Design synthesis and biological evaluation of novel N-nitro acid amide derivatives as lead compounds of herbicide

Article abstract of DOI:10.1155/2016/8583765

A series of N-nitro acid amide derivatives compounds were synthesized based on the active site of target acetohydroxyacid synthase (AHAS, EC: 2.2.1.6) enzyme. All the structures of newly prepared compounds were thoroughly characterized by satisfied IR and ¹H NMR spectra. The IC₅₀ values against AHAS enzyme and EC₅₀ values for herbicidal activity against Amaranthus mangostanus L. and Sorghum sudanense of all synthesized target compounds were determined. The compounds II-10, II-21, and II-22 with IC₅₀ values of 7.09 mg/L, 9.07 mg/L, and 9.11 mg/L and the compounds II-8 and II-22 with EC₅₀ values of 9.87 mg/L and 19.88 mg/L against root of Amaranthus mangostanus L. and Sorghum sudanense were illustrated, respectively. Meanwhile, the possible reasons for the lower activity of compounds were analyzed by molecular docking prediction.

Full text of DOI:10.1155/2016/8583765

Hindawi Publishing Corporation
Journal of Chemistry
Volume 2016, Article ID 8583765, 6 pages
http://dx.doi.org/10.1155/2016/8583765
Research Article
Design Synthesis and Biological Evaluation of Novel N-Nitro
Acid Amide Derivatives as Lead Compounds of Herbicide
Xiaojuan Qi,1 Wenjie Tang,1 Shan Gao,1 Min Gao,1 Changshui Chen,1 and Qingye Zhang1,2
1College of Science, Huazhong Agricultural University, Wuhan 430070, China
2Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University,
Wuhan 430070, China
Correspondence should be addressed to Qingye Zhang; zqy@mail.hzau.edu.cn
Received 4 March 2016; Accepted 7 April 2016
Academic Editor: Teodorico C. Ramalho
Copyright © 2016 Xiaojuan Qi et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A series of N-nitro acid amide derivatives compounds were synthesized based on the active site of target acetohydroxyacid synthase
(AHAS, EC: 2.2.1.6) enzyme. All the structures of newly prepared compounds were thoroughly characterized by satisfied IR and
1H NMR spectra. e IC values against AHAS enzyme and EC values for herbicidal activity against Amaranthus mangostanus
50
50
L. and Sorghum sudanense of all synthesized target compounds were determined. e compounds II-10, II-21, and II-22 with IC
50
values of 7.09 mg/L, 9.07 mg/L, and 9.11 mg/L and the compounds II-8 and II-22 with EC values of 9.87 mg/L and 19.88 mg/L
50
against root of Amaranthus mangostanus L. and Sorghum sudanense were illustrated, respectively. Meanwhile, the possible reasons
for the lower activity of compounds were analyzed by molecular docking prediction.
1. Introduction
To further explore a series of novel structural potential
compounds as excellent herbicides, an idea that joined
the different trisubstituted N-nitro aniline and benzamides,
cinnamic amides together were performed in this study.
Twenty-four N-nitro acid amide derivatives compounds were
synthesized, and all the target compounds were subject to
biological activity tests against AHAS enzyme and herbici-
dal activity tests against Amaranthus mangostanus L. and
Sorghum sudanense. Meanwhile, the possible reasons for
the lower activity of target compounds were analyzed by
molecular docking prediction.
Weed management is a perennial challenge for growers, and
continual innovation is essential to maintain the effectiveness
of management technologies [1]. With the increasing num-
bers of herbicide-resistant weeds emergence [2, 3], there is
an urgent need of new, more selective, and even more potent
herbicides to control the unwanted vegetables.
N-nitro substituted anilines have been demonstrated to
display diversely biological activities, including herbicidal
properties [4], antifungal effects [5], and plant growth reg-
ulating activities [6]. Our laboratory has been engaged over
the years to explore N-nitrourea compounds, and some of
these compounds have acquired patents [7, 8]. Based on the
similarity of structure between sulfonylureas and N-nitrourea
compounds, we supposed they have the same targeted enzyme.
Our hypothesis has been confirmed combining molecular
docking and biological activity assay in our previous study
[9]. Urea functionality is an attractive structural unit; it has
displayed a broad range of biological activities, and it has been
implicated in herbicidal [10], antifungal [11–17], antibacterial
[18], plant growth regulator [19], and so on.
2. Materials and Methods
2.1. Instrumentation and Chemicals. All chemical reagents
were purchased from Shenshi Chemical Instrumentation
Network Ltd. (Wuhan, China) at AR grade. 1H NMR spectra
were recorded on an AM-600 MHz spectrometer (Bruker,
Bremen, Germany) with tetramethylsilane as interior refer-
ence and CDCl as the solvent. Infrared (IR) spectra were
3
acquired on an AVATAR330 infrared spectrometer (Nicolet,
Waltham, MA, USA) with KBr compression method. Melting

2
Journal of Chemistry
R1
NO2
Rꢀ
N
O
O
EtoAc, TEA
SOCl2, CH2Cl2
Rꢀ
Rꢀ
O
Cl
DMF
OH
R3
R2
I-1, I-2
R1
R1
R2
NH2
R3
HNO3
O
O
O
H
N
R2
NO2
O
O
NO2
R3
Intermediate 1
R1
NO2
N
O
O
Rꢀꢀ
SOCl2, CH2Cl2
Rꢀꢀ
EtoAc,TEA
Rꢀꢀ
OH
Cl
DMF
O
R3
R2
II-1· · ·II-22
R1, R2, R3 = F, Cl, Br
Rꢀ = phenyl, -CH3
Rꢀꢀ = phenyl, 4-OCH3Ph, 4-ClPh, 2,4-di-ClPh, 3-NO3Ph, 3-ClPh, 2-FPh, 4-CH3Ph, thienyl
Scheme 1: e synthetic routes of target compounds.
points (m.p.) were determined on an X-4 digital display
microscope melting point apparatus (Tech Instrument Co.
Ltd., Beijing, China). e progress of the reactions was
monitored by thin layer chromatography (TLC) on silica gel
plates visualized with UV light.
and SOCl (7.5 mmol) were dissolved into CH Cl (10 mL)
2
2
2
solvent, two drops of N, N-dimethylformamide (DMF) as
catalyst and triethylamine (TEA) (5 mmol) as acid-binding
agent were added into the above solution. e reaction was
executed for 12 h at room temperature under continuous
stirring, which was detected by TLC. en, the redundant
CH Cl solvent has been removed by reduced pressure
2.2. General Procedure for Intermediate 1. e AC O
2
2
2
distillation at 40∘C. Finally, the crude product of different
substituted acryloyl chlorides was obtained.
(30 mmol) was added into a 50 mL round-bottomed flask
and the temperature was controlled to 10∘C, and HNO
3
e intermediate 1 (3.5 mmol) was dissolved into 10 mL
ethyl acetate solvent in the 100 mL round-bottomed flask, and
the solution was kept into ice water bath. en the obtained
different substituted acryloyl chlorides in the previous step
were dropped into the mixture solution over a period of
0.5 h; the reaction was kept and stirred for about 2 h under
the controlled temperature whilst monitoring its progress
by TLC. At the end of reaction, target compounds were
got from silica gel column with eluent which consisted of
petroleum ether and ethyl acetate, respectively. e synthetic
route for target compounds I1-2 and II1–22 is outlined
in Scheme 1. e physicochemical properties of the target
compounds were summarized in Table 1, and the spectra
(30 mmol) was slowly added over a period of 0.5 h, and then
the reaction was stirred for about 0.5 h. Subsequently, the
mixture was added into another 100 mL round-bottomed
which contained 2,4,6-trisubstituted aniline (20 mmol) and
acetic acid (25 mL) solvent over a period of 0.5 h, and the
temperature was controlled to 15∘C. e reactions were kept
and stirred for about 1 h under the controlled temperature
whilst monitoring its progress by TLC.
en the mixtures were poured into ice water (200 mL),
and a large amount of orange precipitate appeared. e
orange precipitate was filtered under reduced pressure, dis-
solved into NaHCO (5%, 30 mL) solution, and then HCl
3
(2 mol/L) was added until the PH value of the solution
reached 5-6 with a large amount of white precipitate that
appeared again. Finally, the crude product was recrystal-
lized from ethanol to get the intermediate 1. e spec-
tra data of intermediate are included in the Supporting
Information (see Supplementary Material available online at
http://dx.doi.org/10.1155/2016/8583765).
1
data, the H NMR, and IR spectra of target compounds
(as shown in Figure S1–Figure S48) are included in the
Supporting Information.
2.4. Determination of IC50 Values for AHAS Enzyme. e
AHAS enzyme assay of the target compounds was performed
with the same method as our previously reported work [20].
2.3. General Procedure for the Synthesis Target Compounds I1-
2 and II1–22. Different substituted carboxylic acid (5 mmol)
All the IC values of each target compound for AHAS
50
enzyme were calculated as described in the reference.

Journal of Chemistry
3
Table 1: e structure and physical data summary of all target
compounds.
3. Results and Discussion
3.1. Synthesis. e synthetic route for target compounds I1-
2 and II1–22 is outlined in Scheme 1. Traditionally, the key
trisubstituted phenyl-nitramines intermediate 1 was synthe-
sized using nitric acid in the presence of acetic anhydride
with low yield according to the reference method [21, 22].
In this study, the acetyl nitric acid ester was prepared first,
and then trisubstituted phenyl-amine was added to obtain the
intermediates 1 with high yield.
Number
I-1
I-2
Number
II-1
II-2
II-3
II-4
II-5
II-6
II-7
II-8
II-9
II-10
II-11
II-12
II-13
II-14
II-15
II-16
II-17
II-18
II-19
II-20
II-21
II-22
R
Rꢀ
Phenyl
Yield/%
45
42
Yield/%
59
63
51
49
45
43
53
49
55
57
62
70
67
44
73
1,2,3
1,2,3
2,4,6-tri-Cl
2,4,6-tri-Br
-CH
3
R
Rꢀꢀ
2,4,6-tri-F
2,4,6-tri-F
2,4,6-tri-F
2,4,6-tri-F
2,4,6-tri-F
2,4,6-tri-F
2,4,6-tri-F
2,4,6-tri-F
2,4,6-tri-F
2,4,6-tri-Cl
2,4,6-tri-Cl
2,4,6-tri-Cl
2,4,6-tri-Cl
2,4,6-tri-Cl
2,4,6-tri-Cl
2,4,6-tri-Cl
2,4,6-tri-Br
2,4,6-tri-Br
2,4,6-tri-Br
2,4,6-tri-Br
2,4,6-tri-Br
2,4,6-tri-Br
Phenyl
4-OCH Ph
4-ClPh
2,4-di-ClPh
3-NO Ph
3-ClPh
2-FPh
4-CH Ph
ienyl
Phenyl
2,4-di-ClPh
3-NO Ph
3-ClPh
2-FPh
4-CH Ph
ienyl
Phenyl
4-OCH Ph
3-NO Ph
3-ClPh
2-FPh
3
en different substituted acryloyl chlorides were pre-
pared with SOCl (7.5 mmol), using DMF as catalyst and TEA
2
3
as acid-binding agent in the presence of CH Cl solvent. e
2
2
different substituted acryloyl chlorides could not be achieved
for their water and air sensitivity. Hence, different trisubsti-
tuted phenyl-nitramines intermediates 1 were directly added
into the above reaction mixture in the presence of TEA
to afford target compounds in 41–73% yields (as shown in
Table 1).
3
3
3.2. Evaluation IC50 Values of Target Compounds against
AHAS Enzyme. To estimate the IC values of target com-
50
pounds against AHAS enzyme, the method of previous
reported bioactive assay of AHAS in vitro was utilized by
detecting the change in absorbance of acetoin at 525 nm using
UV-Vis absorption spectrophotometry. All of the candidate
compounds were dissolved in DMSO and its concentration
was controlled at 1.5% in final reaction volume. e commer-
cialized herbicide nicosulfuron was taken as a reference. e
detailed experimental data were summarized in Table 2.
3
56
53
71
65
41
57
50
3
2
e result showed that the range of IC values of all the
ienyl
50
compounds was 7 mg/L–510 mg/L, and about three-quarters
of IC values were <40 mg/L. Different trisubstituted phenyl
50
target compounds showed some difference in activity against
AHAS enzyme; the activity of 2,4,6-tri-Br and 2,4,6-tri-Cl
substituted phenyl were similar and generally better than
2,4,6-tri-F substituted phenyl target compound. e com-
pounds II-10, II-21, and II-22 had the best biological activity
2.5. Determination of the Herbicidal Activity. With refer-
ence to the “Agricultural Industry Standard of the People’s
Republic of China Pesticide Indoor Bioassay Test Criteria
(herbicides) AGAR Method,” the Amaranthus mangostanus
L. and Sorghum sudanense as the target plant, the herbicidal
activity of all target compounds were tested.
in the all candidate compounds with IC values of 7.09 mg/L,
50
9.07 mg/L, and 9.11 mg/L, respectively. Although the inhibi-
tion rate of lead compound was lower than the commercial
herbicides, we considered it would be able to act as a lead
compound for the further study of structural optimization so
as to improve the inhibitory activity to AHAS.
Each of the target compounds was dissolved in
dimethyl sulfoxide (DMSO) solution to the concentration of
10000 mg/L, and then the solution was diluted with distilled
water containing 0.1% Tween-80 to the concentration of
10, 50, 100, and 200 mg/L. e concentration of DMSO
in all assays was maintained <1.5%. Twenty seeds of each
plant including Amaranthus mangostanus L. and Sorghum
sudanense were placed into a 9 cm diameter plate containing
two pieces of filter paper and 9 mL solution of tested
compound (0, 10, 50, 100, and 200 mg/L). e plate was
placed in a greenhouse and allowed to germinate for 5 days at
a temperature of 25 1∘C. e mixture of the same amount of
water, DMSO, and Tween-80 was used as the control. Water
was a blank control. Each treatment was repeated thrice
and the lengths of roots and hypocotyl in each plate were
measured and the means were calculated. DPS2000 standard
statistical sofware for data processing system was utilized to
3.3. Determination EC50 Values of Target Compounds for
Herbicidal Activity. e herbicidal activity of all the candi-
date compounds against Amaranthus mangostanus L. and
Sorghum sudanense has been investigated at the dosages
of 0, 10, 50, 100, and 200 mg/L according to the method
described in the experimental section. e inhibition rate
was increased with the concentration of the compound dose;
most of the compounds EC did not exceed 100 mg/L. All of
50
the results of bioassay testing were summarized in Table 3.
According to the determination EC values for herbicidal
50
activity, the target compounds exhibited higher herbicidal
activity against both roots and hypocotyls of dicotyledonous
plant Amaranthus mangostanus L. than monocotyledonous
plant Sorghum sudanense. Most of target compounds showed
perform the regression analysis for the EC values of each
target compound.
50

4
Journal of Chemistry
Table 2: e IC values results summary of candidate compounds
Table 3: Herbicidal activity summary of target compounds.
50
against AHAS.
Amaranthus
Sorghum sudanense
Number
Nicosulfuron
I-1
I-2
II-1
IC (mg/L)
mangostanus L.
50
Number
Root
Hypocotyl
Root
Hypocotyl
0.068
21.06
29.75
23.52
37.6
EC (mg/L) EC (mg/L) EC (mg/L) EC (mg/L)
50
50
50
50
I-1
I-2
110.25
102.61
48.85
148.20
36.92
89.48
46.76
62.11
70.96
87.88
63.51
21.22
37.12
96.34
70.87
187.57
108.38
113.90
113.62
52.78
152.11
56.53
88.28
106.26
139.01
61.84
27.97
129.06
18.90
87.53
102.56
25.64
35.06
42.37
9.87
99.98
91.16
II-1
II-2
II-3
II-4
II-5
II-2
II-3
II-4
II-5
28.66
28.25
36.2
80.82
129.29
50.33
98.45
81.78
II-6
10.43
394.41
24.35
273.38
7. 09
252.81
14.28
12.53
19.93
301.96
509.66
14.64
393.12
17.01
II-7∗
II-8
II-6
II-7
92.66
147.68
108.84
58.54
102.58
108.30
92.12
II-9∗
II-10
II-11∗
II-12
II-13
II-14
II-15∗
II-16∗
II-17c
II-18∗
II-19
II-20
II-21
II-22
II-8
II-9
II-10
II-11
II-12
II-13
II-14
II-15
II-16
II-17
II-18
II-19
II-20
II-21
II-22
85.70
44.19
97.25
58.14
77.33
58.56
84.02
75.31
59.59
80.45
35.09
77.62
82.60
19.88
44.83
74.19
35.91
61.89
17.46
80.23
109.33
105.05
61.97
134.57
69.28
104.52
165.19
111.93
111.08
53.83
22.97
91.90
64.50
20.54
53.44
20.51
75.74
114.64
124.35
126.53
102.88
68.14
253.95
193.37
103.68
156.46
55.52
18.15
9.07
9.11
e concentrations of the “∗” target compounds were 100 mg/L, 200 mg/L,
300 mg/L, 400 mg/L, and 500 mg/L. e concentrations of the nicosulfuron
were 0.01 mg/L, 0.025 mg/L, 0.05 mg/L, 0.075 mg/L, and 0.1 mg/L. e con-
centrations of the rest of the target compounds were 1 mg/L, 5 mg/L, 10 mg/L,
25 mg/L, and 50 mg/L.
O
O−
N+
O
R1
O
O
N
N+
R2
better inhibition activity against root than that of hypocotyl
of the two testing plants.
R1
R1
O
R2
N
R2
−O
O
e target compounds possessed higher herbicidal
activity against root than that of hypocotyl. In particular,
compounds II-8 and II-22 exhibited considerable herbicidal
activity to root of Amaranthus mangostanus L. and Sorghum
Figure 1: e rearrangement in the N-nitro amides part of the target
compound.
sudanense with EC values of 9.87 mg/L and 19.89 mg/L,
50
respectively. e activity of 2,4,6-tri-F substituted phenyl tar-
get compounds was better than 2,4,6-tri-Br and 2,4,6-tri-Cl
substituted phenyl type compounds, such as compounds II-2,
First of all, all the target compounds possess N-nitro
amides part which is unstable and usually occur rearrange-
ment as reported in [23]. e part of target compound may
rearrange during activity testing as shown in Figure 1, and the
rearrangement may result in the reduced inhibition activity.
e interactions between candidate compounds and
AHAS enzyme were predicted by molecular docking analysis.
e structures of all compounds were sketched by Sybyl [24].
e Surflex docking module was performed in this study; the
docking procedure and parameters were set the same as in our
previous reported work [20]. Compared to the binding model
of the known commercialized herbicide sulfonylureas and the
characteristics of amino acids in the active site of AHAS, it
was found that most of synthesized compounds form similar
II-5, II-6, II-7, II-8, and II-9 with EC values of 18.90 mg/L,
50
25.64 mg/L, 35.06 mg/L, 42.37 mg/L, 9.87 mg/L, and
44.83 mg/L against the root of Amaranthus mangostanus L.
3.4. Analysis for the Lower Activity of the Target Compounds.
Most of the synthesized target compounds showed lower
activity than the commercial herbicides and the inconsistence
between IC values and EC values in the biological testing.
50
50
For the discrepancy reason we performed some analysis
based on the compound structure and binding conformation
in the active site of AHAS target.

Journal of Chemistry
5
(a)
(b)
Figure 2: e comparison between the docking conformation of the known commercialized herbicide sulfonylureas (a) and the target
compound II-10 (b) in the active site of AHAS.
binding conformation in the active site of AHAS, as shown
in Figure 2. However, further careful analysis found that the
synthesized compounds cannot form fully orthogonal bend
at the N-nitro amides group for strong conjugation formed
between adjacent the phenyl and carbonyl. Although the N-
nitro amides group and the adjacent aromatic ring are located
in the entrance of channel leading to the active site, they
could not very effectively prevent the substrate entrance. us
the candidate compounds showed lower inhibition activity
compared to sulfonylureas. Next, we would synthesize novel
target compounds with canceled strong conjugation formed
between adjacent phenyl and carbonyl.
Acknowledgments
is work was supported by the Natural Science Foundation
of Hubei Province (no. 2015CFB442).
References
[1] J. M. Green, “Review of glyphosate and ALS-inhibiting her-
bicide crop resistance and resistant weed management,” Weed
Technology, vol. 21, no. 2, pp. 547–558, 2007.
[2] J. Hattori, R. Robert, D. Brown, G. Sunohara, and B. Miki, “Mul-
tiple resistance to sulfonylureas and imidazolinones conferred
by an acetohydroxyacid synthase gene with separate mutations
for selective resistance,” Molecular Genetics and Genomics, vol.
232, pp. 167–173, 1991.
4. Conclusions
[3] G. W. Haughn and C. R. A. Somerville, “A mutation causing
imidazolinone resistance maps to the Csr1 locus of Arabidopsis
thaliana,” Plant Physiology, vol. 92, no. 4, pp. 1081–1085, 1990.
rough this study, twenty-four N-nitro acid amide deriva-
tives compounds were synthesized based on the active site
of target AHAS enzyme, and all of the target compounds
were performed biological testing against AHAS enzyme
and herbicidal activity against Amaranthus mangostanus L.
and Sorghum sudanense. Compounds II-10, II-21, and II-22
[4] B. Cross, R. Hill, and W. H. Gastrock, “Phenylnitramine
herbicides,” U.S. Patent 3844762, 1974.
[5] B. Cross, R. Hill, and H. D. Dawe, “Fungicidal phenylnitramines
and new phenylnitramines,” U.S. Patent 4130645, 1978.
[6] T. D. O’Neal, P. R. Bhalla, and B. Cross, “Method for the control
of stem growth and stem stiffness of graminaceous crops,” U.S.
Patent 4643755, 1987.
[7] C. S. Chen, S. Z. Xu, X. G. Li, M. H. Cao, and J. P. Xiong,
“Antimicrobial activity of N-nitro-N-phenyl-Nꢀ-pyridyl urea
derivative and synthesize,” C.N. Patent 101584338, 2009.
[8] C. S. Chen, S. Z. Xu, X. L. Yue, H. J. Ma, J. H. Li, and Z. J. Wei, “N-
nitro-2,4,6-Trichloroaniline of synthesis and application,” C.N.
Patent 102311361, 2012.
[9] J. N. Jin, H. J. Ma, X. F. Cao et al., “e discovery of the novel
lead compound of N-nitroureas target on acetohydroxyacid
synthase,” Pesticide Biochemistry and Physiology, vol. 104, no. 3,
pp. 218–223, 2012.
[10] P. A. Yonova and G. M. Stoilkova, “Synthesis and bio-
logical activity of urea and thiourea derivatives from 2-
aminoheterocyclic compounds,” Journal of Plant Growth Reg-
ulation, vol. 23, no. 4, pp. 280–291, 2004.
[11] R. H. Tale, A. H. Rodge, G. D. Hatnapure, and A. P. Keche, “e
novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of N-
aryl urea: synthesis, anti-inflammatory, antibacterial and anti-
fungal activity evaluation,” Bioorganic and Medicinal Chemistry
Letters, vol. 21, no. 15, pp. 4648–4651, 2011.
[12] A. P. Keche, G. D. Hatnapure, R. H. Tale, A. H. Rodge, and V. M.
Kamble, “Synthesis, anti-inflammatory and antimicrobial eval-
uation of novel 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole
with IC values of 7.09 mg/L, 9.07 mg/L, and 9.11 mg/L were
50
confirmed, respectively. Compounds II-8 and II-22 exhib-
ited considerable herbicidal activity to root of Amaranthus
mangostanus L. and Sorghum sudanense with EC values of
50
9.87 mg/L and 19.88 mg/L, respectively. Further analysis was
carried out based on the structure and interaction conforma-
tion in the active site of AHAS predicted by molecular dock-
ing to argue possible reason for the lower activity of target
compounds. Based on the interaction mechanism analysis,
further optimization for the lead compound would be per-
formed to improve inhibition activity in our research group.
Disclosure
Xiaojuan Qi and Wenjie Tang both are co-first authors.
Competing Interests
e authors declare that there are no competing interests
regarding the publication of this paper.
Authors’ Contributions
Xiaojuan Qi and Wenjie Tang contributed equally to this
paper.

6
Journal of Chemistry
derivatives bearing urea, thiourea and sulfonamide moieties,”
Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 21, pp.
6611–6615, 2012.
[13] G. D. Hatnapure, A. P. Keche, A. H. Rodge, S. S. Birajdar,
R. H. Tale, and V. M. Kamble, “Synthesis and biological
evaluation of novel piperazine derivatives of flavone as potent
anti-inflammatory and antimicrobial agent,” Bioorganic and
Medicinal Chemistry Letters, vol. 22, no. 20, pp. 6385–6390, 2012.
[14] A. P. Keche, G. D. Hatnapure, R. H. Tale, A. H. Rodge, S.
S. Birajdar, and V. M. Kamble, “Synthesis, anti-inflammatory
and antimicrobial evaluation of novel N1-(quinolin-4yl)ethane-
1,2-diamine phenyl urea derivatives,” Medicinal Chemistry
Research, vol. 22, no. 3, pp. 1480–1487, 2013.
[15] A. P. Keche, G. D. Hatnapure, R. H. Tale, A. H. Rodge, S. S.
Birajdar, and V. M. Kamble, “A novel pyrimidine derivatives
with aryl urea, thiourea and sulfonamide moieties: synthesis,
anti-inflammatory and antimicrobial evaluation,” Bioorganic
and Medicinal Chemistry Letters, vol. 22, no. 10, pp. 3445–3448,
2012.
[16] R. H. Tale, A. H. Rodge, G. D. Hatnapure, A. P. Keche, K.
M. Patil, and R. P. Pawar, “e synthesis, anti-inflammatory,
and anti-microbial activity evaluation of new series of 4-
(3-arylureido)phenyl-1,4-dihydropyridine urea derivatives,”
Medicinal Chemistry Research, vol. 22, no. 3, pp. 1450–1455,
2013.
[17] R. H. Tale, A. H. Rodge, G. D. Hatnapure, A. P. Keche, K. M.
Patil, and R. P. Pawar, “e synthesis, anti-inflammatory and
antimicrobial activity evaluation of novel thioanalogs of 3,4-
dihydrothiopyrimidin-2(1H)-one derivatives of N-aryl urea,”
Medicinal Chemistry Research, vol. 21, no. 12, pp. 4252–4260,
2012.
[18] S. A. Khan, N. Singh, and K. Saleem, “Synthesis, charac-
terization and in vitro antibacterial activity of thiourea and
urea derivatives of steroids,” European Journal of Medicinal
Chemistry, vol. 43, no. 10, pp. 2272–2277, 2008.
[19] J. C. Emerson and L. H. Steimel, “Corrosion inhibitor compo-
sition enhanced by carbamide addition for scale removal on
galvanized metal surfaces,” US 20070164258, 2007.
[20] J. N. Jin, X. J. Qi, D. D. Yao et al., “Rational design and screening
study of novel lead compound based on acetohydroxyacid
synthase structure,” Chemical Biology and Drug Design, vol. 84,
no. 3, pp. 316–324, 2014.
[21] X. G. Li and C. S. Chen, “Synthesis of N-nitro urea compounds
by non-phosgene method,” Journal of Huazhong Agricultural
University, vol. 22, pp. 298–300, 2003.
[22] Z. J. Wei, C. S. Chen, L. B. Shi et al., “Novel N-nitroacetamide
derivatives derived from 2,4-D: design, synthesis, bioevalua-
tion, and prediction of mechanism of action,” Pesticide Biochem-
istry and Physiology, vol. 106, no. 1-2, pp. 68–74, 2013.
[23] E. H. White and R. J. Baumgarten, “N-nitroamides and N-
nitrocarbamates. II. Amino acid derivatives,” e Journal of
Organic Chemistry, vol. 29, no. 12, pp. 3636–3640, 1964.
[24] J. Ruppert, W. Welch, and A. N. Jain, “Automatic identification
and representation of protein binding sites for molecular
docking,” Protein Science, vol. 6, no. 3, pp. 524–533, 1997.

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