Synthesis, characterization, antifungal evaluation and 3D-QSAR study of phenylhydrazine substituted tetronic acid derivatives

Article abstract of DOI:10.1016/j.bmcl.2014.06.074

A series of 3-(1-(2-(substituted phenyl)hydrazinyl)alkylidene)furan-2,4(3H, 5H)-diones were designed and prepared using two synthetic routes. Their structures were confirmed by FT-IR, ¹H NMR, ¹³C NMR, MS, elemental analysis and single-crystal X-ray diffraction. Their bioactivity was evaluated against Botrytis cinerea in vitro. Most target compounds exhibited remarkable antifungal activity. Two compounds 7f and 7h were highly effective and their EC₅₀ values were 0.241 μg/mL and 0.167 μg/mL, respectively, close to that of the control drug procymidone. 3D-QSAR studies of CoMFA and CoMSIA were carried out. Models with good predictive ability were generated with the cross validated q² values for CoMFA and CoMSIA being 0.565 and 0.823. Conventional r² values were 0.983 and 0.945, respectively. The results provided a practical tool for guiding the design and synthesis of novel and more potent tetronic acid derivatives containing substituted phenylhydrazine moiety.

Full text of DOI:10.1016/j.bmcl.2014.06.074

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3772–3776
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, characterization, antifungal evaluation and 3D-QSAR
study of phenylhydrazine substituted tetronic acid derivatives
Ying Hu a,c, Junjun Wang b,c, Aimin Lu a,b, Chunlong Yang a,b,c,
⇑
a Jiangsu Key Laboratory of Pesticide Science, Nanjing Agricultural, Nanjing 210095, PR China
b Ministry of Agriculture, Key Laboratory of Monitoring and Management of Crop Diseases and Pest Insects, Nanjing Agricultural University, Nanjing 210095, PR China
c Department of Science, College of Science, Nanjing Agricultural University, Nanjing 210095, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-(1-(2-(substituted phenyl)hydrazinyl)alkylidene)furan-2,4(3H,5H)-diones were designed
and prepared using two synthetic routes. Their structures were confirmed by FT-IR, 1H NMR, 13C NMR,
MS, elemental analysis and single-crystal X-ray diffraction. Their bioactivity was evaluated against
Botrytis cinerea in vitro. Most target compounds exhibited remarkable antifungal activity. Two
Received 10 May 2014
Revised 23 June 2014
Accepted 25 June 2014
Available online 1 July 2014
compounds 7f and 7h were highly effective and their EC50 values were 0.241 lg/mL and 0.167 lg/mL,
respectively, close to that of the control drug procymidone. 3D-QSAR studies of CoMFA and CoMSIA were
carried out. Models with good predictive ability were generated with the cross validated q2 values for
CoMFA and CoMSIA being 0.565 and 0.823. Conventional r2 values were 0.983 and 0.945, respectively.
The results provided a practical tool for guiding the design and synthesis of novel and more potent
tetronic acid derivatives containing substituted phenylhydrazine moiety.
Keywords:
Tetronic acid
Substituted phenylhydrazine
X-ray diffraction
Antifungal activity
3D-QSAR
Ó 2014 Elsevier Ltd. All rights reserved.
Much attention was paid to the isolation and synthesis of
tetronic acid derivatives owing to the wide range of biological
activities, such as antioxidant,1,2 anti-HIV,3 antiepileptic,4,5 antitu-
mor,6 anti-inflammatory7,8 and insecticidal9,10 ones. Moreover,
some of them exhibited high antimicrobial activities. 5-Hydroxy-
vertinolide and bislongiquinolide were isolated from the fungus
Trichoderma longibrachiatum Rifai aggr., which were antagonistic
to the fungus Mycena citricolo.11 Based on pharmacophore hypoth-
esis, substituted tetronic acid 3-carboxamides were investigated as
inhibitors of undecaprenyl pyrophosphate synthase (UPPS) for use
as novel antimicrobial agents.12 Pestalotic acids A–G were new
furylidene tetronic acid derivatives, isolated from a plant endo-
phyte Pestalotiopsis yunnanensis, showed obvious antimicrobial
activity.13 Vitamin C palmitate was found to be an effective
inhibitor of hyaluronan lyases from Streptococcus pneumoniae and
Streptococcus agalactiae strain 4755.14 5-Spirotetronic acid deriva-
tives containing ninhydrin residue showed good bacteriostatic
activity against Staphylococcus aureus and Escherichia coli.15
fungi.16–19 Based on active groups combination and bioisosterism
principles, eleven substituted phenylhydrazine moieties were
introduced at 3-position of furan-2,4(3H,5H)-dione, respectively
to design and synthesize twenty-five novel tetronic acid deriva-
tives, with a view to reveal the influence of introducing substituted
phenylhydrazines on the fungicidal activity. In addition, CoMFA
and CoMSIA implemented in the SYBYL software packages were
used to develop predictive 3D-QSAR models.20–23 This study also
predicted the substituents of new tetronic acid derivatives with
potential antifungal activities based on 3D-QSAR analysis.
The intermediate 3 was prepared by the reported method,24
starting from L-ethyl lactate, through b-ketoacylation of the hydro-
xyl and cyclization by lactonization and acidification (Scheme 1).
The cyclization was so-called Lacey–Dieckmann condensation.
The key to the lactonization reaction was the choice of an appropri-
ate base. According to the known procedure, various bases have so
far been employed to realize the lactonization.25,26 In this article,
CH3ONa/CH3OH, Na/Toluene and t-BuOK/THF were studied com-
paratively. All the bases with 1.2 equiv were in anhydrous form.
According to the results summarized in Table 1, the reaction
proceeded readily in t-BuOK/THF at reflux, leading to the expected
intermediate 3 in 71.0% yield after 12 h. In the same reaction time,
this yield of entry 3 was apparently higher than 20.3% of entry 2.
Moreover, TLC (ethyl acetate/light petroleum/methanol/acetic
acid, v/v, 10:2:2:0.2) showed the complex oil obtained from entry
1 contained the intermediate 3, but it was difficult to be isolated.
In view of this, it is worth to develop new tetronic acid deriva-
tives for screening high effective fungicides by modifying the sub-
stituents at furandione. In recent years, many compounds
containing a moiety of substituted phenylhydrazine were found
showing noticeable biological activity against the pathogenic
⇑
Corresponding author. Tel.: +86 25 8439 5207.
E-mail address: ycl@njau.edu.cn (C. Yang).
http://dx.doi.org/10.1016/j.bmcl.2014.06.074
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Hu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3772–3776
3773
O
O
H
N
N
H
7a-k
2
R
O
O
O
O
O
OH
O
OH
O
2
ii
O
i
R = H, 2-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 4-Br,
O
NHNH
2
O
2,4-Cl , 4-CH , 3,4-(CH ) , 4-OCH
2
3
3 2
3
O
O
O
2
O
R
H
N
1
2
3
N
H
2
1
8a-k
vi
R
R
O
O
O
OH
O
O
2
iii, iv
v
R
= H, 2-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 4-Br,
Cl
2,4-Cl , 4-CH , 3,4-(CH ) , 4-OCH
O
O
2
3
3 2
3
O
O
O
O
1
5
6a R = CH ;
4
3
1
O
6b R = C H
2
5
H
N
N
H
2
9a-c
R
O
O
2
R
= 3-Cl, 4-Cl, 2,4-Cl
2
Scheme 1. Reagents and conditions: (i) CH3OH, À10 °C to rt, 12 h (82%); (ii) t-BuOK/THF, reflux, 20% HCl (71%); (iii) t-BuOK/THF, rt, 20 h, 5% HCl (95%); (iv) acetic acid, HCl
gas, 1 h (69%); (v) acyl chloride/DMAP/CH2Cl2, À15 °C to rt, 15 h; (vi) ethanol, rt, 3–6 h.
Table 1
ing the cis–trans-isomers, which was caused by the double bond at
The optimization of preparation of the intermediates 3 and 6a
3-position of furan-2,4(3H,5H)-dione.
The isomers of target compounds could be observed by 1H NMR
Entry
Compd
Base
Solvent
Temp.
Yield (%)
and 13C NMR spectrums. The signals for the protons of NH close to
five-membered ring in 1H NMR spectra and almost all the signals
for carbon atoms of furan ring and olefinic carbons in the 13C
NMR spectra were divided into two single peaks, which was the
proof of the existence of cis–trans-isomers.
1
2
3
4
5
6
3
3
3
6a
6a
6a
CH3ONa
Na
t-BuOK
CH3ONa
Na
Methanol
Toluene
THF
Methanol
Toluene
THF
Reflux
rt
Reflux
Reflux
rt
10.7
20.3
71.0
2.6
4.9
9.5
t-BuOK
Reflux
As displayed in Figure 1, the single-crystal X-ray diffraction
study of compound 8a also suggested the existence of cis–
trans-isomerism. The suitable crystal was obtained by slow
evaporation of the solution composed of acetone and petroleum
ether at room temperature. The compound 8a crystallized with
two independent molecules (Molecule A and B) in the asymmetric
unit. In the Molecule A, the intramolecular hydrogen bond
N1–H1Á Á ÁO3 (Fig. 1), together with the atoms C3, C2 and C5,
formed a new six-membered ring. The bond lengths of N1–C5
[1.323(3) Å], N2–C7 [1.407(3) Å], C1–C2 [1.454(3) Å] and C2–C3
[1.409(3) Å] were shorter than their normal bond lengths because
of the presence of an electronic delocalization. Molecule B was
The intermediates 6a–b were tried to be prepared with the
same methods, but the experiments showed that all the yields in
three conditions were very low, even in t-BuOK/THF. So the inter-
mediates 6a–b were tried to be synthesized in another route, start-
ing from 4-chloroacetoacetate, through oxyalkylation, cyclization
and the acetylation at 3-position of furan-2,4(3H,5H)-dione.27,28
The result indicated that the total yields of 6a–b amounted up to
31.4% and 30.7%, respectively.
The synthesis of the target compounds 7a–k, 8a–k, 9a–c were
performed by the reaction of 3 and 6a–b with eleven substituted
phenylhydrazines respectively in ethanol at room temperature.
The reaction was gentle and the progress was monitored by TLC
(ethyl acetate/light petroleum/methanol/acetic acid, v/v,
10:2:2:0.2). The yields of the target compounds ranged from
32.7% to 51.1% (Table 2). Each target compound was found contain-
Table 2
Products and the corresponding yields
Compd
R2
Yield (%)
Compd
R2
Yield (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
2-F
4-F
2-Cl
3-Cl
4-Cl
4-Br
2,4-Cl2
4-CH3
3,4-(CH3)2
4-OCH3
H
47.5
37.5
45.6
51.1
36.2
43.7
48.3
43.9
49.1
42.4
43.1
42.7
32.7
8c
8d
8e
8f
8g
8h
8i
4-F
2-Cl
3-Cl
4-Cl
49.1
47.1
40.1
48.9
38.9
40.3
50.3
43.9
45.9
41.2
50.0
38.2
4-Br
2,4-Cl2
4-CH3
3,4-(CH3)2
4-OCH3
3-Cl
8j
8k
9a
9b
9c
7j
7k
8a
8b
4-Cl
2,4-Cl2
Figure 1. The X-ray crystal structure of compound 8a, shown with 50% probability
displacement ellipsoid.
2-F

3774
Y. Hu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3772–3776
Table 3
similar to Molecule A. The difference between Molecule A and B
was that Molecule B was a cis–trans-isomer due to the disordered
state of O4 and C13, while Molecule A was a trans-isomer.
Gaussian 03W software was used to decide the most stable con-
PLS statistics of CoMFA and CoMSIA 3D-QSAR models
PLS statistics
CoMFA
CoMSIA
q2a
0.565
0.983
0.090
180.464
5
0.823
0.945
0.151
103.152
3
0.164
0.330
0.024
0.024
0.458
former of the compounds.29 The trans-isomer
a and cis-isomer b
r2b
sc
were shown in Figure 2. The compounds 7f and 8a were chosen
as the models for calculation. The HF/3-21G was used for prelimin-
ary optimization, and B3LYP/6-31G⁄ was applied for further
optimization. Single point energies of two compounds were calcu-
lated with DFT method at B3LYP/6-311++G⁄⁄ level. The solvent
effect of DMSO was also taken in account. The calculated results
Fd
ONCe
Stericf
0.498
0.502
Electrostaticg
Donorh
Acceptorh
Hydrophobici
showed that the relative energies of 7fa and 7fb were 0.00 and
a
b
c
1.44 kJ/mol, while those of 8a and 8ab were 0.00 and 1.07 kJ/
a
Cross-validated correlation coefficient from leave-one-out.
Noncross-validated r2.
Standard error of estimate.
F-test value.
Optimum number of principal components.
Steric field contribution.
mol. It should be speculated that trans-isomer was predominant.
This was consistent with the result of the X-ray diffraction study.
The ratios of trans-isomer were estimated at 55–60% according to
the intensities of the two pairs of peaks in the NMR spectrum.
All the target compounds were screened for antifungal activity
against Botrytis cinerea.30 The fungicide procymidone was used as
control drug. Procymidone and iprodione are the general fungi-
cides against B. cinerea. The reports gave the corresponding EC50
d
e
f
g
h
Electrostatic field contribution.
Donor and acceptor, of hydrogen bond fields contribution,
respectively.
i
Hydrophobic field contribution.
values of 0.32 lg/mL and 0.80 l
g/mL, respectively.31,32 These data
demonstrated the potential application value of the high active
title compounds. The results in Table 4 showed that most target
compounds exhibited remarkable fungicidal activity. Among them,
the compounds 7f–h and 8g were highly effective against B. cinerea
and their EC50 values were 0.241
and 0.294 g/mL, respectively, close to or lower than 0.240
of the control drug.
l
g/mL, 0.283
l
g/mL, 0.167
l
l
g/mL
g/mL
l
To analyze the structure–activity relationship, the CoMFA and
CoMSIA 3D-QSAR models with a total of twenty-five target com-
pounds were developed.33,34 The statistical parameters were given
in Table 3. The CoMFA model (q2 = 0.565, r2 = 0.983) was based on
the steric and electrostatic fields, and the CoMSIA model
(q2 = 0.823, r2 = 0.945) was based on the steric, electrostatic, hydro-
phobic, hydrogen bond donor and hydrogen bond acceptor fields.
Partial least-square (PLS) analysis was performed to establish a
linear relationship between the molecular fields and the activity
of molecules. Figure 3 showed the alignment of all target com-
pounds used in the training set. Contour maps for the CoMFA
and CoMSIA models were displayed in Figure 4. Experimental
and predicted pEC50 values for the training set and test set were
reported in Table 4, and the correlation plots of CoMFA and CoMSIA
models were shown in Figures. 5 and 6, respectively.
Steric CoMFA map (Fig. 4A) showed green contour around
4-position of phenyl ring indicating bulky groups were favored at
this position. It was confirmed that the compounds 7f–h, 8f–h
and 9b–c exhibited higher antifungal activity. The yellow contours
around 3-position of phenyl ring indicated that compounds with
bulky groups at this position were less potent. This explained that
the compounds 7e, 8e and 9a had not good fungicidal activity.
Electrostatic CoMFA contour map (Fig. 4B) was shown in red
around 4-position of phenyl ring indicating that negative charge
might play a favorable role on activity, such as the compounds
7f–h, 8f–h, 9b–c. Combined with the steric CoMFA map, the bulky
Figure 3. Alignment of all target compounds in the training set.
groups with negative charges were favored at 4-position of phenyl
ring. That also explained that the compounds 7c and 8c had worse
fungicidal activity than 7f and 8f, respectively, due to the smaller
atom radius of fluorine. The blue contours around almost whole
phenyl ring showed that electronegative atom was disfavored at
other positions except for 4-position. The compounds 7b, 7d–e,
8b and 8d–e were good examples.
The colors of the steric and electrostatic contour maps in the
CoMSIA model had the same meanings as those of the CoMFA
model. Similar to steric CoMFA map, steric CoMSIA contour map
(Fig. 4C) indicated bulky group was favored at 4-position of phenyl
ring. In addition, the green contour around 5-position of furandi-
one nucleus suggested that bulky group should be introduced at
this position. So the compounds 7 showed better bioactivity than
the compounds 8, roughly. In agreement with CoMFA model,
electrostatic CoMSIA map (Fig. 4D) indicated that the group with
negative charge was also favored at 4-position of phenyl ring.
Hydrophobic CoMSIA contour map (Fig. 4E) showed yellow con-
tour around 4-position of phenyl ring indicating that hydrophobic
group was favored at the position, such as the compounds 7f–h,
8f–h and 9b–c. The grey contours around 2- and 3-position of phe-
nyl ring indicated that hydrophobic group played a disfavored role
at these positions. The compounds 7b, 7d–e, 8b and 8d–e were
good examples.
R1
R1
O
O
O
H
N
H
N
R3
N
H
N
H
R2
R2
O
O
O
R3
β
α
R3 = H, CH3
Figure 2. The cis–trans-isomers of target compounds.

Y. Hu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3772–3776
3775
Figure 4. CoMFA and CoMSIA STDEV⁄COEFF contour maps. CoMFA model: (A) Sterically favored areas are in green, and sterically disfavored areas are in yellow. (B) Negative
charge favored areas are in red and disfavored areas are in blue. CoMSIA model: The colors in (C) and (D) have the same meanings as do CoMFA contour maps (A) and (B),
respectively. (E) Hydrophobic favored areas are in yellow and disfavored areas are in gray. (F) Donor and acceptor favored areas are in cyan and magenta, respectively, and
donor and acceptor disfavored areas are in purple and red, respectively.
Table 4
Experimental and predicted pEC50 values of compounds 7a–k, 8a–k and 9a–c (lg/mL)
b
Compd
Actual EC50
Actual pEC50
CoMFA
CoMSIA
b
b
Predicted pEC50
Residual
Predicted pEC50
Residual
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
8a
8b
8c
8d
8e
3.902
1.467
1.139
1.586
1.350
0.241
0.283
0.167
2.270
18.743
13.951
3.997
1.045
0.585
1.801
1.060
0.337
0.294
0.305
2.325
7.904
9.664
1.549
0.360
0.517
0.240
5.409
5.833
5.943
5.800
5.870
6.619
6.548
6.777
5.644
4.727
4.855
5.398
5.981
6.233
5.744
5.975
6.472
6.531
6.515
5.633
5.102
5.015
5.810
6.443
6.286
—
5.397
5.762
5.919
5.716
5.807
6.652
6.501
6.768
5.512
4.902
4.906
5.538
5.916
6.288
5.790
5.993
6.467
6.499
6.625
5.700
5.009
4.958
6.054
6.530
6.759
—
0.0122
0.0718
0.0243
0.0840
0.0629
À0.0333
0.0470
0.0083
0.1316
À0.1748
À0.0508
À0.1393
0.0652
À0.0548
À0.0461
À0.0186
0.0045
0.0322
À0.1097
À0.0668
0.0936
0.0564
À0.2440
À0.0870
À0.4730
—
5.440
5.806
6.133
5.787
5.901
6.508
6.527
6.767
5.313
5.018
4.891
5.644
6.101
6.244
5.765
5.791
6.410
6.592
6.515
5.430
5.041
5.000
5.751
6.460
6.698
—
À0.0311
0.0275
À0.1892
0.0128
À0.0315
0.1105
0.0211
0.0100
0.3305
À0.2906
À0.0358
À0.2458
À0.1206
À0.0109
À0.0209
0.1832
0.0617
À0.0605
0.0004
0.2031
0.0615
0.0148
0.0590
À0.0170
À0.4120
—
8f
8g
8h
8i
8j
8k
9aa
9ba
9ca
Procymidone
a
Compounds in the test set.
pEC50 = Àlog (EC50).
b
Donor and Acceptor CoMSIA contour maps (Fig. 4F) showed that
magenta contour around 2-position of furandione nucleus sug-
gested that hydrogen bond acceptor was favored at this area. While
cyan contours around NH of hydrazine and 2-position of phenyl
ring indicated that hydrogen bond donor was favored. Among
them, ortho-substitution of phenyl ring was worthy for further dis-
cussion. The relation between ortho-substitution and bioactivity
depended on many factors. In this model, hydrogen bond was
not the key factor (donor field contribution was 0.024). So the
introduction of halogen atom at 2-position of phenyl ring could
improve the activity not largely, such as the compounds 7b, 7d,
8b and 8d, but slightly. This could be used to explain that com-
pounds 7h and 8h had little better activity than compounds 7f
and 8f, respectively.
The analysis of contour maps for CoMFA and CoMSIA models
indicated that the introduction of bulky group with negative
charge at 4-position of phenyl ring could largely improve the fun-
gicidal activity. And bulky groups at 2- and 3-position of phenyl
ring played an unfavorable role in bioactivity. The substitution at
5-position of furandione nucleus with methyl was favored in the
current data set. Moreover, carbonyl group at 2-position of furan-
dione nucleus could generate an area with negative charge that

3776
Y. Hu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 3772–3776
Acknowledgments
The authors gratefully acknowledge the financial support of the
National Key Technologies R&D Program of China (No. 2011
BAE06B04).
Supplementary data
Supplementary data (The crystallographic data for the structure
analysis of the compound 8a has been deposited with the Cam-
bridge Crystallographic Data Center, CCDC No. 981945. Copies of
this information can be obtained free of charge from the Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44 1223
336 033; or E-mail: deposit@ccdc.cam.ac.uk or URL: http://
www.ccdc.cam.ac.uk).) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
06.074.
References and notes
Figure 5. Plot of actual and predicted activities for training set and test set based on
CoMFA model.
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elemental analysis and single-crystal X-ray diffraction analysis.
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