Synthesis and biological activity of some 2-(2'-(substituted phenyl-4-thiazolidinone-3-yl)-1'3'-isoxazol-4-yl)aminoquinoline derivatives

Article abstract of DOI:10.1155/2011/962350

Quinoline a heterocyclic nucleus, played a pivotal role in the development of different medicinal agents and in the field of agrochemicals. Several 2-(2'-substituted phenyl-4-thiazolidinon-3-yl)-1'3'-isoxazol-4-yl) amino-quinoline IV(a-k) have been prepar

Full text of DOI:10.1155/2011/962350

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2011, 8(2), 931-937
http://www.e-journals.net
Synthesis and Biological Activity of Some
2-(2’-(Substituted Phenyl-4-thiazolidinone-3-yl)-
1’3’-isoxazol-4-yl)aminoquinoline Derivatives
MUKESH KUMAR AHIRWAR and S.P. SHRIVASTAVA*
Department of Chemistry
Dr. H.S. Gour University Sagar (M.P.)- 470003, India
mukesh_phd@yahoo.co.in
Received 10 April 2010; Accepted 5 June 2010
Abstract: Quinoline a heterocyclic nucleus, played a pivotal role in the
development of different medicinal agents and in the field of agrochemicals.
Several
2-(2’-substituted
phenyl-4-thiazolidinon-3-yl)-1’3’-isoxazol-4-yl)
amino-quinoline IV(a-k) have been prepared 2-(substituted arylideneimino-
1’3’-isoxazol-4’-yl) aminoquinoline III(a-k) and tested for their antimicrobial
and antifungal activity against different microorganism. The structure of
compound III(a-k) and IV(a-k) have confirmed on the basis of their elemental
and spectral analysis such as IR, 1H NMR and Mass spectrometry.
Keywords: Quinoline, Isoxazoles, Thiazolidinones, Antibacterial, Antifungal, Insecticidal activity
Introduction
The chemistry of quinoline has gained increasing attention due to its various diverse
pharmacological activities1-3. Numerous quinoline, derivatives have been prepared and their
pharmacological properties were evaluated. Many of these compounds have proved to be active
anticancer4-5, anti-inflammatory6 antiallergic7 and antimicrobials8-11 antimaralial12 agent. Further,
the utility of quinoline derivatives in the preparation of some dyes and pigment have been
reported13. On the other hand isoxazole derivatives controlled Botrytis cinera on cucumbers have
been found to have antiviral properties against herpes type II virus14. Penicilline derivatives
containing isoxazole ring are found to be antibacterial activities. Isoxazole derivatives15 are used
as corrosion inhibitors for fuels and lubricants16. Moreover thiazolidinones have a broad spectrum
of pharmacological properties i.e. antibacterial17, antifungal18 andantiinflammatory19.
Experimental
The melting points were determined in open capillaries with an electrothermal melting point
apparatus and are uncorrected. IR spectra were recorded on a simadz FT-IR-8400
1
spectrometer and H NMR spectra on Bruker spectrometer (300 MZ) using TMS as an
internal standard. All chemical shift values were recorded as δ (ppm).

932
S. P. SHRIVASTAVA et al.
Synthesis of 2-(chloroacetyl)aminoquinoline (I)
Chloroacetyl chloride (0.02 mole) was added to a solution of 2-aminoquinoline (0.02 mole)
0
in dry benzene (80 mL) at 0-5 C. The reaction mixture was stirred for 4 h at 45 0C. Excess
of benzene was distilled off. The solid thus obtained was washed with petroleum ether and
kept in refrigerator overnight and solid obtained was purified by recrystallization from
benzene to yield compound I, m.p.189 0C, yield 96%.
Synthesis of 2-(2’-amino1’3’-isoxazol-4’-yl)aminoquinoline (II)
A mixture of 2-(chloroacetyl)aminoquinoline (I) (0.02 mole) and urea (0.01 mole) in
0
acetone (90 mL) was refluxed for 12 h at 65-70 C. The excess of solvent was distilled off
and the solid obtained was poured into ice cold water, recrystallized from methanol. Now
the solid was washed with 2% sodium carbonate and then with water to liberate the base
completely, dried and purified by recrystallization from ethanol. M.p. 205 0C, yield 86%.
Synthesis of 2-(substitutedarylideneimino-1’3’-isoxazol-4’-yl)aminoquinoline(IIIa-k)
To a solution of compound II (0.02 mole) in ethanol (60 mL), substituted aromatic
aldehydes (a-k), (0.02 mole) and a few drops glacial acetic acid were added and the mixture
refluxed for 10 h. It was then cooled, concentrated and poured into crushed ice and filtered.
The product thus obtained was purified by recryatallization from methanol to get compound
III(a-k). The related physical data are given in Table 1.
Table 1. Physical characterization data of synthesized compounds III(a-k)
Elements, %
Mol.
Formula
Yield
%
Compd
M.W.
M.P.
C
Calcd. Found Calcd. Found Calcd. Found
H
N
C19H14N4O2 330.32 69
C19H14N4O2 330.32 65
C19H13N4OCl 348.78 67
C19H13N4OCl 348.78 68
C19H13N4OCl 348.78 72
C20H17N4O2 345.36 59
C19H13N5O3 359.31 68
C19H13N5O3 359.21 65
C19H14N4O2 330.32 71
C20H14N4O3 360.34 73
C21H19N5O 376.86 59
205 69.08 69.05 4.27 4.21 16.96 16.93
210 69.08 69.06 4.27 4.21 16.96 16.93
126 65.43 65.39 3.75 3.71 16.06 16.01
121 65.43 65.39 3.75 3.71 16.06 16.01
136 65.43 65.39 3.75 3.71 16.06 16.01
143 69.55 69.51 4.96 4.91 16.22 16.17
235 63.51 63.48 3.64 3.59 19.49 19.45
205 63.51 63.48 3.64 3.59 19.49 19.45
254 69.08 69.05 4.27 4.21 16.96 16.93
247 66.66 66.63 4.47 4.42 15.54 15.47
245 66.92 66.87 5.08 5.02 18.58 18.53
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIJ
IIIk
2-(2’-Substitutedphenyl-4-thiazolidinon-3-yl)-1’3’-isoxazol-4-yl) amino-quinoline IV(a-k)
A solution of compound III (0.02 mole), thioglycolic acid (0.02 mole) and anhydrous zinc
chloride (2 g) in absolute ethanol (60 mL) was refluxed for 8 h, concentrated, cooled and
poured into crushed ice and then filtered. The product obtained (Scheme 1) was recrystallized
from acetone to get compound IV(a-k). The related physical data are given in Table 2.
Spectral Interpretation
Compound II
IR: 3442 cm-1(N-H str.); 3090 cm-1(H-quinoline str.); 2340 cm-1(C-H str. isoxazole); 1680 cm-1
(C=N str. isoxazole), 1560 cm-1(C=N str. quinoline), 928 cm-1(quinoline ring-breathing);
896 cm-1(isoxazole ring breathing).

Synthesis and Biological Activity Study
933
Compound IIa
1H NMR: (CDCl3 in δ ppm): 8.6 δ (s) NH2; 5.7 δ(s) NH; 4.2 δ (s) (2CH of isoxazole);
6.2δ(Unsy.m.) quinoline ring quinoline.
Table 2. Physical characterization data synthesized compound IV(a k)
Elements, %
Yield
Compd. Mol. Formula. M.W.
M.P.
C
H
N
%
Calc. Found Calc. Found Calc. Found
C27H20N4O3S 480.51 67 107 67.48 67.42 4.19 4.15 11.65 11.61
C27H20N4O3S 480.51 71 98 67.48 67.43 4.19 4.19 11.65 11.61
IVa
IVb
IVc C27H19N4O2SCl 498.97 68 118 64.99 64.95 3.80 3.75 11.22 11.18
IVd C27H19N4O2SCl 498.97 72 121 64.99 64.95 3.80 3.75 11.22 11.18
IVe C27H19N4O2SCl 498.97 73 134 64.99 64.95 3.80 3.75 11.22 11.18
IVf
IVg
IVh
IVi
IVJ
IVk
C28H22N4O3S 494.54 59 148 68.00 67.08 4.48 4.43 11.32 11.28
C27H19N5O4S 509.50 68 247 63.64 63.58 3.70 3.67 13.74 13.69
C27H19N5O4S 509.50 59 238 63.64 63.58 3.70 3.67 13.74 13.69
C27H20N4O3S 480.51 63 189 67.48 67.43 4.19 4.15 11.65 11.61
C28H21N4O4S 509.52 65 122 66.00 65.08 4.15 4.11 10.99 10.96
C29H25N5O2S 507.59 76 233 68.62 68.58 4.96 4.92 13.97 13.95
Reaction Sequence:
NH2
N
ClCOCH2Cl
NHCOCH
2Cl
N
(I)
NH2CONH2
N
NH
N
(II)
NH2
O
R
N
OHC
R
N
H
N
CH
N
III(a-k)
O
SHCH2COOH
Anhyd.
ZnCl2
R
N
NH
N
N
O
IV(a-K)
S
O
Scheme 1
R = substitituted group, R = a = 2= OH, A = 4- OH, c = 4- Cl, d = 3-Cl, e = 2-Cl, t = 4-OMe, g = 3-
OH2, h = 2- NO2 , i = 4- OH, , j = 4-OH, 2-OMe, k = 4-N(CH3)2

934
S. P. SHRIVASTAVA et al.
Compound IIIa
IR: 3525 cm-1 (O-H str.); 3426 cm-1(N-H str.); 3096 cm-1(C-H str. quinoline); 2460 cm-1(N=C-
Hstr.); 2343 cm-1(C-Hstr. Isoxazole); 1820 cm-1(N=CHstr.); 1683 (C=Nstr.isoxazole); 1580
cm-1(C=N str.quinoline); 986 cm-1(quinoline ring breathing);926 cm-1(isoxazole ring
breathing).1H NMR: (CDCl3 in δ ppm): 8.8 δ (s)OH; 5.8δ(s)-NH-; 3.2δ (s)-N=CH-; 4.1δ
(2CH isoxazole); 6.1δ (Unsym.m) quinoline ring; 6.9δ (Unsym.m) orthodisubstitutedphenyl.
Compound IVa
IR: 3528 cm-1 (O-H str.); 3427 cm-1(N-H str.); 3096 cm-1 (CH str. quinoline), 3100 cm-1(Ar-H str.)
2346 cm-1-(C-H str. isoxazole),1838 cm-1(C=O str.);1690 cm-1(C=N str. isoxazole); 1560 cm-1 (C=N
str. quinoline); 2985 cm-1(C-H str. thiazoline ring)1120 cm-1 (thiazolone ring breathing); 980
-1
cm-1 (quinoline ring breathing);938 cm (isoxazole ring breathing). 1H NMR: (CDCl3 in δ ppm) 8.6
δ (s) OH; 5.5δ (s) NH; 4.2δ (s) 2H of thiazolone ring; 3.8δ (s) 1H of thiazolone ring; 4.8δ (s) 2H of
isoxazole; 6.0δ (Unsym.m.) quinoline ring 6.2δ (Unsym.m.) ortho-disubstituted phenyl ring.
Results and Discussion
The reaction of chloroacetyl chloride and 2-amino quinoline in dry benzene gave 2-(chloroacetyl)
amino quinoline I. The structure of I was confirmed from its spectral data and analytical studies.
The compound II was obtained by reaction of I with urea in acetone and well characterized using its
spectral and analytical data. Its IR spectrum revealed the presence of NH2 group by exhibiting a
strong absorption at 3442 cm-1 and the formation of isoxazole ring was confirmed by the absence of
C=O str at 1826 cm-1.The NMR spectrum of II in CDCl3 show one singlet at 8.6 δ due to NH2
protons and one singlet at 5.7 δ due to NH proton. The two complex multipletes at 6.2 δ & 4.2 δ
was assigned for five aromatic protons. The C, H, N, analysis of the compound II was in good
agreement with the proposed molecular formula C12H9N3O .The reaction of II with substituted
aromatic aldehyde and few drops of glacial acetic acid gave III(a-k) and was well characterized
using its spectral and analytical data. Its IR spectra revealed the presence of C=N group by
exhibiting a strong absorption at 1683 cm-1 the NMR spectrum of III(a-k) in CDCl3 show two
complex multiplets at δ 6.9 & 6.1 was assigned for seven aromatic protons. Further the reaction of
III(a-k) with thioglycolic acid in the presence of acetic acid was carried out with an interest that the
reaction would proceed as shown in Scheme 1 and at the end, this attempt yield IV(a-k). The IR
spectrum of IV(a-k) shown strong absorption at 1838 cm-1 due to >C=O group. The NMR
spectrum exhibited two singlets at 3.8 & 4.2 for C2-H2 and C5-H protons of thiazolidinone ring.
Three unsymmetrical multiplets appear in 7.3 δ, 6.0 δ, 6.2 δ with eleven aromatic protons. This was
also supported by the mass spectrum of the compound which displayed the molecular ion peak at
480.51. The elemental analysis was also in good agreement with the molecular formula
C27H20N4O3S. All compounds show good to moderate biological activity.
Antimicrobial activity of synthesized quinoline derivatives
Several workers determined antimicrobial activity in vitro using:
a). Turbimetric method
b). Serial dilution tube technique.
c). Diffusion methods.
In the present study the filter paper disc diffusion plate method was employed to evaluate the
antimicrobial activity in vitro. Filter paper disc diffusion plate method16 was used. The medium was
first inoculated with a loopful of broth culture of the organism and shaken for uniform distribution.
It was poured into Petri dish. Discs soaked in test sample solution were placed over the seeded

Synthesis and Biological Activity Study
935
medium and pressed so that all parts of disc come in contact with the medium. The seeded plates
0
0
were incubated at 28 C for 32 h in case of bacteria and 37 C for 72 h in case of fungi. Same
procedure was adopted for standard drugs. The activity was determined by using 4% and 2%
solution of synthesized isoxazole, thiazolidinone derivatives. 4% and 2% solutions of the standard
drugs, streptomycine and tetracycline (for bacteria) and nastytine, amphotericine-B (For fungi) were
also prepared. Related data have been given in Table 3 - 6.
Insecticidal activity of synthesized quinoline derivatives
Cockroaches were selected for the study. 4% (w/v) solution of synthesized compounds of
isoxazole, thiazolidinone was prepared in acetone. 4% (w/v) of solution of synthesized
compounds was injected into the abdominal region of the cockroach with the help of micro
syringe. The time of death, the antennae becomes motionless, the appendages shrunk and
folded towards the ventral side and cockroach lay dorsally. For each sample, four
replications were performed and average KD value noted. Cypermethrin 25% EC was used
as standard. Its 4% (w/v) solution was prepared in acetone. It belongs to pyrethroid group.
Related graphs are given in Figure 1 & 2.
Table 3. Antibacterial activity of the synthesized III(a-k) against various bacteria at two
different concentrations (ppm)
Comp
E. coli
50 100
++++ +++
B. Subtillis
S. aureus
B. fragilis
50 100
++++ +++
K.pneumonie
50
++
+++
+++
++++
++
100
+++
++
++
++
50
++
+++
++
-
100
50
-
100
+
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
++
++
+++
+
++
+++
++
-
+
++
++
+
++
+
+++
++
++
++
+
++
++
+++
+
++
+++
++
+
-
-
++
++
+++
++
++
+
+++
+++
++
++
++++
++
-
+++ +++
++
+
++
+
+++
++
++
+
++
+
+++
++
+++
-
++
+
++
+++
-
+
++
+
+++
++
+++
++
++
++
+
+++
++
+
++
+
++
+++
++
+++
++
++
+++
IIIj
IIIk
++++ +++
++ ++
+
++
++++ = Strongly active, +++ = Moderately active, ++ = Weakly active, +, - = Inactive,
Table 4. Antifungal activity of the synthesized III(a-k)against various fungi at two different
concentrations (ppm).
Comp
A. flavus A. niger
T. viridae
100 50 100 50
++++ ++
F.oxisporum C.albicans
50
+++
+++
++
+++
+++
++
100
+++
++
+
++
++
+++
++
++
+++
++
+
50
+++ ++++
++
+++
++++ +++
100 50
+
+++
100
++ +++
+++ ++
++++ ++
++ +++
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
++
+++
++
+
++
++
+
+++
++ ++++
+++ +++
+++
++++ +++ +++
++
+++
-
++
+
+++
+++
++
++
+
-
++
+
++
++
-
+
++
+++
++
+
+
+++
++
++
-
+
++
+++
++
+
++
++
++
++
+++
+
++
++ +++
+++
++
+++
++
+
++
-
++
+
++
++
IIIj
IIIk
+++
++
++
+++
++
+++ +++
+
++++ = Strongly active, +++ = Moderately active, ++ = Weakly active, +, - = Inactive

936
S. P. SHRIVASTAVA et al.
Table 5. Antibacterial activity of the synthesized IV(a-k) against various bacteria at two
different concentrations (ppm)
E. coli
50 100
++ +++ ++
++ ++ +++
B. fragilis
50 100
S. aureus
B. subtilis
K.pneumonie
Comp
50
++
++
100
50
+++
++
100
50
++
++
+++
+++
++
-
++
100
++
+++
+++
++
++
+
++
+++
++
++
+
IVa
IVb
IVc
++
++
++
++
++
+++
++
+++ ++ +++ + ++
IVd +++ +++ ++ +++ ++++ +++
+++ +++ +++
++
-
++
+
IVe
IVf
IVg
++ +++
++
++ +++
+
++
++ +++
++
++
++
+++
+
+++
+++
++
+
++
+++
+++
++
+
IVh +++ ++ +++ +++
++ ++++ +++
++
+++
IVi
IVj
IVk
+++ ++
++
++
+
++
++
++
-
+
++
++
+
+++
+++
++
+
++
++
+
++
+
+++ +++
++ ++
++++ = Strongly activee, +++ = Moderately active, ++ = Weakly active, +, - = Inactive
Table 6. Antifungal activity of the synthesized IV(a-k) against various fungi at two different
concentrations (ppm)
A. flavus
A. niger
T. viridae
F.oxisporum
C.albicans
Comp
50
100
+++
++
50
100
+++
++
50
++
+++
++
++
+++
+
100
50
++
100
+++
+++
++
50
++
++
+++
++
-
100
+
IVa
IVb
IVc
IVd
IVe
IVf
++
+++
++
++
++
+++
++
+
++
+++
++
+++
++
+++ ++++ - +++
++
++
++
++
++
++
+++
+
++
+++
++
+++
++
+
++
++
+++
+
+
+++
++
++
+++
+
++++
++
+++
++
++
+++
+++
++
++
+
+++
++
IVg ++++
+++
+++
++
++
-
+++
++
IVh
IVi
+
++
-
++
++
+++
++
++
+++
+
+
++
+++
++
+
++
+++
++
IVj
IVk
-
++
++
+++
-
++
+
+++
++
+++
+++
+++
++++ = Strongly activee, +++ = Moderately active, ++ = Weakly active, +, - = Inactive
17
18
16
16
15
15
16
14
12
10
8
14
14
13
12
10
10
7
6
4
2
0
Std. IIIa IIIb IIIc IIId IIIe IIIf IIIg IIIh IIIi IIIj IIIk
Compound code
Figure 1. Insecticidal activity of III(a-k)

Synthesis and Biological Activity Study
937
20
18
16
14
12
10
8
18
16
15
14
14
13
13
12
12
11
10
8
6
4
2
0
Std. Iva IVb IVc IVd IVe IVf IVg IVh IVi IVj IVk
Compound code
Figure 2. Insecticidal activity of IV(a-k)
Acknowledgment
The authors are thankful to SAIF, CDRI Lucknow for providing NMR spectral and mass
spectral data of synthesized heterocyclic derivatives. We are also thankful to Prof. Mehta
Department of Botany for his kind assistance in performing antimicrobial activity in Botany
Department and Prof. O. P. Shrivastava, Head Department of Chemistry, Dr. H.S. Gour
University, Sagar providing IR spectral data and laboratory facilities.
References
1.
Suresh T, Nandhu kumar R, Magesh S and Mohan P S, Indian J Chem., 2003, 42B,
2133-2135.
2.
3.
4.
5.
Rajendran S P and Karvembu R, Indian J Chem., 2002, 41B, 222-224.
Kennedy A D, Summer A L, J Heterocyclic Chem., 1981, 18, 409.
Dogan H N, Duran A and Rollas S, Indian J Chem., 2005, 44B, 2301.
Bol. S A, Horibeck J, Markovic J, Deboer J G, Turesky R J and Constable A,
Careinogenesis, 2000, 21(1), 1-6.
6.
7.
8.
9.
Althuis T H, Moore P F and Hess H J, J Med Chem., 1979, 22, 44-48.
Nargund L V C, Bodiger V V and Yarnal S M, J Pharm Sci., 1992, 81(4), 365-366.
Patel N B and Chouhan I H , Indian J Heterocycl Chem., 2005, 15, 39.
El-sayed O A, El-Baih F M E, El-Aqeel, Sh. I, Al Bassam B A and Hussein, Boll
Chem Farmac., 2002, 141(6), 461-465.
10. Petal N C and Mehta A G, Asian J Chem., 2001, 13(4), 1385-1388.
11. Bari S S, Sharma A K and Sethi M K, Indian J Chem., 1998, 37B, 1114.
12. Ratchanok Pingaevw, Supaluk Prachayasittikul and Somsak Ruchirawat, Molecules,
2010, 15(2), 988-996.
13. Eguchi C, Vashudha N, Iwagami H, Takigava E, Okutsu M, Onuki T and Nakamiya T,
Japan Kokai Tokkyo KOHO, 1979, 7, 984.
14. Shukle S K, Singh S P, Awasthi L P and Mukharjee D D, Indian J Pharm Sci., 1982,
44, 153.
15. Altintas H, Ates O, Birteksoz S, Otuk G, Uzum M and Satana D, Turk J Chem., 2005, 29, 425.
16. Liu H L, Li Z and Anthonsen T, Molecules, 2000, 5, 1055.
17. Vazzana I, Tarranova E, Mattioli F.S and Sparatore F, ARKIVOC, 2004, 5, 364.
18. Gursoy A and Terzioglu N, Turk J Chem., 2005, 29, 247-254.
19. Vagdeevi H M, Vaidya V P, Latha K P, and Padamashali B, Indian J Pharm Sci.,
2006, 68, 719.

International Journal of
Advances in
Organic Chemistry
International
International Journal of
International Journal of
Photoenergy
Medicinal Chemistry
Analytical Chemistry
Physical Chemistry
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Volume 2014
International Journal of
Carbohydrate
Chemistry
Journal of
Quantum Chemistry
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
http://www.hindawi.com
Volume 2014
Volume 2014
Submit your manuscripts at
http://www.hindawi.com
Journal of
The Scientific
Analytical Methods
in Chemistry
World Journal
Hindawi Publishing Corporation
Hindawi Publishing Corporation
http://www.hindawi.com
http://www.hindawi.com
Volume 2014
Volume 2014
International Journal of
Journal of
Journal of
International Journal of
Bioinorganic Chemistry
Spectroscopy
Inorganic Chemistry
Electrochemistry
Applied Chemistry
and Applications
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
http://www.hindawi.com
Volume 2014
Journal of
Journal of
International Journal of
Chromatography
Journal of
Theoretical Chemistry
Catalysts
Research International
Chemistry
Spectroscopy
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Volume 2014
Volume 2014
Volume 2014