Synthesis of new 5-acetyl(arylmethyliden)-4-thiazolidones

Article abstract of DOI:10.1002/hc.20631

A new approach to the synthesis of new heterocyclic compounds with triazine and 4-thiazolidone fragments in one molecule is developed. The synthesis methods comprise [2+3]-cyclocondensation reactions essential in the preparative synthesis of 4-thiazolidon

Full text of DOI:10.1002/hc.20631

Heteroatom Chemistry
Volume 21, Number 6, 2010
Synthesis of New 5-Acetyl(arylmethyliden)-
4-thiazolidones
Svyatoslav V. Polovkovych, Andrii I. Karkhut, Natalia G. Marintsova,
and Volodymyr P. Novikov
Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology,
National University “Lviv Polytechnic,” Bandera Str.12, 79013, Lviv-13, Ukraine
Received 22 March 2010; revised 18 June 2010
conditions all chlorine atoms could be substituted by
ABSTRACT: A new approach to the synthesis
identical or different substituents. The adducts of
of new heterocyclic compounds with triazine and
1,3,5-triazine and 4-thiazolidone revealed potential
4-thiazolidone fragments in one molecule is de-
antiinflammatory, antimicrobial, antiviral, car-
veloped. The synthesis methods comprise [2+3]-
diovascular, and trombolytic activity, indicating
cyclocondensation reactions essential in the prepar-
the significance of synthesis and investigation of
ative synthesis of 4-thiazolidone derivatives. The
new substances from the order of 1,3,5-triazine
reactions of S,N-nucleophiles with C2-cyclization
derivatives in the view of organic, combinatorial,
agents for the synthesis of a number of biolog-
and pharmaceutical chemistry.
ically active 2-triazin-4-thiazolidones were investi-
From the pharmacological point of view, 2,4,6-
gated. The interaction of thiosemicarbazone of sym-
trichloro-1,3,5-triazine is an object of outstand-
triazine with derivatives of α-halogencarboxylic acids
ing interest, offering a possibility to combine sev-
and maleic anhydride resulted in correspondent (2-[2-
eral biologically active fragments in one molecule.
(4,6-dichloro-1,3,5-triazin-2-yl)hydrazino]-5-(3,4,5-
The derivatives of sym-triazine revealed potential
R-p-phenyl-methyliden)-1,3-thiazol-4-ones obtained
anticancer [1–4] and antimicrobial [4–9] activity,
ꢀ
C
in the one-step synthesis. 2010 Wiley Periodicals, Inc.
whereas aryl- and acetyl-substituted 4-thiazolidones
are high-specific ligands to a number of cellular
biotargets, predetermining antidiabetic [10,11], an-
Heteroatom Chem 21:392–396, 2010; View this article on-
line at wileyonlinelibrary.com. DOI 10.1002/hc.20631
titumor [12–15], antimicrobial [16,17], and other
types of pharmacological activity. Aryl- and acetyl-
substituted triazin-4-thiazolidones meet the criteria
of “drug-similarity” for chemical structures accord-
INTRODUCTION
Considerable interest in the derivatives of 1,3,5-
triazine as half products for the synthesis of
substances with a wide spectrum of biological activ-
ity arises from the reactivity of the 2,4,6-trichloro-
1,3,5-triazine molecule, where at certain reaction
ing to Lipinskiy rules [18]. Therefore, such a unique
opportunity to combine in one molecule pharma-
cophores with manifold activity provided by reactive
triazin-4-thiazolidones opens potential for synthesis
of new polyfunctional preparations.
RESULTS AND DISCUSSION
Correspondence to: Volodymyr P. Novikov; e-mail:
vnovikov@polynet.lviv.ua.
Contract grant sponsor: President of Ukraine for Support of the
Scientific Researches of Young Scientists.
In this work, we describe the application of
the Michael condensation reactions for the syn-
thesis of new heterocyclic compounds with tri-
azine and 4-thiazolidone heterocyclic fragments
Contract grant number: GP/F27/0069.
2010 Wiley Periodicals, Inc.
c
ꢀ
392

Synthesis of New 5-Acetyl(arylmethyliden)-4-thiazolidones 393
SCHEME 1 Interaction of 1-(4,6-dichloro-1,3,5-triazin-2-yl)thiosemicarbazide (3) with maleic anhydride.
combined in one molecule. The above-mentioned
group of methods includes mainly reactions of [2+3]-
cyclocondensation, which are preparatively the most
essential in the synthesis of 4-thiazolidone deriva-
tives including 2-triazin-5-acetyl(arylmethyliden)-4-
thiazolidone. These synthetic approaches include
an interaction of S,N-binucleophiles with differ-
ent equivalents of bielectrophylic synthon [C2]2+.
Particularly for the synthesis of several biologi-
cally active 2-triazin-4-thiazolidones, the interac-
tion of thiosemicarbazone of sym-triazine with the
derivatives of α-halogencarboxylic acids [19–21] and
maleic anhydride [22] is used (Schemes 1 and
2). These schemes show that 1-(4,6-dichloro-1,3,5-
triazin-2-yl)thiosemicarbazide 3 as the active S,N-
binucleophil is a promising synthon for the synthe-
sis of new heterocyclic compounds. 1-(4,6-Dichloro-
1,3,5-triazin-2-yl)thiosemicarbazide 3 was obtained
by nucleophilic substitution of one chlorine atom in
2,4,6-trichloro-1,3,5-triazine by thiosemicarbazide
in acetonitrile as a solvent at −7◦C in the presence of
equimolar amount of NaHCO3 (Scheme 1, way a).
The interaction of 1-(4,6-dichloro-1,3,5-triazin-
2-yl)thiosemicarbazide 3 with maleic anhydride as
a C2-cyclization agent depending on the reaction
conditions results in the formation of a carboxyl
compound with the acyclic structure 4-({[2-(4,6-
dichloro-1,3,5-triazin-2-yl)hydrazino] carbonothi-
oyl}amino)-4- oxobut-2-enoic acid 4, or a cycliza-
tion product {2-[2-(4,6-dichloro-1,3,5-triazin-2-yl)
hydrazino] -4-oxo-4,5-dihydro-1, 3-thiazol -5-yl} ace-
tic acid 5.
12–18 h or at a temperature 45–55◦C for 1 h
(Scheme 1, way b).
The reaction of [3+2]-cyclocondensation of 1-(4,
6-dichloro-1,3,5-triazin-2-yl)thiosemicarbazide
3
with maleic anhydride, resulting in a cyclic structure
{2-[2-(4,6-dichloro-1,3,5-triazin-2-yl)hydrazino]-4-
oxo-4,5-dihydro-1,3-thiazol-5-yl}acetic acid 5 was
carried out in DMF at 100–110◦C for 4 h (Scheme 1,
way c).
The interaction of 1-(4,6-dichloro-1,3,5-triazin-
2-yl)thiosemicarbazide 3 with maleic anhydride is
a [2+3]-cyclocondensation reaction. It is known
that thiourea occurs in thione and thiol tau-
tomeric forms being active in the Michael reac-
tions of S H addition. The formation of product
4 with a linear structure in mild reaction con-
ditions witnesses the progress of acylation with
opening of anhydride cycle (Scheme 1, way b),
whereas in harsh conditions it results in the
product of cyclocondensation 5 (Scheme 1, way
d). From these data, we can conclude that the
[2+3]-cyclocondensation reaction between 1-(4,6-
dichloro-1,3,5-triazin-2-yl)thiosemicarbazide 3 and
maleic anhydride (Scheme 1, way c) passes through
the stage of intermediate product 4 formation.
The interaction of 1-(4,6-dichloro-1,3,5-triazin-
2-yl)thiosemicarbazide 3 with monochloroacetic
acid occurs as [3+2]-cyclocondensation of S,N-
binucleophiles with formation of correspond-
ing 2-[2-(4,6-dichloro-1,3,5-triazin-2-yl)hydrazino]-
1,3-thiazol-4-one 7. A reaction was carried out in
DMF with an equimolar amount of triethylamine at
the temperature 100–110◦C (Scheme 2, way e).
The product (Scheme 2, way e) 2-[2-(4,6-
dichloro-1,3,5-triazin-2-yl)hydrazino]-1,3-thiazol-4-
one 7 contains a methylene fragment active in
Acylation adduct 4-({[2-(4,6-dichloro-1,3,5-tria-
zin-2-yl)hydrazino]carbonothioyl}amino)-4-oxobut-
2-enoic acid 4 was synthesized in mild reaction
conditions in DMF at room temperature for
Heteroatom Chemistry DOI 10.1002/hc

394 Polovkovych et al.
reaction progress was monitored by thin-layer chro-
matography on 0.2-mm silica gel (Silufol UV-254).
1-(4,6-Dichloro-1,3,5-triazin-2-yl)thiosemicarb-
azide 3
To a suspension of 10 mmol of 2,4,6-trichloro-1,3,5-
triazine in 15 mL of anhydrous acetonitrile, 10 mmol
of thiosemicarbazide was added the and the mix-
ture was stirred at temperature −7◦C in the pres-
ence of NaHCO3 for 1 h. The obtained precipitate
was filtered and washed with cold water. Yield 71%,
mp = 177◦C. IR (KBr), cm−1: 3200, 1650 (NH), 1450
(C S), 1410, 1230, 820 (C N triazine), 720 (C Cl),
680 (C SH).
4-({[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydra-
zino]carbonothioyl}amino)-4-oxobut-2-enoic
Acid 4
SCHEME
2
Synthesis of 5-arylmethyliden-2-[2-(4,6-
dichloro - 1,3,5 - triazin - 2 - yl)hydrazino] - 1,3 - thiazol - 4 - ones
(6a–i).
A
mixture
of
1-(4,6-dichloro-1,3,5-triazin-2-
yl)thiosemicarbazide 3 (10 mmol) and maleic
anhydride (10 mmol) in DMF (20 mL) was stirred
at temperature 20–25◦C for 14 h or 45–55◦C for 1 h.
The solid product formed was collected by filtration.
Yield 57%, mp >250◦C. IR (KBr), cm−1: 3210, 1650
(NH), 1740, 1680 (C O), 1640, 1600 (C C), 1615
( COOH), 1410, 1230, 820 (C N triazine), 720
(C Cl). H NMR DMSO-d6 (δ, ppm): 10.21 (s, 1H,
COOH), 10.02 (s, 1H, NH), 9.48 (s, 1H, NH), 8.75 (s,
1H, NH), 6.95, 6.90 (dd, 2H, J = 15.2 Hz).
the Knoevenagel reaction and, therefore, is easily
transformed in situ in arylmethyliden derivatives by
addition of corresponding R-substituted aromatic
aldehydes into the reaction mixture. A reaction
was carried out also in DMF with the presence
of triethylamine at the temperature 100–110◦C,
resulting in 5-arylmethyliden-2-[2-(4,6-dichloro-
1,3,5-triazin-2-yl)hydrazino]-1,3-thiazol-4-ones 6a–i
(Scheme 2, way f).
The products 6a–i were synthesized in an alter-
native way by the interaction of an initial 1-(4,6-
dichloro-1,3,5-triazin-2-yl)thiosemicarbazide 3 with
monochloroacetic acid and a number of aromatic
aldehydes in one stage in DMF in the presence of
double the amount of triethylamine at 100–110◦C
(Scheme 2, way g).
Therefore, new application of the [2+3]-
cyclocondensation reaction of S,N-nucleophiles and
C2-cyclization agents for the synthesis a number
of biologically active 2-triazin-4-thiazolidones using
the interaction of thiosemicarbazone of sym-triazine
with monochloroacetic acid and maleic anhydride
was reported.
1
{2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydra-
zino]-4-oxo-4,5-dihydro-1,3-thiazol-5-yl}acetic
Acid 5
Way c. A mixture of 1-(4,6-dichloro-1,3,5-triazin-2-
yl)thiosemicarbazide 3 (10 mmol) and maleic an-
hydride (10 mmol) in DMF (20 mL) was stirred at
temperature 100–110◦C for 4 h. The solid product
formed was collected by filtration.
Way d.
A
mixture of 4-({[2-(4,6-dichloro-
1,3,5-triazin-2-yl)hydrazino]carbonothioyl}amino)-
4-oxobut-2-enoic acid 4 (10 mmol) in DMF (20 mL)
was stirred at temperature 100–110◦C for 3 h. The
solid product formed was collected by filtration.
Yield 73%, mp = 221◦C. IR (KBr), cm−1: 3200, 1650
(NH), 1740, 1690 (C O), 1610 (–COOH), 1410, 1230,
EXPERIMENTAL
Melting points were determined in open capillary
tubes. Infrared (IR) spectrums were recorded on a
Specord-80M spectrophotometer in potassium bro-
1
820 (C N triazine), 720 (C Cl). H NMR DMSO-d6
(δ, ppm): 10.12 (s, 1H, COOH), 9.78 (s, 1H, NH),
8.85 (s, 1H, NH), 2.81 d, 2.98 d, 4.25 m (CH2CH
JAB = 15.0 Hz, JAX = 9.0 Hz, JBX = 4.5 Hz).
1
mide pellets as described elsewhere. H NMR spec-
tra were recorded on a Varian VXR (300 MHz). The
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of New 5-Acetyl(arylmethyliden)-4-thiazolidones 395
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-
5-(4-methoxybenzylidene)-1,3-thiazol-4-one 6b. Yield
71%, mp = 198◦C. IR (KBr), cm−1: 3210, 1660 (NH),
1750, 1690 (C O), 1410, 1230, 810 (C N triazine),
710 (C Cl). 1H NMR DMSO-d6 (δ, ppm): 9.18 (s,
1H, NH), 8.67 (s, 1H, NH), 7.15 (d, 2H, J = 8.2 Hz,
arom.), 6.96 (d, 2H, J = 8.2 Hz, arom.), 7.40 (s, 1H,
CHAr), 3.77 (s, 3H, OCH3).
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-
1,3-thiazol-4-one 7
A
mixture
of
1-(4,6-dichloro-1,3,5-triazin-2-
yl)thiosemicarbazide 3 (10 mmol) and chloroacetic
acid (10 mmol) in DMF (20 mL) was stirred at
temperature 100–110◦C for 3 h in the presence of
a equimolar amount of triethylamine. The solid
product formed was collected by filtration. Yield
76%, mp = 212◦C. IR (KBr), cm−1: 3200, 1650 (NH),
1740, 1690 (C O), 1410, 1230, 820 (C N triazine),
720 (C Cl). 1H NMR DMSO-d6 (δ, ppm): 9.18 (s, 1H,
NH), 8.67 (s, 1H, NH), 4.47 (s, 2H, CH2).
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-
5-(3,4-(dimethoxy)benzylidene)-1,3-thiazol-4-one 6c.
Yield 73%, mp = 176◦C. IR (KBr), cm−1: 3220, 1670
(NH), 1730, 1690 (C O), 1420, 1230, 820 (C N tri-
azine), 720 (C Cl). 1H NMR DMSO-d6 (δ, ppm):
10.11 (s, 1H, NH), 8.77 (s, 1H, NH), 6.92 (d, 1H,
J = 7.2 Hz, arom.), 6.83 (m, 2H, arom.), 3.76 (s, 3H,
OCH3), 3.73 (s, 3H, OCH3), 7.41 (s, 1H, CHAr).
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-
5-(3-ethoxy-4-hydroxybenzylidene)-1,3-thiazol-4-one
6d. Yield 65%, mp = 211◦C. IR (KBr), cm−1: 3210,
1650 (NH), 1730, 1690 (C O), 1410, 1230, 820 (C N
General Methods of Synthesis of 5-
Arylmethyliden-2-[2-(4,6-dichloro-1,3,5-triazin-
2-yl)hydrazino]-1,3-thiazol-4-ones 6a–i
Way f. A mixture of 2-[2-(4,6-dichloro-1,3,5-triazin-
2-yl)hydrazino]-1,3-thiazol-4-one 7 (10 mmol) and
aromatic aldehyde (12 mmol) in DMF (20 mL) was
stirred at temperature 100–110◦C for 4 h in the pres-
ence of an equimolar amount of triethylamine. The
solid product formed was collected by filtration.
Way g. A mixture of 1-(4,6-dichloro-1,3,5-triazin-
2-yl)thiosemicarbazide 3 (10 mmol), chloroacetic
acid (10 mmol), and aromatic aldehyde (12 mmol) in
DMF (20 mL) was stirred at temperature 100–110◦C
for 4–7 h in the presence of triethylamine (20 mmol).
The solid product formed was collected by filtration.
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-
5-benzylidene-1,3-thiazol-4-one 6a. Yield 76%, mp =
187◦C. IR (KBr), cm−1: 3190, 1650 (NH), 1730, 1690
(C O), 1410, 1220, 820 (C N triazine), 720 (C Cl).
1H NMR DMSO-d6 (δ, ppm): 9.24 (s, 1H, NH), 8.85
(s, 1H, NH), 7.65 (d, 2H, J = 8.6 Hz, arom.), 7.33 (t,
2H, arom.), 7.11 (t, 1H, arom.), 7.47 (s, 1H, CHAr).
1
triazine), 710 (C Cl). H NMR DMSO-d6 (δ, ppm):
10.17 (s, 1H, NH), 8.97 (s, 1H, NH), 8.86 (s, 1H,
OH), 6.73 (d, 1H, J = 8.0 Hz, arom.), 6.71 (s, 1H,
arom.), 6.63 (d, 1H, J = 8.0 Hz, arom.), 4.02 (m, 2H,
CH2CH3), 5.45 (s, 1H, CHAr), 1.19 (t, 3H, CH2CH3).
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-5-
(3,5-di-tert-butyl-4-hydroxybenzylidene)-1,3-thiazol-4-
one 6e. Yield 55%, mp = 157◦C. IR (KBr), cm−1:
3210, 1650 (NH), 1740, 1690 (C O), 1410, 1230, 810
1
(C N triazine), 720 (C Cl). H NMR DMSO-d6 (δ,
ppm): 10.01 (s, 1H, NH), 8.95 (s, 1H, NH), 8.06 (s,
1H, OH), 7.68 (s, 2H, arom.), 7.58 (s, 1H, CHAr),
1.42 (s, 18H, C(CH3)3).
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-5-
(4-(dimethylamino)benzylidene)-1,3-thiazol-4-one 6f.
Yield 77%, mp = 182–184◦C. IR (KBr), cm−1: 3210,
1660 (NH), 1740, 1690 (C O), 1410, 1210, 820 (C N
1
triazine), 720 (C Cl). H NMR DMSO-d6 (δ, ppm):
TABLE 1 Elemental Analysis of Obtained Compounds
Compounds
Formula
Calculated
Found
3
4
5
C4H4Cl2N6S
C8H6Cl2N6O3S
C8H6Cl2N6O3S
C 20.10, N 35.15, S 13.41
C 28.50, N 24.93, S 9.51
C 28.50, N 24.93, S 9.51
C 42.52, N 22.89, S 8.73
C 42.33, N 21.16, S 8.07
C 42.17, N 19.67, S 7.50
C 42.17, N 19.67, S 7.50
C 50.91, N 16.96, S 6.47
C 43.91, N 23.90, S 7.82
C 40.54, N 21.82, S 8.32
C 38.87, N 20.92, S 7.98
C 35.00, N 18.84, S 7.19
C 25.82, N 30.11, S 11.49
C 20.24, N 35.03, S 13.25
C 28.58, N 24.71, S 9.36
C 28.46, N 24.82, S 9.47
C 42.73, N 22.69, S 8.88
C 42.19, N 21.32, S 8.01
C 42.03, N 19.86, S 7.39
C 42.31, N 19.76, S 7.36
C 50.72, N 16.81, S 6.55
C 43.99, N 23.73, S 7.64
C 40.62, N 21.67, S 8.19
C 38.89, N 20.83, S 7.79
C 35.11, N 18.93, S 7.28
C 25.74, N 30.29, S 11.62
6a
6b
6c
6d
6e
6f
6g
6h
6i
C
13H8Cl2N6OS
14H10Cl2N6O2S
C15H12Cl2N6O3S
C
C
C
15H12Cl2N6O3S
21H24Cl2N6O3S
C15H13Cl2N7OS
C13H7Cl2FN6OS
C13H7Cl3N6OS
C13H7Cl3BrN6OS
C6H4Cl2N6OS
7
Heteroatom Chemistry DOI 10.1002/hc

396 Polovkovych et al.
[5] Kreutzberger, A.; Richter, B. Archiv Pharm 1983, 316,
213–217.
[6] Arenas, J. E.; Cload, S. T.; Fleming, E. S. WO Patent
99/36410, 1999.
[7] Ghaib, A.; Menager, S.; Verite, P.; Lafont, O. Farmaco
2002, 57, 109–116.
[8] Srinivas, K.; Srinivas, U.; Bhanuprakash, K.;
Harakishore, K.; Murthy, U. S. N.; Jayathirtha Rao,
V. Eur J Med Chem 2006, 41, 1240–1246.
[9] Zhou, Y.; Sun, Z.; Froelich, J. M.; Hermann, T.; Wall,
D. Bioorg Med Chem Lett 2006, 16, 5451–5456.
[10] Bailey, C. J. Trends Pharmacol Sci 2000, 21, 259–
264.
[11] Reginato, M. J.; Lazar, M. A. Trends Endocrinol
Metab 1999, 10, 9–13.
[12] Liu, W. J.; Bulgaru, A.; Haigents, M.; Perez-Soler, R.;
Mani, S. Curr Med Chem 2003, 3, 217–223.
[13] Degterev, A.; Lugovskoy, A.; Cardone, M.; Mulley, B.;
Wagner, G.; Mitchison, T.; Yuan, J. Nature Cell Biol
2001, 3, 173–182.
10.19 (s, 1H, NH), 8.89 (s, 1H, NH), 7.17 (d, 2H,
J = 8.1 Hz, arom.), 6.96 (d, 2H, J = 8.1 Hz, arom.),
7.51 (s, 1H, CHAr), 2.77 (s, 6H, N(CH3)2).
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-5-
(4-fluorobenzylidene)-1,3-thiazol-4-one 6g. Yield
78%, mp = 123–125◦C. IR (KBr), cm−1: 3195, 1655
(NH), 1730, 1690 (C O), 1410, 1220, 820 (C N
1
triazine), 720 (C Cl). H NMR DMSO-d6 (δ, ppm):
10.07 (s, 1H, NH), 8.54 (s, 1H, NH), 7.96 (t, 2H,
J = 8.5 Hz, arom.), 7.36 (t, 2H, J = 8.5 Hz, arom.),
7.43 (s, 1H, CHAr).
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-5-
(4-chlorobenzylidene)-1,3-thiazol-4-one 6h. Yield
71%, mp = 126–128◦C. IR (KBr), cm−1: 3220, 1650
(NH), 1730, 1690 (C O), 1410, 1230, 810 (C N
triazine), 720 (C Cl) cm−1 1H NMR DMSO-d6 (δ,
ppm): 10.11 (s, 1H, NH), 8.71 (s, 1H, NH), 7.27 (d,
2H, J = 8.7 Hz, arom.), 6.92 (d, 2H, J = 8.7 Hz,
arom.), 7.55 (s, 1H, CHAr).
[14] Murthy Madiraju, S. R.; Shore Gordon, C.; Johnson
Roy, A.; Steenaart Nancy, A. Patent US2003119894
USA A61K31/404, 2003.
2-[2-(4,6-Dichloro-1,3,5-triazin-2-yl)hydrazino]-5-
(4-bromobenzylidene)-1,3-thiazol-4-one 6i. Yield
67%, mp = 142–144◦C. IR (KBr), cm−1: 3200, 1660
(NH), 1740, 1670 (C O), 1410, 1220, 820 (C N
[15] Cutshall, N. S.; O’Day, C.; Preshdo, M. Bioorg Med
Chem Lett 2005, 15, 3374–3379.
[16] Andres, C. J.; Bronson, J. J.; D’Andrea, S. V.;
Deshpande, M. S.; Falk, P. J.; Grant-Young, K. A.;
Harte, W. E.; Ho, H. T.; Misco, P. F.; Robertson, J. G.;
Stock, D.; Sun, Y.; Walsh, A. W. Bioorg Med Chem
Lett 2000, 10, 715–717.
1
triazine), 720 (C Cl). H NMR DMSO-d6 (δ ppm):
10.13 (s, 1H, NH), 8.79 (s, 1H, NH), 7.22 (d, 2H,
J = 8.4 Hz, arom.), 6.98 (d, 2H, J = 8.4 Hz, arom.),
7.50 (s, 1H, CHAr).
The data of elemental analysis of all obtained
compounds are presented in Table 1.
[17] El Zoeiby, A.; Sanschagrin, F.; Levesque, R. C. Mol
Microbiol 2003, 47, 1–12.
[18] Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney,
P. J. Adv Drug Delivery Rev 1997, 23, 3–25.
[19] Ottana, R.; Maccari, R.; Barreca, M. L.; Bruno, G.;
Rotondo, A.; Rossi, A.; Chiricosta, G.; Di Paola, R.;
Sautebin, L.; Cuzzocrea, S.; Vigorita, M. G. Bioorg
Med Chem 2005, 13, 4243–4252.
REFERENCES
[1] Goldin, A.; Wolpert-Defilippes, M. K. Bull Cancer
1979, 66, 61–66.
[20] Ram, V. J.; Pandey, H. N.; Singh, S. N. J. Indian Chem
Soc 1972, 49, 181–183.
[21] Joshi, C. K.; Pathak, V. N.; Chaturvedi, R. K. Phar-
mazie 1986, 41, 475–478.
[22] Tenirio, R. P.; Carvalho, C. S.; Pessanha, C. S.; De
Lima, J. G.; De Faria, A. R.; Alves, A. J.; De Melo,
E. J. T.; Goes, A. J. S. Bioorg Med Chem Lett 2005,
15, 2575–2578.
[2] Foster, B. J.; Harding, B. J.; Leyland-Jones, B.; Hoth,
D. Cancer Treatment Rev 1986, 13, 197–217.
[3] Menicagli, R.; Samaritani, S.; Signore, G.; Vaglini, F;
Dalla Via, L. J Med Chem 2004, 47, 4649–4652.
[4] Saczewski, F.; Bulakowska, A.; Bednarski, P.;
Grunert, R. Eur J Med Chem 2006, 41, 219–225.
Heteroatom Chemistry DOI 10.1002/hc