9
86.7 ꢉ 1.7
87.8 ꢉ 1.9
90.4 ꢉ 1.8
53.5 ꢉ 3.4
36.7 ꢉ 1.6
64.4 ꢉ 1.1
30.7 ꢉ 2.7
21.9 ꢉ 1.1
51.6 ꢉ 2.2
53.3 ꢉ 2.5
37.2 ꢉ 2.0
31.8 ꢉ 1.5
18.3 ꢉ 2.6
34.9 ꢉ 1.3
18.2 ꢉ 2.5
9.3 ꢉ 1.4
7.3 ꢉ 2.6
19.7 ꢉ 2.9
14.3 ꢉ 1.3
13.5 ꢉ 1.9
19
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
38.5 1.7
29.1 2.6
43.4 1.6
33.2 2.2
59.4 1.8
31.4 2.7
27.9 1.4
20
80.7 ꢉ 1.1
64.2 ꢉ 2.1
87.1 ꢉ 2.2
71.6 ꢉ 1.7
90.0 ꢉ 1.9
65.2 ꢉ 1.9
36.9 ꢉ 2.0
21
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
31.9 2.2
18.5 0.7
38.1 2.5
28.4 0.9
43.6 2.7
21.8 1.8
17.3 1.1
22
100.0 ꢉ 0
87.1 ꢉ 1.1
100.0 ꢉ 0
100.0 ꢉ 0
100.0 ꢉ 0
100.0 ꢉ 0
41.9 ꢉ 1.5
23
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
34.7 1.4
22.1 1.9
36.4 1.2
31.4 2.9
39.2 1.7
25.4 2.6
14.8 2.9
24
31.3 ꢉ 2.2
17.2 ꢉ 0.7
35.6 ꢉ 1.8
25.8 ꢉ 1.5
37.2 ꢉ 2.7
19.8 ꢉ 1.5
13.6 ꢉ 1.8
25
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
ꢉ
37.3 1.2
22.1 2.3
39.1 0.8
31.8 2.0
48.8 1.5
28.9 2.5
12.5 1.2
26
27
28
29
39.7 ꢉ 0.9
70.6 ꢉ 2.0
30.7 ꢉ 1.8
73.4 ꢉ 1.7
26.3 ꢉ 1.5
100 ꢉ 0
30.6 ꢉ 1.7
30.2 ꢉ 1.2
22.9 ꢉ 1.3
35.3 ꢉ 1.3
27.4 ꢉ 1.1
100 ꢉ 0
43.3 ꢉ 1.2
81.9 ꢉ 1.9
33.8 ꢉ 2.0
85.3 ꢉ 1.7
57.6 ꢉ 2.4
87.5 ꢉ 1.6
36.6 ꢉ 1.9
61.3 ꢉ 2.1
28.7 ꢉ 1.6
50.7 ꢉ 1.4
17.0 ꢉ 3.3
95.0 ꢉ 1.7
47.8 ꢉ 2.7
89.4 ꢉ 2.1
37.8 ꢉ 0.9
86.7 ꢉ 2.2
73.1 ꢉ 1.8
91.3 ꢉ 1.9
34.2 ꢉ 1.1
37.8 ꢉ 2.2
25.6 ꢉ 1.7
43.3 ꢉ 0.7
29.6 ꢉ 1.7
100 ꢉ 0
19.4 ꢉ 2.3
20.9 ꢉ 2.7
14.6 ꢉ 2.7
13.3 ꢉ 1.5
18.3 ꢉ 2.4
100 ꢉ 0
Cuminic acid
Carbendazim
______
a
Data are given as mean of triplicates ꢉ SD.
As shown in Table 2, compounds 1–29 showed inhibitory activity against the seven fungi in the following order:
B. cinerea H. maydis R. solani S. sclerotiorum C. diplodiella G. zeae C. lagenarium. If the activity of compounds
1, 9, and 17 were compared with that of compounds 2, 10, and 18, respectively, it is obvious that the methyl group at position 5
of the thiazole ring causes their activity to decrease remarkably, which needs to be further studied. In accordance with the
results of compounds 3–6, it could be found that when the hydrogen atom at position 6 of the benzothiazole ring was
substituted by CH , Cl, and NO group, respectively, their antifungal activity exhibited the following order: CH
H Cl NO .
3
2
3
2
Compounds 11–14 also produced the same results, whereas the antifungal activity order of compounds 19–22 was
NO CH Cl, which also needs to be further investigated. It was noteworthy that although compound 8 displayed
H
2
3
inhibitory activity against R. solani, G. zeae, H. maydis, S. sclerotiorum, B. cinerea, and C. diplodiella, it showed a promoting
effect against C. lagenarium.
Although a definite structure–activity relationship could not be found through the target compounds, the interesting
results obtained can be used for further designing and synthesizing more similar compounds to study their quantitative
structure–activity relationship (QSAR) so that more bioactive compounds or lead compounds may be discovered.
1114

EXPERIMENTAL
All chemicals and solvents were purchased from commercial sources unless otherwise specified. R. solani, G. zeae,
H. maydis, S. sclerotiorum, B. cinerea, C. diplodiella, and C. lagenarium were obtained from the ChineseAcademy ofAgricultural
1
13
Sciences. They were preserved at 4ꢃC. NMR spectra ( H and C NMR) were taken on a Bruker 300 MHz spectrometer using
deuterated dimethyl sulfoxide (DMSO-d ) as solvent. Melting points were determined using an X-4B micro-melting point
6
apparatus and were not corrected.
Preparation of Acyl Chlorides (1a, 2a, and 3a). Thionyl chloride (15 mL) was added to 0.01 mol of the corresponding
acids. The mixture was heated under reflux at 80ꢃC for 2 h with the help of a drying tube filled with anhydrous calcium
chloride. The reaction was monitored by thin-layer chromatography (TLC). When the reaction was completed, excess thionyl
chloride was removed under reduced pressure. The crude products were used in the subsequent reaction without further
purification (Scheme 1).
General Procedure for Target Compounds 1–29. Compound H N-X (0.01 mol) or NH -Y-NH (0.005 mol) was
2
2
2
completely dissolved in CH Cl . Triethylamine (Et N) or pyridine (3 mL) was added to the mixture (Scheme 1). Under
2
2
3
stirring, the acyl chloride (1a, 2a, or 3a) was slowly added to the mixture at room temperature. Afterwards, the reaction
mixture was stirred for another 5 h at 20–70ꢃC.After the reaction was completed, the mixture was washed with HCl (10%) and
NaOH (10%) in turn. The solvent was removed under reduced pressure. The progress of the reactions was monitored by TLC.
The crude products of compounds 7, 8, and 25–27 were recrystallized with dimethyl sulfoxide (DMSO) and water (15:1), and
the rest were recrystallized from anhydrous ethanol.
Determination of Crystal Structure of Compound 11. The pure compound 11 was dissolved in anhydrous ethanol
and heated under reflux for 1 h. The solution obtained was kept at room temperature for 2 days. A light brown prismatic single
crystal was obtained. A suitable crystal was selected and mounted on an Xcalibur Eos diffractometer. The crystal was kept at
293.15 K during data collection. Using Olex2 [20], the structure was solved with the Superflip [21–23] structure solution
program using charge flipping and refined with the ShelXL [24] refinement package using least squares minimization.
Assay of Antifungal Activity. The antifungal activity of compounds 1–29 against R. solani, G. zeae, H. maydis,
S. sclerotiorum, B. cinerea, C. diplodiella, and C. lagenarium was determined using the plate growth rate method [25].
The synthesized compounds and carbendazim (purity 90%) and cuminic acid were dissolved in DMSO, respectively.
The solution obtained was diluted with 0.1% Tween-80 solution. For primary screenings, they were determined at a concentration
of 100 mg/L. The solution was added to the sterile potato dextrose agar (PDA) medium at 45ꢃC, mixed to homogeneity, and
transferred to sterile Petri dishes to solidify. A mycelium agar disc (5 mm in diameter) of the target fungi was placed in the
center of PDA plates. They were incubated at 28ꢃC in the dark until the target fungi used as controls covered the surface of
these plates. Control groups were treated with the corresponding solution without the synthesized compound or carbendazim.
The diameter of the fungi in the cultures was measured, and the inhibition of growth was calculated according to the formula
of Abbott. Every experiment was replicated three times.
ACKNOWLEDGMENT
This project was supported by the Scientific Research Fund of Sichuan Provincial Education Department
(No. 13ZA0206), the Key Scientific Research Fund of Xihua University (No. Z1013314), the Innovation Fund of Postgraduates
of Xihua University (No. YCJJ 2015050), and the Research Center for Advanced Computation, Xihua University.
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