Synthesis and antioxidant activity evaluation of novel 5,7-dimethyl-3 H -Thiazolo[4,5-B]Pyridines

Article abstract of DOI:10.1080/10426507.2013.777723

5,7-Dimethyl-3H-thiazolo[4,5-b]pyridine-2-one was obtained under the reaction of 4-iminothiazolidin-2-one with acetylacetone. Further structural modifications include the introduction of diversity at the N³ and C⁶ positions. The anti

Full text of DOI:10.1080/10426507.2013.777723

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Synthesis and Antioxidant Activity
Evaluation of Novel 5,7-dimethyl-3H-
Thiazolo[4,5-B]Pyridines
Taras I. Chaban a , Volodymyr V. Ogurtsov a , Ihor G. Chaban a ,
Olena V. Klenina a & Josef D. Komarytsia a
a Danylo Halytsky Lviv National Medical University , Lviv , Ukraine
Accepted author version posted online: 05 Apr 2013.Published
online: 20 Sep 2013.
To cite this article: Taras I. Chaban , Volodymyr V. Ogurtsov , Ihor G. Chaban , Olena V. Klenina &
Josef D. Komarytsia (2013) Synthesis and Antioxidant Activity Evaluation of Novel 5,7-dimethyl-3H-
Thiazolo[4,5-B]Pyridines, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:11,
1611-1620, DOI: 10.1080/10426507.2013.777723
To link to this article: http://dx.doi.org/10.1080/10426507.2013.777723
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Phosphorus, Sulfur, and Silicon, 188:1611–1620, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.777723
SYNTHESIS AND ANTIOXIDANT ACTIVITY EVALUATION
OF NOVEL 5,7-DIMETHYL-3H-THIAZOLO[4,5-b]PYRIDINES
Taras I. Chaban, Volodymyr V. Ogurtsov, Ihor G. Chaban,
Olena V. Klenina, and Josef D. Komarytsia
Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
GRAPHICAL ABSTRACT
Abstract 5,7-Dimethyl-3H-thiazolo[4,5-b]pyridine-2-one was obtained under the reaction
of 4-iminothiazolidin-2-one with acetylacetone. Further structural modifications include the
introduction of diversity at the N3 and C6 positions. The antioxidant activity of the synthesized
compounds was evaluated in vitro by the method of scavenging effect on 2,2-diphenyl-1-
picrylhydrazyl (DPPH) radicals.
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the following free supple-
mental files: Additional figures]
Keywords Thiazolo[4,5-b]pyridines; DPPH; antioxidant activity
Received 15 November 2012; accepted 15 February 2013.
Address correspondence to Olena V. Klenina, Danylo Halytsky Lviv National Medical University, Pekarska
Str., 69, Lviv 79010, Ukraine. E-mail: olena klenina@yahoo.com
1611

1612
T. I. CHABAN ET AL.
INTRODUCTION
Different environmental stress factors like pollution, drought, temperature, excessive
light intensities, and nutritional limitation are able to increase the production of reactive
oxygen species (ROS) (e.g., superoxide, hydroxyl, peroxyl, and alkoxy radicals).1,2 Their
highly reactive potential is discussed to be responsible for some human diseases, for
example, cancer and cardiovascular diseases, and is able to cause oxidative damages to
proteins, DNA, and lipids in both humans and microorganisms.3
Antioxidants can interfere with the oxidation process by reacting with free radicals,
and also by acting as reactive species scavenger. Several enzymes like superoxide dismu-
tase, catalase peroxidase are able to scavenge ROS.4 Carotenoids, fatty acids, tocopherol,
flavonoids, alkaloids, Selenium, and ascorbic acid, are the examples for nonenzymatic
classes of natural substances, which are able to protect the organism from oxidative dam-
age.5 There are also a few synthetical antioxidative compounds (butylated hydroxyl anisole,
butylated hydroxyrotoluene, propyl gallate, tertiary butyl hydroquinone, and nordihydro
guaretic acid) used as drugs.6
The antioxidant activities of the individual compounds may depend on their structural
features.
4-Azolidone is widely used in modern medical chemistry as a scaffold for molecular
rational design of drug candidates. The thiazolidine-based heterocycles and their analogs
fused to the pyridine ring were shown to posses the wide range of biological actions. Some
of thiazolo[4,5-b] pyridines were described as potent antimicrobial agents.7 They also
show potent inhibitory activities for Aβ42 fibrillization for Alzheimer’s disease treatment.8
Among substances of this type, several compounds were found to possess fungicidal,
antiexcudative, antimicrobial, and antitumor actions.9–12 Some of them are H3 receptor
antagonists,13,14 or act as antagonists of metabotropic glutamate receptors 5 (mGluR5),15
they are of high inhibitory activity with respect to the receptors of the epidermal growth
factor,16 and were revealed to activate the GK enzyme in vitro and significantly reduce
glucose levels.17
The objective of the present work was to synthesize a series of novel 3H-thiazolo[4,5-
b]pyridine-2-ones by the structural modification of the core heterocycle in its N3 and С6
positions for further pharmacological screening in vitro as antioxidants.
RESULTS AND DISCUSSION
Chemistry
One of the efficient synthetic approaches for thiazolo[4,5-b]pyridine system construc-
tion used in modern medial chemistry is the protocol based on [3+3] cyclocondensation
of 4-iminothiazolidone-218 on account of its N,C-binucleophylic properties with dielectro-
phylic reagents like acetylacetone forming the above-mentioned fused heterocycle (1).19
For broadening the scope of N3-substituted 5,7-dimethyl-3H-thiazolo[4,5-b]pyridine-
2-ones, we involved compound 1 into cynoethylation reaction taking the advantage of the
good leaving hydrogen atom property of the NH-group. We discovered that the high yield of
the product can be achieved by introducing the equimolar amounts of the compound 1 and
acrylonitrile in pyridine–water medium 5:1; 3-(5,7-dimethyl-2-oxo-thiazolo[4,5-b]pyridin-
3-yl)-propionitryl (2) prepared in this way was subjected to hydrolysis leading to 3-(5,7-
dimethyl-2-oxo-thiazolo[4,5-b]pyridin-3-yl)-propionic acid formation (3) (Scheme 1).

SYNTHESIS OF NOVEL THIAZOLOPYRIDINES AS ANTIOXIDANTS
1613
Scheme 1
The next stage of our strategy includes the core heterocycle structural modification
in its C6 position. The direct functionalization proceeding has exposed to be of a small
introducing possibility owing to the low nucleophilic activity of the compound 1 in the
C6 position. However, 5,7-dimethyl-6-arylazo-3Н-thiazolo[4,5-b]pyridine-2-one (4) was
yielded by α-arylazoacetone20 treatment with 4-iminothiazolidone-2 (Scheme 2).
Scheme 2
Сompound 4 represents a convenient intermediate in order to afford 6-amino-5,7-
dimethyl-3Н-thiazolo[4,5-b]pyridine-2-one (5) as a building block for more elaborate func-
tionalizations of thiazolo[4,5-b]pyridine-2-one moiety in its C6 position. The reductive
cleavage of compound 4 was proceeded leading to obtaining of compound 5. The syn-
thetic strategy developed showed the compound 5 high yielding may be achieved in acetic
acid–pyridine medium by using zinc dust as a reduction agent.
The amine group presence in C6 position of compound 5 provides an entry for 6-
arylidenamino- (6a-d) and 6-acetylamino derivatives (7a-b) generation. Acetic acid was
found to be the most suitable medium for the reaction of compound 5 with aromatic
aldehydes and dioxane—for the reaction of compound 5 with chloroanhydrides of aliphatic
acids (Scheme 3).
Chloroacetamides are highly reactive chemicals, which, on being involved into alkyla-
tion reactions form the basis for creating and continuous supplementing of building blocks,
a wide collection for combinatorial chemistry including biologically active substances and
combinatorial libraries designed on their basis.
Compound 7b may be considered as a key intermediate in 6-sulfanylacetamide
derivatives of 5,7-dimethyl-3Н-thiazolo[4,5-b]pyridine-2-one that are obtained on being
treated with appropriate thiols. The reaction mixture reflux for 30 min and in 96% ethanol
medium were optimal conditions for compounds 8a–d formation proceeding in good yields
(Scheme 4).
Thus, the series of thiazolo[4,5-b]pyridin-2-one acetamides has been diversified by
alkylation reactions applying N-substituted 2-chloroacetamide 7b as alkylating agent, em-
ploying it into the reactions with heteryl moiety thiols, which can be considered an effective
and general route to a wide range of acetamides preparation.

1614
T. I. CHABAN ET AL.
Scheme 3
Scheme 4
1
The structures of the obtained compounds were confirmed by H and 13C NMR
spectroscopy and elemental analysis. All these new compounds gave spectroscopic data
in accordance with the proposed structures. The 1H NMR spectra of all compounds show
the protons signals of methyl groups in pyridine ring as singlets in the δ 2.42–2.57 and
2.61–2.64 ppm. The compound 4 spectrum shows the signal of phenyl radical as two duplets
at 7.53–7.63 and 7.75–7.92 ppm. The N3H proton was not resolved for the compound 2 that
proves the cyanoethylation reaction. The 1H NMR spectrum of the compound 2 hydrolysis
product (3) contains the signal of COOH-group as singlet at 12.47 ppm while its reductive
cleavage product (5) spectrum contains a singlet signal at 4.67 ppm, which indicates the
presence of aminogroup at C6 position of thiazolopyridine ring. However the absence of

SYNTHESIS OF NOVEL THIAZOLOPYRIDINES AS ANTIOXIDANTS
1615
Table 1 Values of absorbance and % inhibition of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridine-2-ones
The compound
or standard
Absorbance of
a sample, As
The compound
or standard
Absorbance
of a sample, As
% Inhibition
% inhibition
Ascorbic acid
1
2
3
4
5
6a
6b
0.580 0.015
0.730 0.030
0.740 0.020
0.720 0.015
0.715 0.025
0.465 0.020
0.480 0.015
0.690 0.025
24.68
5.19
3.90
6.49
7.14
39.61
37.67
10.39
6c
6d
7a
7b
8a
8b
8c
8d
0.685 0.020
0.690 0.020
0.425 0.015
0.720 0.030
0.700 0.025
0.710 0.020
0.699 0.015
0.710 0.020
11.04
10.39
44.81
6.49
9.01
7.80
9.25
8.10
aminogroup signal in compounds 7a,b proves both Schiff bases formation and the reaction
of their acylation. 1H NMR spectra of the compounds 8a–d contain characteristic aromatic
signals, which prove 6-sulfanylacetamido derivatives of 5,7-dimethyl-3Н-thiazolo[4,5-
b]pyridine-2-one formation.
In Vitro Antioxidant Assay
The antioxidant activity was determined on basis of free-radical-scavenging activity
of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical. DPPH radical has found many ap-
plications due to its high stability in a methanolic solution and intense purple color. In its
oxidized form, the DPPH radical has an absorbance maximum centered at a wavelength
about 520 nm. The absorbance decreases when the radical is reduced by antioxidants. Its
reduction affords 2,2-diphenyl-1-picrylhydrazine (DPPH-H), or the corresponding anion
(DPPH−) in basic medium. The DPPH radical acts as a scavenger for other odd-electron
species, which afford para-substitution products at phenyl rings.
The DPPH method is described as a simple, rapid, and convenient method for screen-
ing of many samples for radical-scavenging activity. These advantages make the DPPH
method interesting for testing newly synthesized compounds to scavenge radicals and to
find out promising antioxidant drug candidates.
In the present paper we demonstrate that modified spectrophotometric method makes
use of the DPPH radical and its specific absorbance properties. The free-radical-scavenging
activities of each compound were assayed using a stable DPPH and were quantified by
decolorization the solution being mixed with DHHP at a wavelength of 540 nm. The
absorbance of DPPH solution in ethanol (150 μmoles/L) was measured as 0.770. The
absorbances and free-radical-scavenging activities% inhibitions of standard (ascorbic acid)
and each compound are listed in Table 1.
CONCLUSIONS
A series of novel 5,7-dimethyl-3Н-thiazolo[4,5-b]pyridine-2-one derivatives pos-
sessing antioxidant activity were prepared by the structural modification of the core hetero-
cycle in N3 and C6 positions. Therefore we have shown that the proposed approaches provide
the possibility to design 5,7-dimethyl-3Н-thiazolo[4,5-b]pyridine-2-ones diversity with a
considerable chemical novelty; first identified antioxidant activity among 5,7-dimethyl-
3Н-thiazolo[4,5-b]pyridine-2-ones. When compared with existing antioxidants, some of

1616
T. I. CHABAN ET AL.
our compounds were found to be more potent. Thus the core fused heterocycle may be
considered as a promising scaffold for antioxidant drug candidate development. Further
optimization of the structure to improve their activities is currently in progress.
EXPERIMENTAL
Materials
All chemicals were of analytical grade and commercially available. All reagents and
solvents were used without further purification and drying.
Chemistry
1H and 13C NMR spectra of compounds in DMSO-d6 solution were registered on
a spectrometer Varian Mercury VX-400 (400 MHz), internal reference tetramethylsilane
(TMS). The elemental analysis experimental data on contents of nitrogen and sulfur corre-
spond to the calculated ones ( 0.3%).
5,7-Dimethyl-3H-Thiazolo[4,5-b]Pyridin-2-One (1). Sodium (2.5 g, 109
mmol) was dissolved in anhydrous methanol (125 mL), and to the solution obtained
4-iminothiazolidin-2-one (6.8 g, 50 mmol) and acetylacetone (8 mL) were added at 20◦С.
The mixture was left standing for 5 days with the intermittent stirring, then it was acidified
with acetic acid to рН ∼5, five-fold diluted with water, the precipitate was filtered off,
washed with water, and dried. Compound 1 was obtained as a white crystalline powdered
solid, well soluble in dimethylformamide (DMF), DMSO, solutions of alkali and mineral
acids, sparingly soluble in the other organic solvents.
Yield 74%, melting point (m.p.) = 277–278◦С (ethanol).
1H NMR, δ, ppm: 2.27 s (3H, CH3), 2.40 s (3H, CH3), 6.91 s (1H, Py), 12.44 s (1H,
NH). 13C NMR, δ, ppm: 19.3, 23.3, 118.7, 127.4, 137.4, 139.3 141.4, 168.6. Found%: C,
53.31; H, 4.47; N, 15.54. Calculated for C8H8N2OS%: C, 53.02; H, 4.49; N, 15.44.
3-(5,7-Dimethyl-2-Oxo-Thiazolo[4,5-b]Pyridin-3-yl)-Propionitryl
(2). A
mixture of pyridine (50 mL) and water (10 mL) with acrylonitrile (3 mL) was added
to the compound 1 (10 mmol). The reaction mixture was refluxed 5 h. On cooling the
precipitation was achieved with petroleum ether–water mixture (3:1). The precipitate was
recrystallized from ethanol, filtered off, and dried. This compound was isolated as a white
crystalline powdered solid, well soluble in ethanol, chloroform, dioxane, DMF, and acetic
acid.
Yield 67%, m.p. = 99–100◦С.
1H NMR, δ, ppm: 2.33 s (3H, CH3), 2.48 s (3H, CH3), 3.06 t (2H, CH2), 4.23 t (2H,
CH2), 7.04 s (1H, Py). Found%: C, 56.02; H, 4.89; N, 18.24. Calculated for C11H11N3OS%:
C, 56.63; H, 4.75; N, 18.01.
3-(5,7-Dimethyl-2-Oxo-Thiazolo[4,5-b]Pyridin-3-yl)-Propionic Acid (3).
The mixture of the compound 2 (10 mmol), acetic acid (30 mL), and hydrochloric acid
(15 mL) were placed into the round-bottomed flask. The reaction mixture was refluxed for
3 h and the product was precipitated with water. The mixture was left standing for 24 h at
ambient temperature, and next, the precipitate was filtered off and treated with toluene.
The precipitate was recrystallized from ethanol, filtered off, and dried. This compound
was isolated as a white crystalline powdered solid, well soluble in ethanol, chloroform,
dioxane, DMF, and acetic acid.

SYNTHESIS OF NOVEL THIAZOLOPYRIDINES AS ANTIOXIDANTS
1617
1
Yield 60%, m.p. = 103–104◦С. H NMR, δ, ppm: 2.31 s (3H, CH3), 2.47 s (3H,
CH3), 2.69 t (2H, CH2), 4.17 t (2H, CH2), 7.01 s (1H, Py), 12.47 s (1H, COOH). Found%:
C, 52.02; H, 4.69; N, 11.35. Calculated for C11H12N2O3S%: C, 52.37; H, 4.79; N, 11.10.
5,7-Dimethyl-6-Phenylazo-3Н-Thiazolo[4,5-b]Pyridin-2-One (4). Metallic
sodium (0.2 mol) was dissolved in anhydrous methanol (100 mL), and to the solution
obtained 4-iminothiazolidin-2-one (50 mmol) and α-phenylazoacetylacetone (50 mmol)
were added at 20◦С. The mixture was left standing for 7 days with the intermittent stirring,
then it was acidified with acetic acid to рН ∼5, five-fold diluted with water. The precipitate
was filtered off, washed with water, and dried at 100–110◦С. The precipitate next was
recrystallized from toluene. Compound 4 was obtained as a brick-red crystalline powdered
solid, well soluble in DMF, DMSO, alkalis, and mineral acids solutions, feebly soluble in
benzene, toluene, alcohols, and almost insoluble in water.
Yield 86%, m.p. = 258–259◦С (decomp., toluene).
1H NMR, δ, ppm: 2.42 s (3H, CH3), 2.61 s (3H, CH3), 2.69 t (2H, CH2), 7.59–7.61 m
(3H, C6H5), 7.80 d (2H, J = 8.0 Hz, C6H5), 12.78 s (1H, NH). Found%: C, 58.81; H, 4.32;
N, 19.79. Calculated for C14H12N4OS%: C, 59.14; H, 4.25; N, 19.70.
6-Amino-5,7-Dimethyl-3H-Thiazolo[4,5-b]Pyridin-2-One (5). To a solution
of pyridine (20 mL) and acetic acid (15 mL) compound 2 (1.42 g, 5 mmol) was added. The
mixture was heated to boiling, compound 2 completely dissolved. To the solution obtained
activated zinc powder (2.3 g, 35 mmol) was added at heating in several portions within
1 h, the solution decolorized. Next, it was filtered; the filtrate, cooled to room temperature,
was diluted with 50 mL of water and left standing for 4 h. The separated precipitate was
filtered off, washed with water, and dried. The precipitate was recrystallized from acetic
acid. This compound was isolated as a white crystalline powdered solid, well soluble in
DMF, DMSO, alkalis, and mineral acids solutions, and insoluble in water.
Yield 62%, m.p. = 280–281◦С (decomp.).
1H NMR, δ, ppm: 2.11 s (3H, CH3), 2.83 s (3H, CH3), 4.67 s (2H, NH2), 11.89 s (1H,
NH). 13C NMR, δ, ppm: 16.2, 20.8, 117.0, 124.5, 137.1, 139.0, 140.0, 168.6. Found%: C,
49.25; H, 4.65; N, 21.52. Calculated for C8H9N3OS%: C, 49.21; H, 4.65; N, 21.52.
General Procedure for the Synthesis of 6-Arylidenamino-5,7-Dimethyl-
3Н-Thiazolo[4,5-b]Pyridin-2-Ones (6 a–d). The mixture of the compound 5 (5 mmol)
and the appropriate aromatic aldehyde (5 mmol) was added to acetic acid (15 mL). The
reaction mixture was refluxed 30 min. On cooling the crystalline precipitate was filtered
off, washed with acetic acid, and dried. The obtained compounds were recrystallized from
acetic acid.
6-[(2-thienylmethylene)amino]-5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-
2-one (6a). Yield 72%, m.p. = 275–276◦С (decomp.).
1H NMR, δ, ppm: 2.13 s (3H, CH3), 2.29 s (3H, CH3), 7.24 s (1H, thiophene), 7.67 s
(1H, thiophene), 7.98 d (2H, J = 4.4 Hz, thiophene), 8.54 s (1H, CH), 12.09 s (1H, NH).
13C NMR, δ, ppm: 16.2, 20.8, 117.0, 124.5, 125.0, 131.0, 134.8, 137.2, 139.0, 165.7, 168.6.
Found%: C, 53.75; H, 3.73; N, 14.65. Calculated for C13H11N3OS2%: C, 53.96; H,
3.83; N, 14.52.
6-[(4-chlorobenzylidene)amino]-5,7-dimethyl-3H- thiazolo[4,5-b]pyridin-
2-one (6b). Yield 68%, m.p. = 290–291◦С (decomp.).
1H NMR, δ, ppm: 2.12 s (3H, CH3), 2.28 s (3H, CH3), 7.61 d (2H, J = 6.5 Hz, aryl),
7.98 d (2H, J = 6.5 Hz, aryl), 8.46 s (1H, CH), 12.40 s (1H, NH). 13C NMR, δ, ppm: 16.7,
21.1, 129.6, 130.7, 131.4, 134.9, 137.1, 164.9, 168.9. Found%: C, 56.75; H, 3.73; N, 13.40.
Calculated for C15H12ClN3OS%: C, 56.69; H, 3.81; N, 13.22.

1618
T. I. CHABAN ET AL.
6-[(4-bromobenzylidene)amino]-5,7-dimethyl-3H- thiazolo[4,5-b]pyridin
1
-2-one (6c). Yield 55%, m.p. = 270–271◦С (decomp.). H NMR, δ, ppm: 2.13 s (3H,
CH3), 2.19 s (3H, CH3), 7.77 d (2H, J = 8.2 Hz, aryl), 7.91 d (2H, J = 8.3 Hz, aryl),
8.45 s (1H, CH), 12.38 s (1H, NH). Found%: C, 49.55; H, 3.30; N, 11.40. Calculated for
C15H12BrN3OS%: C, 49.74; H, 3.34; N, 11.60.
6-[(2-hydroxybenzylidene)amino]-5,7-dimethyl-3H-thiazolo[4,5-b]pyrid
in-2-one (6d). Yield 68%, m.p. = 252–253◦С.
1H NMR, δ, ppm: 2.18 s (3H, CH3), 2.35 s (3H, CH3), 7.01–7.03 t (2H, aryl), 7.47 t
(1H, J = 8.2 Hz, aryl), 7.66 d (1H, J = 7.8 Hz, aryl), 8.69 s (1H, CH), 12.47 s (1H, OH),
12.58 s (1H, NH). 13C NMR, δ, ppm: 17.1, 21.3, 117.2, 118.4, 119.6, 119.7, 131.9, 132.7,
134.1, 139.5, 145.1, 160.6, 168.9, 169.6. Found%: C, 59.75; H, 4.52; N, 14.24. Calculated
for C15H13N3O2S%: C, 60.19; H, 4.38; N, 14.04.
General Procedure for the Synthesis of 6-Acylamino-5,7-Dimethyl-3Н-
Thiazolo[4,5-b]Pyridin-2-Ones (7a,b). The compound 5 (5 mmol), an appropriate
aliphatic chloroanhydride (5 mmol), and triethylamine (5 mmol) were added to dioxane
(20 mL). The reaction mixture was refluxed 15 min. On cooling the crystalline precipitate
was filtered off, washed with methanol and dried. The obtained compounds were re-
crystallized from methanol.
N-(5,7-dimethyl-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-b]pyridin-6-yl)aceta
mide (7a). Yield 60%, m.p. = 150–151◦С.
1H NMR, δ, ppm: 2.07 s (3H, COCH3), 2.14 s (3H, CH3), 2.32 s (3H, CH3), 9.46 s
(1H, NH), 12.41 s (1H, NH). 13C NMR, δ, ppm: 16.5, 20.9, 40.3, 117.3, 130.8, 129.6,
143.0, 143.1, 166.6. Found%: C, 50.35; H, 4.72; N, 17.85. Calculated for C10H11N3O2S%:
C, 50.62; H, 4.67; N, 17.71.
2-chloro-N-(5,7-dimethyl-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-b]pyridin-
1
6-yl) acetamide (7b). Yield 65%, m.p. = 135–136◦С. H NMR, δ, ppm: 2.15 s (3H,
CH3), 2.33 s (3H, CH3), 4.32 s (2H, CH2), 9.86 s (1H, NH), 12.43 s (1H, NH). 13C NMR,
δ, ppm: 16.8, 21.0, 66.8, 116.6, 126.2, 139.7, 147.5, 152.7, 166.0, 169.0. Found%: C,
44.70; H, 3.80; N, 15.70. Calculated for C10H10ClN3O2S%: C, 44.20; H, 3.71; N, 15.46.
General Procedure for the Synthesis of 6-Sulfanylacetamido-5,7-
Dimethyl-3Н-Thiazolo[4,5-b]Pyridine-2-Ones (8a–d). The compound 7b (5 mmol)
and the appropriate thiol (5 mmol) were added to anhydrous methanol (20 mL). The
reaction mixture was refluxed 1 h. On cooling the crystalline precipitate was filtered off,
washed with methanol, and dried. The obtained compounds were recrystallized from
methanol.
2-{[4-amino-5-(4-methyl-4,5-dihydrofuran-3-yl)-1,2,4-triazolidin-3-yl]th
io}-N-(5,7-dimethyl-2-oxo-2,3-dihydro[1,3]thiazolo[4,5-b]pyridin-6-yl) acetam
ide (8a). Yield 70%, m.p. = 150–151◦С.
1H NMR, δ, ppm: 2.13 s (3H, CH3), 2.29 s (3H, CH3), 2.51 s (3H, CH3), 4.17 s (2H,
CH2), 6.09 s (2H, NH2), 7.05 s (1H, aryl), 7.68 s (1H, aryl), 9.87 s (1H, NH), 12.51 s (1H,
NH). 13C NMR, δ, ppm: 11.2, 16.9, 21.0, 35.0, 114.8, 116.5, 123.0, 126.7, 137.8, 139.8,
144.3, 147.9, 148.5, 152.8, 167.2, 169.1. Found%: C, 47.41; H, 3.85; N, 22.60. Calculated
for C17H17N7O3S2%: C, 47.32; H, 3.97; N, 22.72.
2-(2,3-Dihydro-1,3-benzothiazol-2-yl thio)–N-(5,7-dimethyl-2-oxo-2,3-dih
ydro [1,3] thiazolo[4,5-b pyridin-6-yl) acetamide (8b). Yield 66%, m.p. =
172–173◦С. 1H NMR, δ, ppm: 2.16 s (3H, CH3), 2.33 s (3H, CH3), 4.42 s (2H, CH2), 7.39
t (1H, aryl), 7.50 t (1H, aryl), 7.84 d (1H, aryl), 8.04 d (1H, aryl), 9.95 s (1H, NH), 12.45 s

SYNTHESIS OF NOVEL THIAZOLOPYRIDINES AS ANTIOXIDANTS
1619
(1H, NH). 13C NMR, δ, ppm: 16.9, 21.1, 36.9, 119.3, 121.5, 122.4, 125.1, 126.7, 126.9,
135.3, 139.8, 153.0, 166.4, 166.4, 169.1. Found%: C, 50.71; H, 3.88; N, 13.70. Calculated
for C17H16N4O2S3%: C, 50.48; H, 3.99; N, 13.85.
N-(5,7-Dimethyl-2-oxo-2,3-dihydro-thiazolo[4,5-b]pyridin-6-yl)-2-(5-phe
nyl-[1,3,4] oxadiazol-2-ylsulfanyl) acetamide (8c). Yield 80%, m.p. = 184–185◦С.
1H NMR, δ, ppm: 2.23 s (3H, CH3), 2.37 s (3H, CH3), 4.48 s (2H, CH2), 7.49 s (2H, aryl),
7.55 s (1H, aryl), 7.83 s (2H, aryl), 10.89 s (1H, NH), 12.70 s (1H, NH). 13C NMR, δ, ppm:
16.8, 21.0, 43.1, 123.0, 126.6, 130.0, 132.8, 139.7, 162.0, 166.0, 169.1, 177.9. Found%:
C, 52.40; H, 3.73; N, 16.68. Calculated for C18H15N5O3S2%: C, 52.29; H, 3.66; N, 16.94.
N-(5,7-Dimethyl-2-oxo-2,3-dihydro-thiazolo[4,5-b]pyridin-6-yl)-2-[1-(4-
methyl-1-vinyl-penta-1,3-dienyl)-1H-tetrazol-5-ylsulfanyl]-acetamide (8d).
1
Yield 75%, m.p. = 179–180◦С. H NMR, δ, ppm: 2.06 s (3H, aryl-CH3), 2.40 s (3H,
CH3), 2.48 s (3H, CH3), 3.39 s (2H, CH2), 7.52 d (2H, J = 8.8 Hz, aryl), 7.65 d (2H, J =
8.8 Hz, aryl), 10.04 s (1H, NH), 14.29 s (1H, NH). 13C NMR, δ, ppm: 16.9, 21.0, 21.2,
36.8, 107.4, 121.9, 125.2, 126.5, 130.4, 131.8, 133.5, 139.7, 140.5, 148.0, 154.4, 165.9,
169.0. Found%: C, 50.60; H, 4.08; N, 22.73. Calculated for C18H17N7O2S2%: C, 50.57;
H, 4.01; N, 22.93.
Free Radical Scavenging Assays
The antioxidant activity was determined on basis of free-radical-scavenging activity
of stable DPPH. The effect of the studied compounds on DPPH radicals were estimated
according to the method of Blois21,22 with minor modifications. The solution of DPPH in
ethanol with the concentration of 150 μmoles/L (4 mL) was mixed with the compound or
control solution in ethanol, its concentration been 250 μmoles/L (0.2 mL). The reaction
mixture was vortex mixed thoroughly and incubated at room temperature in the dark for
60 min. Simultaneously a control was prepared as ascorbic acid solution in ethanol (0.2 mL)
mixed with DPPH solution in ethanol (4 mL) without sample fraction. Reduction in the
absorbance of the mixture was measured at 540 nm using ethanol as blank. Ascorbic acid
was used as a standard. Also the absorbance of DPPH solution was measured. Percentage of
free-radical-scavenging activity was expressed as percent inhibition and it was calculated
using the following formula:
ADPPH − AC
% Inhibition =
× 100 %
ADPPH
where ADPPH is the absorbance of DPPH free radicals solution, Ac is the absorbance of a
sample.
Each experiment was performed in triplicate and average values were recorded.
Results are expressed as the means S.D.
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