Synthesis, antifungal activities and 3D-QSAR study of N-(5-substituted-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamides

Article abstract of DOI:10.1016/j.ejmech.2009.01.012

A series of cyclopropanecarboxamide were prepared and tested for antifungal activity in vivo. The preliminary bioassays indicated that some compounds are comparable to the commercial fungicides. To further explore the comprehensive structure-activity relationship on the basis of fungicidal activity data, comparative molecular field analysis (CoMFA) was performed, and a statistically reliable model with good predictive power (r² = 0.8, q² = 0.516) was achieved. Based on the CoMFA, compound 7p was designed and synthesized, which was found to display a good antifungal activity (79.38%) as 7g and 7h.

Full text of DOI:10.1016/j.ejmech.2009.01.012

European Journal of Medicinal Chemistry 44 (2009) 2782–2786
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, antifungal activities and 3D-QSAR study of N-(5-substituted-1,3,
4-thiadiazol-2-yl)cyclopropanecarboxamides
,
,
,
Xing-Hai Liu a 1, Yan-Xia Shi b 1, Yi Ma a 1, Chuan-Yu Zhang a, Wei-Li Dong a, Li Pan a, Bao-Lei Wang a,
Bao-Ju Li b , Zheng-Ming Li
,
a,
*
*
a State-Key Laboratory of Elemento-Organic Chemistry, National Pesticidal Engineering Centre (Tianjin), Tianjin Key Laboratory of Pesticide Science, Nankai University,
Weijin Road 94, Tianjin, China
b Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, 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 cyclopropanecarboxamide were prepared and tested for antifungal activity in vivo. The
preliminary bioassays indicated that some compounds are comparable to the commercial fungicides. To
further explore the comprehensive structure–activity relationship on the basis of fungicidal activity data,
comparative molecular field analysis (CoMFA) was performed, and a statistically reliable model with
good predictive power (r2 ¼ 0.8, q2 ¼ 0.516) was achieved. Based on the CoMFA, compound 7p was
designed and synthesized, which was found to display a good antifungal activity (79.38%) as 7g and 7h.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Received 31 August 2008
Received in revised form
22 December 2008
Accepted 8 January 2009
Available online 22 January 2009
Keywords:
Cyclopropanecarboxamide
1,3,4-Thiadiazole
Antifungal activity
3D-QSAR
Synthesis
1. Introduction
a series of cyclopropanecarboxamide compounds were prepared,
and their fungicidal activities were tested. The preliminary bio-
Cyclopropane derivatives, often as bioactive compounds, have
been studied for years. At the end of 1960s, some cyclopropane
compounds, such as pyrethroids [1], were marketed as low toxic
pesticides. Also some pharmaceuticals contain cyclopropane group,
such as ciprofloxacin monohydrochloride [2]. So synthesis of
broader spectrum and highly bioactive substituted cyclopropane
compounds, especially heterocycle substituted ones which are
bioactive themselves, becomes the hot spot in the agricultural and
medicinal chemistry field. Additionally, sulfur and nitrogen linked
heterocyclic compounds received considerable attention in recent
times because of their pharmacological and pesticidal importance
[3–6]. 2-Amino-5-substituted-1,3,4-thiadiazoles are very useful
starting materials for the synthesis of various bioactive molecules
and applied in medicine and agriculture [7–10] (Fig. 1).
logical tests showed that some compounds exhibit good activity to
Sclerotinia sclerotiorum (Lib.) de Bary, Corynespora cassiicola,
Botrytis cinerea, Fusarium oxysporum f. sp. cucumerinum, Cercospora
arachidicola, and Rhizoctonia solanii. The structure–activity rela-
tionship was also studied.
2. Results and discussion
2.1. Chemistry
The cyclopropane-1,1-dicarboxylic acid, prepared from 1,2-
dichlorethane and diethyl malonate was cyclized for 16 h at
refluxing temperature. In order to optimize the reaction time,
microwave assistant irradiation was applied which shortened the
reaction time to 40 min. The cyclopropane-1,1-dicarboxylic acid
was obtained from the hydrolysis of diethyl cyclopropane-1,1-
dicarboxylate, but the yield of this step is low, about 50%. Cyclo-
propanecarbonyl chloride was prepared from the cyclopropane
dicarboxylic acid and SOCl2, without isolation further reacted with
5-substituted-2-amino-1,3,4-thiadizoles at room temperature [12]
as shown in Scheme 1. Several procedures are available for the
one-step synthesis of 2-amino-5-substituted-1,3,4-thiadiazoles
In our previous paper, we reported the synthesis of some
cyclopropane derivatives which target herbicidal target KARI
(ketol-acid reductoisomerase) [11–13]. As continued our work,
* Corresponding authors.
E-mail addresses: libj@mail.caas.net.cn (B.-J. Li), nkzml@finechembio.cn
(Z.-M. Li).
1
These authors contributed equally to this work.
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.01.012

X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 2782–2786
2783
O
O
(PLS) approach was used to derive the 3D-QSAR, in which the
CoMFA descriptors were used as independent variables, and ED
values were used as dependent variables. The data were analyzed
by CoMFA method and fungicidal activity against B. cinerea data
(C4H9)4NHSO4
K2CO3
COOC2H5
COOC2H5
Cl
Cl
O
O
1
(% I) at 500
m
g mLꢀ1 being converted to ED ¼ log(I/((100 ꢀ I) ꢁ MW))
160
NaOH
COOH
COOH
HCl/H2O
COONa
COONa
[15] as a dependent variable. The observed and calculated activity
values for all the compounds are shown in Table 2, and the plots
of the predicted versus the actual activity values for all the
compounds are shown in Fig. 5.
3
2
SOCl2
COOH
COCl
The cross-validation with the leave-one-out (LOO) option and
the SAMPLS program, rather than column filtering, was carried out
to obtain the optimal number of components to be used in the final
analysis. After the optimal number of components was determined,
a non-cross-validated analysis was performed without column
filtering. The modeling capability (goodness of fit) was judged by
the correlation coefficient squared, r2, and the prediction capability
(goodness of prediction) was indicated by the cross-validated r2
O
Et3N, THF
R
S
N
4
5
HN
N
N
N
NH2NHCSNH2
7a-7q
R COOH
R
NH2
S
POCl3,Ref or MW
6
R=H, CH3, C2H5, n-Pr, iso-Pr, n-Bu, Ph, o-CH3Ph, m-CH3Ph, p-ClPh,
o-ClPh, o-FPh, p-NO2Ph, Py, furan, p-OCH3Ph, cyclopropane
(q2). The 3D-QSAR models gave
a
good q2 (cross-validated
r2) ¼ 0.516 and r2 (non-cross-validated r2) ¼ 0.800, two compo-
nents. The compound 7i was illustrated to explain the field
contributions of different properties obtained from the CoMFA
analyses. The steric and electrostatic contribution contour maps of
CoMFA are plotted in Fig. 4. As shown in Fig. 4a, green displays 2-
positions or 3-position of benzene ring where a bulky group would
be favorable for higher antifungal activity.2 In contrast, yellow
indicates 5-position of benzene ring where a decrease in the bulk of
the target molecules is favored. For example, some compounds
bearing 2-methyl, 3-methyl of benzene ring, such as 7h, and 7i,
displayed higher antifungal activity against B. cinerea. As shown in
Fig. 4b, the title compounds bearing an electron-donating group at
the 2-position, 3-position or 4-position of benzene ring can
improve the antifungal activity, such as 7h and 7i.
Scheme 1. The synthesis route of title compounds.
derivative. Yet the reaction of substituted aryl and alkyl acid with
thiosemicarbazide in the presence of dehydrating agent POCl3
affords a series of 2-amino-5-substituted-1,3,4-thiadiazoles under
microwave irradiation.
2.2. Fungicidal activities
The in vivo fungicidal results of all of the compounds against S.
sclerotiorum (Lib.) de Bary, R. solanii, F. oxysporum, C. cassiicola, and
B. cinerea were listed in Table 1. As shown in Table 1, Compounds 7b
and 7l were found to display good fungicidal activities against R.
solanii, F. oxysporum, C. cassiicola, and B. cinerea, compounds 7a,
7c–f, 7m–o did not display obvious fungicidal activities against
S. sclerotiorum (Lib.) de Bary, R. solanii, F. oxysporum, C. cassiicola,
and B. cinerea. Compound 7k have fair to good fungicidal activity
with the commercial fungicide pyrimethanil against F. oxysporum.
Among them, these compounds displayed the highest fungicidal
activity against B. cinerea. All compounds did not exhibit good
fungicidal activity against S. sclerotiorum (Lib.) de Bary at the
According to the above CoMFA analysis, compound 7p
(R ¼ p-OMe Ph) was designed, synthesized and tested its anti-
fungal activity against B. cinerea. The results indicated that the
inhibition of compound 7p is 79.38%, whose inhibition is as good
as 7g and 7h.
3. Conclusion
Using easily obtainable compounds 5, we have prepared a new
series of cyclopropanecarboxamide analogues 7 containing 1,3,4-
thiadiazoles in good yields. Some of these compounds 7g, 7h, 7i, 7p
exhibited excellent activity as displayed in Table 1. According to the
CoMFA model, when R is substituted benzene groups, substituents
at 2-position, 3-position or 4-position of the benzene ring are
favored with electron-donating and bulky groups. Meanwhile,
electron-withdrawing group is disfavored on these positions, such
as NO2 group.
concentration of 500 m .
g mLꢀ1
2.3. Quantitative structure–activity relationship (3D-QSAR)
Molecular modeling was performed using SYBYL 6.91 software
(Tripos, Inc.) [14]. Each structure was fully geometry-optimized
using a conjugate gradient procedure based on the TRIPOS force
field and Gasteiger and Hu¨ckel charges. Because these compounds
share a common skeleton, 10 atoms marked with an asterisk were
used for rms-fitting onto the corresponding atoms of the template
structure (Figs. 2 and 3).
4. Experimental section
CoMFA steric and electrostatic interaction fields were calculated
at each lattice intersection on a regularly spaced grid of 2.0 Å. The
grid pattern was generated automatically by the SYBYL/CoMFA
routine, and an sp3 carbon atom with a van der Waals radius of
1.52 Å and a þ1.0 charge was used as the probe to calculate the
steric (Lennard-Jones 6–12 potential) field energies and electro-
static (Coulombic potential) fields with a distance-dependent
dielectric at each lattice point. Values of the steric and electrostatic
fields were truncated at 30.0 kcal/mol. The CoMFA steric and
electrostatic fields generated were scaled by the CoMFA-STD
method in SYBYL. The electrostatic fields were ignored at the lattice
points with maximal steric interactions. A partial least-squares
4.1. Materials and methods
All reagents are analytical grade. Melting points were deter-
mined using a X-4 apparatus and were uncorrected. 1H NMR
spectra were measured on a Bruker AC-P500 instrument (300 MHz)
using TMS as an internal standard and DMSO-d6 as solvent. HRMS
data was obtained on a FTICR-MS instrument (Ionspec 7.0T).
2
For interpretation of the references to color in this text, the reader is referred to
the web version of this article.

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X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 2782–2786
Fig. 1. The pesticides containing 1,3,4-thiadizole ring.
7c: white crystal, yield 81.2%, m.p. 197–198 ꢂC; 1H NMR (CDCl3)
: 1.04–1.19 (m, 4H, cyclopropane–CH2), 1.38 (t, 3H, CH3), 2.21–2.26
Table 1
The antifungal activities of compounds 7a–7q in vivo at 500
m
g mLꢀ1
.
d
(m, 1H, cyclopropane–CH), 3.02 (q, 2H, CH2), 13.14 (s, 1H, NH);
FTICR-MS for C8H11N3OS: found 196.0556, calcd. 196.0550.
No.
Sclerotinia
sclerotiorum solanii
(Lib.) de
Rhizoctonia Fusarium
Corynespora Botrytis
oxysporum cassiicola
cinerea
7d: white crystal, yield 84.5%, m.p.175–176 ꢂC; 1H NMR (CDCl3)
d:
Bary
1.02 (t, 3H, CH3), 1.05–1.21 (m, 4H, cyclopropane–CH2), 1.81 (m, 2H,
CH2), 2.25–2.31 (m,1H, cyclopropane–CH), 2.98 (t, 2H, CH2),13.43 (s,
1H, NH); FTICR-MS for C9H13N3OS: found 210.0704, calcd. 210.0707.
7e: white crystal, yield 84.5%, m.p. 127–128 ꢂC; 1H NMR (CDCl3)
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
24.00
23.00
51.70
40.00
47.70
10.30
24.00
37.50
20.00
23.90
25.50
23.00
43.06
14.00
5.00
37.00
5.00
17.00
84.00
10.00
1.00
20.00
2.00
16.00
21.00
11.00
28.00
91.00
84.00
13.00
14.00
0
22.52
52.43
49.66
46.63
29.30
21.92
17.43
50.79
8.38
19.69
21.45
68.27
18.56
34.06
15.73
33.26
13.28
83.73
67.54
32.09
57.87
41.98
26.02
80.53
75.09
90.67
13.49
35.11
67.54
30.27
29.66
38.76
79.38
66.59
23.00
35.00
11.00
44.00
9.00
36.00
39.00
62.00
44.00
5.00
d: 0.92–0.96 (t, 3H, CH3), 1.04–1.19 (m, 4H, cyclopropane–CH2), 1.43
(m, 2H, CH2), 1.56 (m, 2H, CH2), 1.75 (m, 2H, CH2), 2.19–2.22 (m, 1H,
cyclopropane–CH), 13.00 (s, 1H, NH); FTICR-MS for C10H15N3OS:
found 210.0702, calcd. 210.0707.
7f: white crystal, yield 90.1%, m.p. 183–184 ꢂC; 1H NMR (CDCl3)
d: 1.03–1.29 (m, 4H, cyclopropane–CH2), 1.40 (d, 6H, CH3), 2.26–
2.28 (m, 1H, cyclopropane–CH), 3.33–3.40 (m, 1H, CH), 7.26–7.71
(m, 4H, Ar-H), 13.27 (s, 1H, NH); FTICR-MS for C9H13N3OS: found
224.0865, calcd. 224.0863.
16.00
8.00
0
7g: white crystal, yield 86.5%, m.p. 249–251 ꢂC; 1H NMR (CDCl3)
33.0
26.70
96.70
ꢀ9.00
12.00
37.00
7q
21.00
d: 1.11–1.26 (m, 4H, cyclopropane–CH2), 2.35 (m, 1H, cyclopropane–
dimehachlon
Jinggangmycin
Thiophanate
methyl
Chlorothalonil
Pyrimethanil
CH), 7.47–7.92 (m, 5H, Ar-H), 13.33 (bs, 1H, NH); FTICR-MS for
C12H11N3OS: found 244.0550, calcd. 244.0550.
92.10
97.00
7h: white crystal, yield 82.6%, m.p. 216–218 ꢂC; 1H NMR (CDCl3)
86.43
d: 1.04–1.25 (m, 4H, cyclopropane–CH2), 2.39–2.45 (m, 1H, cyclo-
99.17
propane–CH), 2.56 (s, 3H, CH3), 7.29–7.65 (m, 4H, Ar-H), 13.07
(bs, 1H, NH); FTICR-MS for C13H13N3OS: found 260.0841, calcd.
260.0852.
7i: white crystal, yield 80.6%, m.p. 262–265 ꢂC; 1H NMR (CDCl3)
4.2. Synthesis
d: 1.11–1.26 (m, 4H, cyclopropane–CH2), 2.31–2.36 (m, 1H, cyclo-
4.2.1. General procedure
propane–CH), 2.43 (d, 3H, CH3), 7.26–7.71 (m, 4H, Ar-H),13.19 (s,1H,
NH); FTICR-MS for C13H13N3OS: found 260.0841, calcd. 260.0852.
4.2.1.1. Preparation of 7a. The acid chloride was prepared according
the reference [12]. Dropwised the acid chloride to substituted 2-
amino-5-substituted-1,3,4-thiadiazoles (7.50 mmol), then vigor-
ously stirred at ambient temperature for 4 h. The corresponding
amide 7 precipitated immediately. The product was filtered,
washed with THF, dried, and recrystallized from EtOH–H2O to give
the title compounds 7.
7j: white crystal, yield 84.6%, m.p. > 300 ꢂC; 1H NMR (DMSO)
d:
0.93–1.02 (m, 4H, cyclopropane–CH2), 1.98–2.05 (m, 1H, cyclopro-
pane–CH), 7.60 (d, J ¼ 8.55 Hz, 2H, Ar-H), 7.95 (d, J ¼ 8.54 Hz, 2H, Ar-
H), 12.99 (bs, 1H, NH); FTICR-MS for C12H10ClN3OS: found 280.0296,
calcd. 280.0306.
7a: white crystal, yield 84.6%, m.p. 254–255 ꢂC; 1H NMR (CDCl3)
d: 1.08–1.25 (m, 4H, cyclopropane–CH2), 1.59 (s, 1H, Het-H), 2.29–
2.35 (m, 1H, cyclopropane–CH), 8.78 (s, 1H, NH); FTICR-MS for
C6H7N3OS: found 168.0229, calcd. 168.0237.
7b: white crystal, yield 85.1%, m.p. > 300 ꢂC; 1H NMR (CDCl3)
d:
1.05–1.19 (m, 4H, cyclopropane–CH2), 1.55 (t, 3H, CH3), 2.16–2.26
(m, 1H, cyclopropane–CH), 12.85 (s, 1H, NH); FTICR-MS for
C7H9N3OS: found 182.0395, calcd. 182.0394.
O
*
*
S
*
R
*
*
*
*
HN
*
N
*
N
*
Fig. 2. The asterisk skeleton of title compounds.
Fig. 3. Superposition modes of compounds.

X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 2782–2786
2785
Table 2
The structures, activities and total score of compounds.
No.
R1
ED
ED00
Residue
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
H
Me
Et
Pr
ꢀ1.51
ꢀ1.94
ꢀ2.62
ꢀ2.19
ꢀ2.46
ꢀ2.8
ꢀ1.89
ꢀ1.92
ꢀ2.23
ꢀ2.27
ꢀ2.4
0.38
ꢀ0.02
ꢀ0.39
0.08
ꢀ0.06
ꢀ0.45
0.69
Iso-Pr
Bu
Ph
o-Me Ph
m-Me Ph
p-Cl Ph
o-Cl Ph
o-F Ph
p-NO2 Ph
Py
ꢀ2.35
ꢀ2.46
ꢀ1.9
ꢀ1.77
ꢀ1.93
ꢀ1.42
ꢀ2.71
ꢀ2.1
ꢀ0.03
ꢀ1.54
ꢀ2.75
ꢀ2.13
ꢀ2.46
ꢀ2.67
ꢀ2.48
ꢀ2.57
0.12
0.04
0.03
ꢀ0.36
ꢀ0.16
ꢀ0.29
0
ꢀ2.82
ꢀ2.83
ꢀ2.77
ꢀ2.57
Furan
ED ¼ experimental value, ED00 ¼ predictive value of ED.
7k: white crystal, yield 88.4%, m.p. 253–255 ꢂC; 1H NMR (DMSO)
d: 0.93–1.02 (m, 4H, cyclopropane–CH2), 1.98–2.05 (m, 1H, cyclo-
propane–CH), 7.68 (d, J ¼ 7.29 Hz, 2H, Ar-H), 8.08 (d, J ¼ 7.73 Hz, 2H,
Ar-H), 12.99 (bs, 1H, NH); FTICR-MS for C12H10ClN3OS: found
280.0296, calcd. 280.0306.
Fig. 5. CoMFA predicted as experimental pED values.
7l: white crystal, yield 83.6%, m.p. > 300 ꢂC; 1H NMR (DMSO)
d:
12.88 (bs, 1H, NH); FTICR-MS for C13H13N3O2S: found 276.0781,
calcd. 276.0801.
0.73–1.16 (m, 4H, cyclopropane–CH2), 1.94–2.03 (m, 1H, cyclopro-
pane–CH), 7.39–7.69 (m, 3H, Ar-H), 8.25 (m, 1H, Ar-H),13.00 (bs,1H,
NH); FTICR-MS for C12H10FN3OS: found 264.0597, calcd. 264.0601.
7m: white crystal, yield 85.4%, m.p. > 300 ꢂC; 1H NMR (DMSO)
7q: white crystal, yield 84.4%, m.p. 194–196 ꢂC; 1H NMR (CDCl3)
d
: 1.02–1.18 (m, 8H, cyclopropane–CH2), 2.17–2.02 (m, 1H, cyclo-
propane–CH), 2.29–2.32 (m, 1H, cyclopropane–CH), 12.97 (s, 1H,
NH); FTICR-MS for C9H11N3OS: found 210.0690, calcd. 210.0696.
d: 0.94–0.99 (m, 4H, cyclopropane–CH2), 1.98–2.02 (m, 1H, cyclo-
propane–CH), 8.18 (d, J ¼ 8.83 Hz, 2H, Ar-H), 8.32 (d, J ¼ 8.81 Hz, 2H,
Ar-H), 13.11 (bs, 1H, NH); FTICR-MS for C12H10N4O3S: found
289.0392, calcd. 289.0401.
4.3. Antifungal activity
7n: white crystal, yield 89.7%, m.p. 238–239 ꢂC; 1H NMR
Fungicidal activities of compounds of series 7 against S. scle-
rotiorum (Lib.) de Bary, R. solanii, F. oxysporum, C. cassiicola, and B.
cinerea were evaluated using pot culture test according to reference
[16]. The culture plates were cultivated at (24 ꢃ1) ꢂC. Fungicidal
activities of commercial fungicides dimehachlon, jinggangmycin,
Thiophanate methyl, chlorothalonil, pyrimethanil as a control
against above mentioned five fungi were evaluated at the same
condition. The relative inhibition rate of the circle mycelium
compared to blank assay was calculated via the following equation:
(DMSO) d: 0.92–0.98 (m, 4H, cyclopropane–CH2), 1.98–2.01 (m, 1H,
cyclopropane–CH), 7.54 (m, 1H, Py-H), 8.29 (m, 1H, Py-H), 8.66 (m,
1H, Py-H), 9.01 (m, 1H, Py-H), 13.03 (bs, 1H, NH); FTICR-MS for
C11H10N4OS: found 247.0637, calcd. 247.0648.
7o: white crystal, yield 86.5%, m.p. 272–273 ꢂC; 1H NMR (CDCl3)
d: 1.01–1.25 (m, 4H, cyclopropane–CH2), 2.24–2.26 (m, 1H, cyclo-
propane–CH), 6.56 (d, J ¼ 1.68 Hz, 1H, furan-H), 7.03 (d, J ¼ 3.43 Hz,
1H, furan-H), 7.58 (s, 1H, furan-H), 13.00 (s, 1H, NH); FTICR-MS for
C10H9N3O2S: found 236.0483, calcd. 236.0488.
7p: white crystal, yield 84.5%, m.p. 264–267 ꢂC; 1H NMR (DMSO)
dex ꢀ d0ex
d: 0.95–0.99 (m, 4H, cyclopropane–CH2), 1.98–2.02 (m, 1H, cyclo-
Relative inhibition rate ð%Þ ¼
ꢁ 100%
dex
propane–CH), 3.84 (s, 3H, CH3), 7.15 (d, 2H, Ar-H), 7.90 (d, 2H, Ar-H),
Fig. 4. Steric and electrostatic contribution contour maps of CoMFA.

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X.-H. Liu et al. / European Journal of Medicinal Chemistry 44 (2009) 2782–2786
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This work was funded by National Key Basic Research Program
of China (No. 2003 CB114406), National Natural Science Foundation
Key Project of China (No. 20432010), High Performance Computing
Project of Tianjin Ministry of Science and Technology of China (No.
043185111-5), Natural Science Foundation Project of Tianjin
Ministry of Science and Technology of China (No. 07JCYBJC00200 &
08JCYBJC00800), Specialized Research Fund for the Doctoral
Program of Higher Education (No. 20070055044).
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