Synthesis and cytotoxicity of new 2-oxo-7-phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid amides

Article abstract of DOI:10.1080/10426507.2019.1633318

The synthesis and anticancer activity evaluation of new thiazolo[4,5-b]pyridine-5-carboxylic acid amides is described. The structures of the synthesized compounds were confirmed by spectroscopic data and a single crystal X-ray diffraction analysis for 2.4

Full text of DOI:10.1080/10426507.2019.1633318

Phosphorus, Sulfur, and Silicon and the Related Elements
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Synthesis and cytotoxicity of new 2-oxo-7-
phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-
carboxylic acid amides
Andrii Lozynskyi, Borys Zimenkovsky, Iryna Ivasechko, Julia Senkiv, Andrzej
Gzella, Olexandr Karpenko, Rostyslav Stoika & Roman Lesyk
To cite this article: Andrii Lozynskyi, Borys Zimenkovsky, Iryna Ivasechko, Julia Senkiv, Andrzej
Gzella, Olexandr Karpenko, Rostyslav Stoika & Roman Lesyk (2019): Synthesis and cytotoxicity
of new 2-oxo-7-phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid amides, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2019.1633318
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1633318
Synthesis and cytotoxicity of new 2-oxo-7-phenyl-2,3-dihydrothiazolo[4,5-b]
pyridine-5-carboxylic acid amides
a
a
b
b
c
d
Andrii Lozynskyib , Borys Zimenkovsky , Iryna Ivasechko , Julia Senkiv , Andrzej Gzella , Olexandr Karpenko ,
a
Rostyslav Stoika , and Roman Lesyk
a
b
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine; Institute
c
of Cell Biology NAS of Ukraine, Lviv, Ukraine; Department of Organic Chemistry, Poznan University of Medical Sciences, Poznan, Poland;
d
Enamine Ltd, Kiev, Ukraine
ABSTRACT
ARTICLE HISTORY
The synthesis and anticancer activity evaluation of new thiazolo[4,5-b]pyridine-5-carboxylic acid
amides is described. The structures of the synthesized compounds were confirmed by spectro-
scopic data and a single crystal X-ray diffraction analysis for 2.4. The synthesized compounds were
screened for their in vitro anticancer activity according to US NCI protocols. The most active 7-(4-
fluorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4-chlorophenyl)amide 2.2
and 7-(4-chlorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4-chlorophenyl)a-
mide 2.5 were screened for their cytotoxicity effects on C6 Rat glioma cells and U373 Human glio-
blastoma astrocytoma cells which revealed promising results comparable to temozolamide as
reference control according MTT assay data.
Received 19 January 2019
Accepted 14 June 2019
KEYWORDS
2
-oxo-4-phenyl-but-3-enoic
acids; thiazolo[4,5-b]pyridin-
(3H)-one; X-ray study;
anticancer activity; cell lines
2
GRAPHICAL ABSTRACT
Introduction
received considerable attention recently due to their diverse
biological activity and clinical applications. Many literature
The development of synthetic organic chemistry is often
best expressed in the synthesis of biologically significant
molecules. Thus, among biologically relevant molecules there
is interest in the pyridine heterocyclic framework, which
represents a privileged structural motif found in a number
of natural compounds many of which displaying activities
against a diverse set of biological targets.
polycyclic pyridine architectures including five and six- protease factor Xa (fXa)
membered sulfur and nitrogen heterocycles are important tyrosine kinases (EGFR) proteins of number of
[
6]
reports of these compounds indicate antioxidant,
anti-
antifun-
Furthermore,
some thiazolopyridine derivatives were found as efficient
[
7,8]
[9]
[10]
cancer,
anti-inflammatory,
antimicrobial,
[
9]
[11]
gal and herbicidal activities (Figure 1).
[
12]
antagonists of metabotropic glutamate (mGluR5),
H3
[
1,2]
[13,14]
[15]
For instance, receptors,
inhibitors of the cAMP PDE III,
serine
[
16]
and cellular trans-membrane
[
17]
structural components of bioactive molecules, and as a human tumors.
result, they serve as attractive targets in the modern drug
Earlier we reported the [3 þ 3]-cyclization of 4-amino-
[
3–5]
discovery process.
Bicyclic heterocycles, with condensed 5H-thiazol-2-one and A,b-unsaturated ketones or A-ketoa-
thiazole and pyridine moieties, the thiazolopyridines have cids providing series of thiazolo[4,5-b]pyridin-2(3H)-one
CONTACT Roman Lesyk
dr_r_lesyk@org.lviv.net;
roman.lesyk@gmail.com
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo
Halytsky Lviv National Medical University, 69 Pekarska, Lviv, 79010, Ukraine.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1633318.
ß 2019 Taylor & Francis Group, LLC

2
A. LOZYNSKYI ET AL.
O
H
N
N
R
N
O
H N
O
2
H
N
O
N
N
S
N
H
O
O
Ar
S
S
2
.1 Ar = 4-F-C H , 80%
R
6
4
Ar
Ar
O
2.2 Ar = 4-F-C
2.3 Ar = 4-MeO-C H , R = Me, 75%
6 4
H , R = Cl, 80%
H N
2
a
6
4
c
O
2
.4 Ar = 4-MeO-C H , R = Br, 78%
N
H
6 4
HOOC
O
c
2.5 Ar = 4-Cl-C H , R =Cl, 70%
6 4
O
H
OH
N
O
N
H N
H
N
HO
SOCl2
2
HO
N
H
N
O
N
N
H
Cl
O
S
b
O
c
S
S
1.1-1.3 Ar 1.1 Ar = 4-F-C H
6 4
Ar
1
1
.2 Ar = 4-MeO-C H
Ar
6
4
.3 Ar = 4-Cl-C H
2.6 Ar = 4-Cl-C H , 64%
6 4
6
4
Scheme 1. Synthesis of 2-oxo-7-phenyl-2,3-dihydro-thiazolo[4,5-b]pyridine-5-carboxylic acid amides. Reagents, conditions and yields: (a) arylidene pyruvic acids
(
2
APAs) (1.0 equiv), AcOH, reflux 1 h, (Ref. [7]); (b) SOCl reflux 0.5 h; (c) appropriate amine (1.0 equiv), TEA (1.0 equiv), dioxane, 64–80%.
H
N
H
N
O
Me
N
O
CO CH
N
2
3
S
S
CF3
N
N
S
MeO
N
O
Cl
cAMP PDE III Inhibitor
Herbicidal Activity
Singh B. et al. 1994
OMe
Hegde S.G. et al., 1993
Anticancer activity
N
N
S
Lozynskyi A. et al., 2018
H
N
Me
H
N
Me
H N
N
NC
N
N
S
O
Cl
NH
N
N
HO
S
2
N
O
Me
F
O
O
Antimicrobial activity
Antioxidant activity
EGFR tyrosine kinase inhibitor
Leysen D.C. et al., 1984
Chaban T. et al., 2013
Lin R. et al., 2009
Figure 1. Structures of biologically active thiazolopyridine derivatives.
derivatives and futher their evaluation of biological activities obtained derivatives were utilized in the [3 þ 3]-cyclocon-
effects on human hepatocellular carcinoma (HepG2) cell line densation reaction with 4-amino-5H-thiazol-2-one in glacial
[
7]
and mouse fibroblasts (Balb/c 3T3 clone A31) cell lines.
acetic acid, providing 2-oxo-7-phenyl-2,3-dihydrothia-
As a consequence, as continuation of our work we decided zolo[4,5-b]pyridine-5-carboxylic acids. The compound series,
to synthesize amides based on previous described 2-oxo-7- which contain N-arylamide fragment in position 5 of thia-
phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acids. zolo[4,5-b]pyridine core, were synthesized in order to inves-
Also, we have studied the biological activities of the newly tigate the influence of the substituent nature on the
synthesized compounds for their anticancer properties antitumor activity realization. The target thiazolo[4,5-b]pyri-
according to the DTP NCI protocol and cytotoxicity effects dine-5-carboxylic acid amides were synthesized from 2-oxo-
on several cancer cell lines, which subsequently would allow 7-phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic
the identification a number of highly active and low toxic acids, which were transformed into acid chlorides and used
agents with promising anticancer activity.
in the acylation reaction of respective amines.
The characterization data of the synthesized thiazolo[4,5-
b]pyridine-5-carboxylic acid amides are presented in experi-
mental part. Analytical and spectral data ( H and C NMR)
Results and discussion
1
13
The general methods for synthesis of target thiazolo[4,5- confirmed the structure of the synthesized compounds. In
1
b]pyridin-2(3H)-one derivatives 2.1–2.6 are depicted in the H NMR spectra the NH proton of the thiazole cycle
Scheme 1.
shows a broad singlet at d 12.05–13.21 and the NH protons
The starting 2-oxo-4-phenyl-but-3-enoic acids were syn- of the amide group have been found as a singlet at d
thesized using known methods from appropriate aromatic 8.47–10.44. The CH protons of the pyridine ring appear as a
[
18]
aldehydes and pyruvic acid in methanol medium.
The singlet at d 7.48–7.94 ppm. The structure of 2.4 was also

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
[
19]
confirmed by X-ray diffraction analysis (Figure 2).
Its
The planar system comprising C9, O10 and N11 atoms
molecular structure and the atom-labelling scheme are pre- belonging to N-(4-bromophenyl)-5-carboxamide molecular
sented in Figure 2.
fragment forms with the mean plane of 2-oxo-2,3-dihy-
ꢀ
Structural studies performed for 7-(4-methoxyphenyl)-2- dro[4,5-b]pyridine system the dihedral angle of 9.6(3) . The
oxo-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4- spatial arrangement of the mentioned atom-system is also
bromophenyl)amide (2.4) revealed that 2-oxo-2,3-dihydro- defined by the torsion angle N4–C5–C9–N11 of 7.7(2)
ꢀ
thiazolo[4,5-b]pyridine moiety, a central fragment of the which reveals that C4–C5 and C9–N11 bonds are
molecule, is almost planar (r.m.s. ¼ 0.0244 Å) (Supplemental synperiplanar.
materials Table S1). Its mean plane forms with two phenyl
In the crystal lattice the molecules are connected with
i
ii
rings (C12 – C17) and (C19 – C24) belonging to N-(4-bro- N3–H3ꢁꢁꢁO10 and N11–H11ꢁꢁꢁO8 hydrogen bonds into
mophenyl)-5-carboxamide and 7-(4-methoxyphenyl) resi- layers parallel to bc plane. The thickness of the layer is simi-
ꢀ
dues the dihedral angles of 18.73(7) and 41.99(5) , lar to the value of parameter a. The connection between the
respectively.
molecules located within the layer is strengthened by the
ii
iii
weak hydrogen bonds C13–H13ꢁꢁꢁO8 and C21–H21ꢁꢁꢁS1
(Supplemental materials Table S2, Figure 3).
It is worth noting that the geometry of 2-oxo-2,3-dihy-
drothiazolo[4,5-b]pyridine molecule fragment in 2.4 is close
to that observed for 2-oxo-7-phenyl-2,3-dihydrothiazolo[4,5-
[
7]
b]pyridine-5-carboxylic acid in our previous report. In the
crystal structure, the asymmetric unit of this compound is
composed of a molecular complex consisting of one dime-
thylamine and two symmetry-independent molecules of 2-
oxo-7-phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic
acid. The first one forms the ammonium cation as a result
of the proton transfer from the carboxyl group of one of the
two 2-oxo-2,3-dihydrothiazolo[4,5-b]pyridine molecules.
In the electrically neutral molecule of 2-oxo-7-phenyl-2,3-
dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid bonds,
C11–O12 and C11–O13 have length values of 1.304(3) and
1
.216(3) A˚ while in the negatively charged molecule they
have values of 1.272(3) and 1.235(3) A˚, respectively.
The biological activity of thiazolopyridines was observed
in our previous studies of 2-oxo-7-aryl-2,3-dihydrothia-
zolo[4,5-b]pyridine-5-carboxylic acids as possible anticancer
agents. Although these compounds possess slight in vitro
Figure 2. ORTEP view of 2.4 showing displacement ellipsoids at the 30% prob-
ability level. H atoms are shown as spheres of arbitrary radii.
Figure 3. The hydrogen-bonding in the crystal structure of 2.4. For symmetry codes, see Table S2. H atoms not involved in hydrogen-bonding have been omitted
for clarity.

4
A. LOZYNSKYI ET AL.
Table 1. Anticancer screening data in concentration 10.00 lM.
6
0 cell lines assay in 1 dose 10.00 lM conc.
Mean
growth, %
Range of
growth, %
The most sensitive
cell lines
Growth % of the most
sensitive cell lines
Comp. NSC
2
.1 797454
96.72
75.80 to 115.70
NCI-H522 (Non-small cell lung cancer)
PC-3 (Prostate cancer)
75.82
75.80
2
.2 797462
7.71
ꢂ86.10 to 72.22
HL-60(TB) (Leukemia)
HOP-92 (Non-small cell lung cancer)
SF-539 (CNS cancer)
SNB-75 (CNS cancer)
ꢂ30.55
ꢂ24.25
ꢂ4.01
ꢂ5.08
ꢂ86.10
ꢂ8.82
ꢂ0.62
ꢂ12.74
ꢂ13.14
ꢂ8.30
24.25
SK-MEL-5 (Melanoma)
UACC-257 (Melanoma)
OVCAR-4 (Ovarian cancer)
CAKI-1 (Renal cancer)
BT-549 (Breast cancer)
MDA-MB-468 (Breast cancer)
NCI-H522 (Non-small cell lung cancer)
SK-MEL-2 (Melanoma)
SK-MEL-5 (Melanoma)
UACC-62 (Melanoma)
A498 (Renal cancer)
RPMI-8226 (Leukemia)
2
2
.3 789584
.4 789585
68.26
36.54
9.83 to 102.28
29.18
37.21
31.25
9.83
ꢂ9.13 to 84.94
14.18
NCI-H522 (Non-small cell lung cancer)
SK-MEL-2 (Melanoma)
SK-MEL-5 (Melanoma)
ꢂ9.13
ꢂ5.01
8.56
UACC-62 (Melanoma)
8.05
A498 (Renal cancer)
T-47D (Breast cancer)
HL-60(TB) (Leukemia)
K-562 (Leukemia)
MOLT-4 (Leukemia)
RPMI-8226 (Leukemia)
HOP-62 (Non-small cell lung cancer)
NCI-H460 (Non-small cell lung cancer)
NCI-H522 (Non-small cell lung cancer)
COLO 205 (Colon cancer)
HT29 (Colon cancer)
SF-29 (CNS cancer)
MALME-3M (Melanoma)
SK-MEL-2 (Melanoma)
SK-MEL-5 (Melanoma)
UACC-257 (Melanoma)
UACC-62 (Melanoma)
SK-OV-3 (Ovarian cancer)
A498 (Renal cancer)
SN12C (Renal cancer)
UO-31 (Renal cancer)
ꢂ2.87
ꢂ0.89
ꢂ53.72
ꢂ12.81
ꢂ24.22
ꢂ6.18
ꢂ19.01
ꢂ5.14
ꢂ26.29
ꢂ52.11
ꢂ24.05
ꢂ12.48
ꢂ13.80
ꢂ29.35
ꢂ19.62
ꢂ24.94
ꢂ14.73
ꢂ24.27
ꢂ43.80
ꢂ9.70
ꢂ5.54
ꢂ13.47
ꢂ30.91
ꢂ14.42
ꢂ22.78
ꢂ3.42
2
.5 789575
ꢂ3.85
ꢂ53.72 to 32.04
PC-3 (Prostate cancer)
MDA-MB-231/ATCC (Breast cancer)
HS 578T (Breast cancer)
T-47D (Breast cancer)
MDA-MB-468 (Breast cancer)
cytostatic effect (GPmean ¼ 88.57-100.81%), they had a good
The most active compounds of 7-(4-fluorophenyl)-2-oxo-
ability for structural modification in position 5 of thiazolo- 2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4-
pyridine[7]core which significantly enhanced anticancer chlorophenyl)amide (2.2) and 7-(4-chlorophenyl)-2-oxo-2,3-
potency. Thus, the synthesized 2-oxo-7-phenyl-2,3-dihy- dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4-chloro-
drothiazolo[4,5-b]pyridine-5-carboxylic acid amides 2.1–2.5 phenyl)amide (2.5) were found to be effective with the aver-
were submitted and evaluated at the single concentration of age cell growth indices (GPmean) of 7.71 and -3.85%,
ꢂ5
1
0
M towards panel of approximately sixty cancer cell respectively. Thus, compound 2.2 demonstrated high cyto-
lines. The human tumor cell lines were derived from nine toxic effect on melanoma cell line SK-MEL-5 (GP ¼ -86.10%),
different cancer types: leukemia, melanoma, lung, colon, leukemia HL-60(TB) (GP¼ ꢂ30.55%) and Non-Small Cell
CNS, ovarian, renal, prostate, and breast cancers. Primary Lung Cancer line HOP-92 (GP¼ ꢂ24.92%). Compound 2.5
anticancer assays were performed according to the US NCI was found to be effective against leukemia HL-60(TB)
protocol, which was described elsewhere (see e.g. http://dtp. (GP ¼ ꢂ53.72%), colon cancer COLO 205 (GP ¼ ꢂ52.11%)
[
20–22]
nci.nih.gov).
The results of primary screening are and Non-small cell lung cancer NCI-H522 (GP ¼ ꢂ26.29%)
reported as the percent cancer cell line growth (GP%) and cell lines.
presented in Table 1. The range of growth % shows the low-
Finally, compounds 2.2 and 2.5 possessed considerable
est and the highest growth % found among different cancer activity against all tested human tumor cell lines and were
cell lines.
selected in advanced assay against a panel of approximately

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
sixty tumor cell lines at 10-fold dilutions of five concentra-
tions (100 lM, 10 lM, 1 lM, 0.1 lM and 0.01 lM).
The SAR study revealed that the anticancer potency of
synthesized 2-oxo-7-phenyl-2,3-dihydro-thiazolo[4,5-b]pyri-
[
20–22]
The percentage of growth was evaluated spectrophotometric- dine-5-carboxylic acid amides is sensitive to the nature of
ally versus controls that were not treated with test agents. N-arylamide fragment in position 5 of thiazolopyridine core.
The 48 h continuous drug exposure protocol followed and In our previous report we revealed that the presence of car-
SRB (sulforodamine B) protein assay was used to estimate boxylic group in position 7 of thiazolo[4,5-b]pyridine core is
cell viability or growth. Based on the cytotoxicity assays, unfavorable for anticancer potency and established slight
three antitumor activity dose-response parameters were cal- cytotoxicity among 2-oxo-7-phenyl-2,3-dihydro-thiazolo[4,5-
culated for experimental agents against each cell line: GI50
–
b]pyridine-5-carboxylic acids. Thus, among these derivatives
molar concentration of the compound that inhibits 50% net was identified only 7-(4-fluorophenyl)-2-oxo-2,3-dihydro-
cell growth; TGI – molar concentration of the compound thiazolo[4,5-b]pyridine-5-carboxylic acid with moderate
activity on non-small cell lung cancer NCI-H522 cell line
leading to total inhibition; and LC50 - molar concentration
of the compound leading to 50% net cell death.
Furthermore, mean graph midpoints (MG_MID) were calcu-
lated for each of the parameters, giving an average activity
parameter over all cell lines for tested compounds. For the
calculation of the MG_MID the insensitive cell lines were
included with the highest tested concentration
[
7]
(
GP ¼ 62.31%). Whereas, 2-oxo-7-phenyl-2,3-dihydro-thia-
zolo[4,5-b]pyridine-5-carboxylic acid amides with electron-
withdrawing groups (Cl > Br > CH ) in N-arylamide frag-
3
ment exhibit higher anticancer activity. However, empirical
study revealed that the presence of morpholinylamide frag-
ment in thiazolo[4,5-b]pyridine core is unfavorable for anti-
cancer potency. This statement about critical influence of
different substituents is also observed in previous systematic
studies of thiazolo[4,5-b]pyridine-2(3H)-one derivatives
based on a,b-unsaturated ketones and 1,3-diketones as pos-
These compounds showed a broad spectrum of growth
inhibition activity against all human tumor cells with aver-
age GI /TGI values 1.57/7.31 lM (2.2) and 2.01/15.71 lM
5
0
(2.5), respectively (Table 2). The selectivity index (SI)
[
7,8]
sible anticancer agents.
obtained by dividing the full panel MG-MID (lM) of the
compounds 2.2 and 2.5 by their individual subpanel MG-
MID of cell line (lM) was considered as a measure of com-
pound’s selectivity. The active compounds 2.2 and 2.5 in
the present study were found to be nonselective at both the
GI50 and TGI levels (selectivity indexes 2.17–7.85/0.54–7.77
The cytotoxicity of 2-oxo-7-phenyl-2,3-dihydrothia-
zolo[4,5-b]pyridine-5-carboxylic acid amides were deter-
mined against C6 Rat glioma cells and U373 Human
glioblastoma astrocytoma cell cell line on the example of the
most active compounds 2.2 and 2.5 using the MTT assay.
The tested compounds were added to cultured cells in dif-
ferent final concentrations (0–100 lM), and then the cells
were treated for 72 h (Figure 4). The IC50 was calculated
and used while comparing the values of the cytotoxic effect.
Thus, the MTT cytotoxicity assay shown that the com-
pounds 2.2 and 2.5 have antineoplastic effect and reduce
cell viability of C6 Rat glioma cells and U373 Human glio-
blastoma astrocytoma cells. These compounds had stronger
cytotoxic effect than Temozolomide, which is used in glio-
blastoma treatment. IC50 of these compounds during 72 h
incubation are 56,2mM, 22,3mM for C6 and 32,2 and
(2.2)
and
2.95–5.00/2.87–5.25
(2.5),
respectively)
(Supplemental materials Table S4). However, the mentioned
derivative demonstrated a certain selectivity profile toward
some individual cell line at TGI level. Thus, selectivity
indexes of 2.2 were 3.15–7.77 for RPMI-8226 (Leukemia),
HOP-92 (NCS lung cancer), SK-MEL-2 and UACC-62
(Melanoma). At the same time, compound 2.5 at TGI level
moderate selectivity was observed for Non-Small Cell Lung
Cancer cell lines NCI-H522 (SI ¼ 5.03), HOP-92 (SI ¼ 3.98),
Colon cancer cell line COLO 205 (SI ¼ 4.43), CNS cancer
cell line SF-295 (SI ¼ 3.59), Melanoma cell lines SK-MEL-2
5
9,5 mM for 2.2 and 2.5 respectively. IC50 for TMZ is higher
(
SI ¼ 3.93), SK-MEL-5 (SI ¼ 5.25) and Renal cancer cell line
than 190 mM.
A498 (SI ¼ 4.59).
NCI’s COMPARE algorithm (see e.g. http://dtp.nci.nih.
[
23,24]
gov)
allows to assume biochemical mechanisms of
Experimental
action of novel compounds on the basis of their in-vitro
activity profiles compared to standard agents. We performed
COMPARE computations for synthesized highly active com-
pound 2.5 against the NCI ‘‘Standard Agents’’ database at
the GI50 and TGI levels (Table 3). However, obtained
Chemistry
The starting 2-oxo-4-phenyl-but-3-enoic acids and 2-oxo-7-
phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acids
1.1–1.3 were obtained according to the methods described
Pearson correlation coefficients (PCC) did not allow to dis- previously.[
7]
tinguish cytotoxicity mechanism of tested compounds with
Melting points were measured in open capillary tubes
high probability. The compound 2.5 showed the highest cor- and were uncorrected. The elemental analyses were per-
1
relation at the TGI level with alkylating agent formed using the Perkin–Elmer 2400 CHN analyzer. The H
1
3
1
Cyanomorpholino-ADR (PCC ¼ 0.606) and inhibitor of and C NMR spectra were recorded on Varian Gemini ( H
13
RNA
synthesis
Morpholino-ADR
(PCC ¼ 0.576). at 400 and C at 100 MHz) instrument in DMSO-d6.
Interestingly, significant correlations of compound 2.5 have Chemical shifts are reported in ppm units with use of d
been found at GI50 level with Bryostatin 1 (modulator of scale. Mass spectra were obtained using electrospray (ES)
protein kinase C) in the COMPARE test.
ionization techniques on an Agilent 1100 Series LCMS. The

6
A. LOZYNSKYI ET AL.
Table 2. Influence of compounds 2.2 and 2.5 on the Growth of Individual Tumor Cell Lines.
GI50, lM
TGI, lM
LC50, lM
Disease
Cell line
2.2
2.5
2.2
2.5
2.2
2.5
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
MG_MID
A549/ATCC
EKVX
0.65
–
2.50
1.27
1.27
2.52
1.21
3.63
2.06
2.49
1.63
2.58
0.52
2.26
1.24
2.81
2.19
0.40
1.79
1.63
2.17
2.40
1.27
2.13
1.58
2.90
2.01
2.56
1.56
2.43
3.64
1.70
1.88
2.29
2.88
2.31
2.75
2.70
1.18
1.57
0.68
1.19
1.04
1.81
2.83
2.32
2.02
3.41
2.04
1.98
2.08
2.38
2.64
0.47
2.27
1.95
2.77
2.12
–
9.90
–
40.3
6.68
>100.0
11.8
14.2
>100.0
45.49
12.7
11.7
8.85
3.94
9.18
6.85
9.72
12.6
3.12
8.74
3.54
14.5
10.8
9.54
6.29
10.3
15.2
10.02
22.3
4.37
11.6
>100.0
8.03
11.8
26.35
10.6
6.25
10.3
11.2
3.99
17.8
2.99
4.69
4.91
8.08
28.9
7.45
9.98
29.3
12.8
7.61
7.47
14.78
20.6
3.42
8.89
13.1
7.42
20.1
–
81.9
–
81.5
32.3
33.1
56.2
57.0
69.2
>100.0
30.5
4.64
22.8
55.0
>100.0
16.7
>100.0
54.42
8.26
51.2
6.14
44.1
59.7
48.4
>100.0
45.40
>100.0
18.5
28.7
93.2
36.0
23.5
49.98
17.8
>100.0
68.7
>100.0
9.71
>100.0
7.10
>100.0
21.9
58.35
69.2
58.0
>100.0
>100.0
44.3
>100.0
24.2
70.81
6.01
41.2
9.52
14.4
9.41
>100.0
19.5
9.37
26.17
>100.0
>100.0
>100
>100.0
20.0
>100.0
>100.0
>100.0
>100.0
>100.0
>100.0
>100
>100.0
>100.0
80.6
0.58
0.72
0.39
0.67
0.60
2.45
1.64
2.04
0.20
1.11
1.19
2.11
1.73
0.47
1.43
1.76
2.25
1.43
1.73
3.02
1.81
3.01
2.14
2.59
1.10
2.07
2.73
2.02
1.50
2.00
1.68
1.70
1.88
3.01
1.59
1.39
0.49
1.11
0.36
1.46
1.78
0.94
1.99
2.34
1.72
2.32
1.57
1.80
1.35
0.46
1.69
2.15
1.70
1.99
1.88
1.61
1.60
0.65
3.70
2.17
1.31
1.77
2.13
1.73
0.73
0.68
1.39
1.57
10.9
4.02
2.22
10.5
7.50
10.1
6.11
5.69
0.94
3.93
5.79
6.12
4.29
5.42
5.37
3.82
10.9
2.96
10.1
11.4
6.04
16.2
8.77
17.2
3.80
5.71
16.2
5.33
4.71
8.82
4.43
6.80
5.13
17.4
3.93
10.1
2.13
5.06
2.32
6.36
7.06
11.4
9.12
7.90
4.93
10.9
5.41
8.10
2.85
3.35
4.02
4.99
3.99
7.93
4.94
3.89
4.49
13.3
28.9
21.1
11.3
4.78
13.1
6.89
5.25
4.97
7.71
7.31
NSC lung cancer
HOP-62
HOP-92
43.7
NCI-H266
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
MG_MID
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
MG_MID
SF-268
>100.0
>100.0
>100.0
>100.0
73.9
88.68
7.71
Colon cancer
>100.0
>100.0
82.5
>100.0
61.8
>100.0
78.85
>100.0
>100.0
88.7
>100.0
>100.0
65.3
92.33
46.5
33.0
84.0
>100.0
44.5
>100.0
16.6
>100.0
34.5
62.12
>100.0
49.2
>100.0
>100.0
>100.0
>100.0
>100.0
92.74
>100.0
>100.0
37.7
>100.0
84.8
>100.0
–
CNS cancer
Melanoma
SF-295
SF-539
SNB-19
SNB-75
U251
MG_MID
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
MG_MID
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
MG_MID
786-0
A498
ACHN
CAKI-1
RXF 393
SN12C
nr-10
UO-31
MG_MID
PC-3
Ovarian cancer
Renal cancer
1.59
1.97
1.66
3.31
2.48
1.78
1.66
3.04
2.08
0.58
1.73
1.81
2.01
5.36
11.27
12.2
26.5
19.3
9.26
3.56
21.5
6.88
5.46
6.62
8.88
15.71
24.5
78.14
>100.0
>100.0
>100
>100.0
7.62
>100.0
60.3
>100.0
>100.0
77.98
83.51
Prostate Cancer
Breast cancer
DU-145
MG_MID
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
T-47D
MDA-MB-468
MG_MID
>100.0
73.0
>100.0
>100.0
82.16
55.41
MG_MID

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Table 3. COMPARE analysis results for highly-active compound 2.5.
a
b
End point
PCC
Target
Bryostatin 1
Cyanomorpholino-ADR
Morpholino-ADR
Aclacinomycin A
Echinomycin
Tamoxifen
Anguidine
MX2HCl
Mitramycin
Fluorodopan
ICRF-187
Target Vector NSC
Target mechanism of action
GI50
TGI
0.504
0.606
S339555
S357704
S354646
S208734
S526417
S180973
S141537
S619003
S24559
S73754
S169780
S58514
S332598
Modulator of protein kinase C
Alkylating agent
Inhibitor of RNA synthesis
0
0
0
0
0
0
0
0
0
0
0
.576
.574
.555
.552
.534
.524
.522
.521
.513
.508
.506
Inhibitor of DNA replication and RNA and protein synthesis
Inhibitor of hypoxia inducible factor 1 alpha (HIF1alpha).
Antagonist of the estrogen receptor
Inhibitor of initiation of protein synthesis
Topoisomerase II inhibitor
Inhibitor of RNA synthesis
Alkylating agent
Topoisomerase II inhibitor
Chromomycin A3
Rhizoxin
RNA polymerase inhibitor
Microtubulin formation-modulating agent (microtubule polymerization inhibitor)
a
Only correlations with PCC ꢃ 0.50 were selected, as significant.
b
Putative mechanisms of action were identified with the use of literature sources.
Figure 4. Result of cytotoxic action of compounds 2.2, 2.5 and Temozolomid on C6 Rat glioma cells and U373 Human glioblastoma astrocytoma cells during 72 h
of treatment (MTT assay).
1
13
Supplemental Materials contains sample H and C NMR 145.5 (d, J ¼ 30.0 Hz, C–F), 151.4 (C-5), 163.2 (d,
spectra of products (Figures S2–S12).
J ¼ 186.0 Hz, C–F), 166.2 (C ¼ O), 168.7 (C ¼ O). ESI-MS
þ
m/z 360 (M þ H) . Anal. Calcd for C H FN O S: C, 56.82;
17
14
3 3
H, 3.93; N, 11.69. Found: C, 56.70; H, 3.85; N, 11.52.
General procedure for synthesis of 2-oxo-7-phenyl-2,3-
dihydro-thiazolo[4,5-b]pyridine-5-carboxylic acid
amides 2.1–2.6
7
-(4-Fluorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyri-
dine-5-carboxylic acid (4-chlorophenyl)amide (2.2). Yield
ꢀ
1
7
5%, mp 324-326 C (DMF:AcOH). H NMR (400 MHz,
DMSO-d ): d 7.39-7.54 (m, 4H, arom.), 7.79 (d, 2H,
A mixture of the appropriate 2-oxo-7-phenyl-2,3-dihydro-
6
J ¼ 8.2 Hz, arom.), 7.86 (d, 2H, J ¼ 7.6 Hz, arom.), 7.91 (s,
thiazolo[4,5-b]pyridine-5-carboxylic acid (5 mmol) and
freshly distilled thionyl chloride (1.2 g) was heated under 1H, CH), 10.44 (s, 1H, NH), 13.20 (s, 1H, NH). C NMR
1
3
reflux for 2 h, cooled to room temperature, and treated with (100 MHz, DMSO-d ): d 116.8 (C-6), 117.0 (C-7a), 119.3 (d,
6
hexane (10 ml). The precipitate was separated by filtration J ¼ 5.0 Hz, C–F), 121.6 (C-7), 125.2 (C-3a), 130.3 (arom.),
and used without further purification. To a solution of the 130.4 (arom.), 132.7 (arom.), 137.0 (arom.), 140.4 (arom.),
corresponding amine (10 mmol) and triethylamine (1 ml) in 145.7 (d, J ¼ 30.0 Hz, C–F), 151.3 (arom.), 155.7 (C-5), 163.3
anhydrous dioxane (10 ml) was added the solution of (d, J ¼ 198.0 Hz, C–F), 166.2 (C ¼ O), 168.5 (C ¼ O). ESI-MS
þ
respective
2-oxo-7-phenyl-2,3-dihydrothiazolo[4,5-b]pyri- m/z 400/402 (M þ H) . Anal. Calcd for C19
H11ClFN O S: C,
3 2
dine-5-carboxylic acid chloride (10 mmol) in of the same 57.08; H, 2.77; N, 10.51. Found: C, 57.20; H, 2.65; N, 10.40.
solvent (10 ml). The mixture was heated for 30 min at
7-(4-Methoxyphenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyri-
00 C, cooled, and diluted with water (100 ml). The precipi- dine-5-carboxylic acid p-tolylamide (2.3). Yield 78%, mp
tate was separated by filtration and recrystallized a mixture 255-257 C (DMF:AcOH). H NMR (400 MHz, DMSO-d
DMF:acetic acid (1:2) or DMF:ethanol (1:2).
d 2.28 (s, 3H, CH ), 3.84 (s, 3H, OCH ), 7.14-7.19 (m, 4H,
-(4-Fluorophenyl)-5-(morpholine-4-carbonyl)-3H-thia-
arom.), 7.67-7.69 (m, 4H, arom.), 7.90 (s, 1H, CH), 10.12 (s,
ꢀ
1
ꢀ
1
):
6
3
3
7
ꢀ
13
zolo[4,5-b]pyridin-2-one (2.1). Yield 80%, mp 245-247 C 1H, NH), 12.95 (s, 1H, NH). C NMR (100 MHz, DMSO-
1
(
DMF:AcOH). H NMR (400 MHz, DMSO-d ): d 3.48-3.56
d
): d 21.0 (CH
6
), 55.9 (OCH ), 115.4 (C-6), 116.4 (C-7a),
3 3
6
(
m, 2H, morpholine), 3.61-3.66 (m, 2H, morpholine), 7.36- 120.2 (C-7), 128.5 (C-3a), 129.5 (arom.), 129.7 (arom.),
7
.48 (m, 3H, CH, arom.), 7.74 (dd, 2H, J ¼ 5.6, 8.4 Hz, 133.6 (arom.), 136.1 (arom.), 143.9 (arom.), 147.8 (arom.),
13
arom.), 12.92 (s, 1H, NH). C NMR (100 MHz, DMSO-d ): 150.3 (C-5), 161.0 (arom.), 162.5 (C ¼ O), 168.8 (C ¼ O).
6
þ
d 44.9 (CH ), 45.5 (CH ), 66.7 (CH ), 67.2 (CH ), 116.8 (C- ESI-MS
m/z
392
(M þ H) .
Anal.
Calcd
for
2
2
2
2
6
1
), 117.0 (C-7a), 119.3 (d, J ¼ 5.0 Hz, C–F), 121.4 (C-7), C H Cl N O S: C, 54.82; H, 2.66; N, 10.09. Found: C,
19
11
2 3 2
30.3 (C-3a), 130.4 (arom.), 132.9 (arom.), 142.6 (arom.), 54.91; H, 2.55; N, 10.19.

8
A. LOZYNSKYI ET AL.
7-(4-Methoxyphenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyri-
MTT assay
dine-5-carboxylic acid (4-bromopheyl)amide (2.4). Yield 67%, The cytotoxic activity of the new compounds 2.2, 2.5 and
ꢀ
1
mp 300-302 C (DMF:AcOH). H NMR (400 MHz, DMSO- Temozolomid (which is used in glioblastoma treatment)
d ): d 3.83 (s, 3H, OCH ) 7.14 (d, 2H, J ¼ 8.8 Hz, arom.), toward C6 Rat glioma cells and U373 Human glioblastoma
6
3
7
.55 (d, 2H, J ¼ 8.9 Hz, arom.), 7.68 (d, 2H, J ¼ 8.8 Hz, astrocytoma cells was evaluated using MTT assay. The 7000
arom.), 7.79 (d, 2H, J ¼ 8.9 Hz, arom.), 7.89 (s, 1H, CH),
cells/well were seeded in 96-well plates in 200 mL DMEM,
13
ꢀ
1
0.39 (s, 1H, NH), 12.95 (s, 1H, NH). C NMR (100 MHz,
supplemented with 10% FBS and incubated for 72 h at 37 C
DMSO-d ): d 55.9 (CH ), 115.4 (C-6), 116.2 (C-7a), 116.5
6
3
in CO incubator with studied compounds at concentration
2
(
(
(
arom.), 120.5 (C-7), 122.4 (arom.), 128.5 (C-3a), 129.5
arom.), 132.1 (arom.), 143.8 (arom.), 147.5 (arom.), 150.5
5
, 10, 50, 100 and 200 mM. After incubation, 20 lL MTT
reagent were added, incubated for 4 h, and measured in
accordance with the manufacturer’s recommendations
(Sigma, USA).
C-5), 161.0 (arom.), 163.1 (C ¼ O), 168.8 (C ¼ O). ESI-MS
þ
m/z 457 (M þ H) . Anal. Calcd for C H BrN O S: C,
20
14
3 3
5
2.64; H, 3.09; N, 9.21. Found: C, 52.80; H, 3.15; N, 9.12.
-(4-Chlorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyri-
dine-5-carboxylic acid (4-chlorophenyl)amide (2.5). Yield
7
Conclusion
ꢀ
1
7
0%, mp 306-308 C (DMF:AcOH). H NMR (400 MHz,
In summary, we have demonstrated the convenient method
to synthesis of thiazolo[4,5-b]pyridine-5-carboxylic acid
amides with moderate to good yields. The synthesized com-
pounds were assessed for their antitumor according to the
DTP NCI protocol and cytotoxicity capacities against C6
Rat glioma cells and U373 Human glioblastoma astrocytoma
cell lines. The preliminary results allowed to identify two
DMSO-d ): d 7.43 (d, 2H, J ¼ 8.5 Hz, arom.), 7.66 (d, 2H,
6
J ¼ 8.2 Hz, arom.), 7.74 (d, 2H, J ¼ 8.2 Hz, arom.), 7.85 (d,
2
1
(
1
1
1
H, J ¼ 8.5 Hz, arom.), 7.92 (s, 1H, CH), 10.39 (s, 1H, NH),
13
3.03 (s, 1H, NH). C NMR (100 MHz, DMSO-d ): d 116.9
6
C-6), 121.1 (C-7a), 122.1 (C-7), 128.2 (C-3a), 129.2 (arom.),
30.0 (arom.), 135.2 (arom.), 135.3 (arom.), 137.6 (arom.),
42.9 (arom.), 147.7 (arom.), 150.4 (C-5), 162.9 (C ¼ O),
most active compound 2.2 and 2.5 with mean GI /TGI
50
þ
50
68.6 (C ¼ O). ESI-MS m/z 417/419 (M þ H) . Anal. Calcd
values 1.57/7.31 lM and 2.01/16.42 lM in the NCI 60 cell-
line assay with certain sensitivity profile towards some indi-
vidual cell lines. The cytotoxicity effects of 2.2 and 2.5 on
C6 Rat glioma cells and U373 Human glioblastoma astrocy-
toma cell showed that of these compounds have good activ-
ities comparable to Temozolomid as reference control in
MTT assays. Considering all the above, the construction of
novel chemical entities as possible chemotherapeutic agents
among thiazolo[4,5-b]pyridine-5-carboxylic acid amides is
justified and promising direction in the modern medi-
cinal chemistry.
for C H Cl N O S: C, 54.82; H, 2.66; N, 10.09. Found: C,
1
9
11
2
3
2
5
4.91; H, 2.55; N, 10.19.
-(4-Chlorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyri-
dine-5-carboxylic acid (2-hydroxyethyl)amide (2.6). Yield
7
ꢀ
1
6
4%, mp 430-432 C (DMF:EtOH). H NMR (400 MHz,
DMSO-d ): d 2.72 (brs, 2H, CH ), 2.87 (brs, 2H, CH ), 4.87
6
2
2
(
s, 1H, OH), 7.55 (d, 2H, J ¼ 8.6 Hz, arom.), 7.68 (d, 2H,
J ¼ 8.6 Hz, arom.), 7.94 (s, 1H, CH), 8.47 (s, 1H, NH), 12.45
1
3
(s, 1H, NH). C NMR (100 MHz, DMSO-d ): d 47.1 (CH ),
6 2
5
3
8.4 (CH ), 119.1 (C-6), 121.6 (C-7a), 128.6 (C-7), 129.6 (C-
2
a), 133.9 (arom.), 135.3 (arom.), 142.3 (arom.), 145.7
(
arom.), 151.4 (C-5), 166.2 (C ¼ O), 168.2 (C ¼ O). ESI-MS
þ
m/z 350/352 (M þ H) . Anal. Calcd for C H ClN O S: C,
15
12
3 3
Acknowledgements
5
1.51; H, 3.46; N, 12.01. Found: C, 51.41; H, 3.55; N, 12.11.
The authors are grateful to Dr. V. L. Narayanan from Drug Synthesis
and Chemistry Branch, National Cancer Institute, Bethesda, MD, USA,
for in vitro evaluation of anticancer activity.
Pharmacological evaluation
Cytotoxic activity against malignant human tumor cells
Primary anticancer assay was performed on a panel of
approximately sixty human tumor cell lines derived from
ORCID
Andrii Lozynskyi
http://orcid.org/0000-0001-7151-2159
http://orcid.org/0000-0002-3322-0080
nine neoplastic diseases, in accordance with the protocol of Roman Lesyk
the Drug Evaluation Branch, National Cancer Institute,
[
20,21]
Bethesda.
References
[
1] Pinder, A. R. Pyrrolidine, Piperidine, and Pyridine Alkaloids.
Cell lines and culture conditions
Nat. Prod. Rep. 1986, 3, 171–180. DOI: 10.1039/np9860300171.
C6 Rat glioma cells and U373 Human glioblastoma astrocy-
toma cells were obtained from the Collection of the Institute
of Molecular Biology and Genetics, National Academy of
Science of Ukraine (Kyiv, Ukraine). Cells were cultured in
Dulbecco’s modified Eagle’s medium (DMEM, Sigma, St.
[2] Abele, E.; Abele, R.; Lukevics, E. Pyridine Oximes: Synthesis,
Reactions, and Biological Activity. (Review). Chem. Heterocycl.
Compd. 2003, 39, 825–865. DOI: 10.1023/A:1026181918567.
[3] Hill, M. D. Recent Strategies for the Synthesis of Pyridine
Derivatives. Chem. Eur. J. 2010, 16, 12052–12062. DOI: 10.
1002/chem.201001100.
Louis, USA) supplemented with 10% fetal bovine serum
[
4] Movassaghi, M.; Hill, M. D.; Ahmad, O. K. Direct Synthesis of
Pyridine Derivatives. J. Am. Chem. Soc. 2007, 129,
10096–10097. DOI: 10.1021/ja073912a.
ꢀ
(
Sigma). Cells were grown in CO incubator at 37 C, 5%
2
CO and 95% humidity.
2

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
9
[
5] Da Settimo, A.; Primofiore, G.; Da Settimo, F.; Simorini, F.; La
Motta, C.; Martinelli, A.; Boldrini, E. Synthesis of Pyrrolo[3,4-
c]Pyridine Derivatives Possessing an Acid Group and Their in
Vitro and in Vivo Evaluation as Aldose Reductase Inhibitors.
Eur. J. Med. Chem. 1996, 31, 49–58. DOI: 10.1016/S0223-
Hamel, L. T.; et al. Novel and Potent Adenosine 3’,5’-Cyclic
Phosphate Phosphodiesterase III Inhibitors: thiazolo[4,5-
b][1,6]Naphthyridin-2-Ones. J. Med. Chem. 1995, 38,
2546–2550. DOI: 10.1021/jm00014a007.
[
[
16] Komoriya, S.; Kobayashi, S.; Osanai, K.; Yoshino, T.; Nagata,
T.; Haginoya, N.; Nakamoto, Y.; Mochizuki, A.; Nagahara, T.;
Suzuki, M.; et al. Design, Synthesis, and Biological Activity of
Novel Factor Xa Inhibitors: Improving Metabolic Stability by S1
and S4 Ligand Modification. Bioorg. Med. Chem. 2006, 14,
5
234(96)80006-7.
[
[
6] Chaban, T. I.; Ogurtsov, V. V.; Chaban, I. G.; Klenina, O. V.;
Komarytsia, J. D. Synthesis and Antioxidant Activity Evaluation
of Novel 5,7-Dimethyl-3H-Thiazolo[4,5-b]Pyridines. Phosphorus
Sulfur Silicon Relat. Elem. 2013, 188, 1611–1620. DOI: 10.1080/
1309–1330. DOI: 10.1016/j.bmc.2005.09.056.
1
0426507.2013.777723.
17] Lin, R.; Johnson, S. G.; Connolly, P. J.; Wetter, S. K.; Binnun,
E.; Hughes, T. V.; Murray, W. V.; Pandey, N. B.; Moreno-
Mazza, S. J.; Adams, M.; et al. Synthesis and Evaluation of 2,7-
Diamino-Thiazolo[4,5-d]Pyrimidine Analogues as anti-Tumor
Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase
Inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 2333–2337. DOI:
7] Lozynskyi, A.; Zimenkovsky, B.; Radko, L.; Stypula-Trebas, S.;
Roman, O.; Gzella, A. K.; Lesyk, R. Synthesis and Cytotoxicity
of New Thiazolo[4,5-b]Pyridine-2(3H)-One Derivatives Based
on a,b-Unsaturated Ketones and a-Ketoacids. Chem. Pap. 2018,
72, 669–681. DOI: 10.1007/s11696-017-0318-1.
[
8] Chaban, T. I.; Panchuk, R. R.; Klenina, O. V.; Skorokhyd,
N. R.; Ogurtsov, V. V.; Chaban, I. G. Synthesis and Evaluation
of Antitumor Activity of Some Thiazolo[4,5-b]Pyridines.
Biopolym. Cell 2012, 28, 389–396. DOI: 10.7124/bc.000075.
10.1016/j.bmcl.2009.02.067.
[
18] Allais, C.; Constantieux, T.; Rodriguez, J. Highly Efficient
Synthesis of Trans-b,c-Unsaturated-a-Keto Amides. Synthesis
2009, 13, 469–473. DOI: 10.1055/s-0029-1216869.
[9] El-Gaby, M. S. A.; Al-Sehemi, A. G.; Mohamed, Y. A.; Ammar,
Y. A. Recent Trends in Chemistry of Thiazolopyridines. [19] The crystallographic data of 2.4 in the CIF form are available as
Phosphorus Sulfur Silicon Relat. Elem. 2006, 181, 631–674. DOI:
0.1080/10426500500269885.
10] Leysen, D. C.; Haemers, A.; Bollaert, W. Thiazolopyridine
Analogs of Nalidixic Acid. 2. Thiazolo[4,5-b]Pyridines. J.
Heterocycl. Chem. 1984, 21, 1361–1366. DOI: 10.1002/jhet.
Electronic Supplementary data from the Cambridge
Crystallographic Data Centre, deposition number CCDC-
1889263; http://www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK; fax: ¸t 44 1223 336033; e-mail:
deposit@ccdc.cam.uk).
1
[
[
[
[
5
570210522.
11] Hegde, S. G.; Mahoney, M. D. Synthesis and Herbicidal Activity
of 5-(Haloalkyl)-Substituted Thiazolo[4,5-b]Pyridine-3(2H)-
Acetic Acid Derivatives. J. Agric. Food Chem. 1993, 41,
[
20] Boyd, M. R.; Paull, K. D. Some Practical Considerations and
Applications of the National Cancer Institute in Vitro
Anticancer Drug Discovery Screen. Drug Dev. Res. 1995, 34,
2
131–2134. DOI: 10.1021/jf00035a058.
91–109. DOI: 10.1002/ddr.430340203.
12] Kulkarni, S. S.; Newman, A. H. Discovery of Heterobicyclic
Templates for Novel Metabotropic Glutamate Receptor Subtype
[
21] Boyd, M. R. Cancer Drug Discovery and Development; Humana
Press: Totowa, New Jersey, 1997.
22] Shoemaker, R. H. The NCI60 Human tumour cell line anti-
cancer drug screen. Nat. Rev. Cancer 2006, 6, 813–823. DOI:
5
Antagonists. Bioorg. Med. Chem. Lett. 2007, 17, 2987–2991.
[
DOI: 10.1016/j.bmcl.2007.03.066.
13] Walczy nꢀ ski, K.; Zuiderveld, O. P.; Timmerman, H. Non-
10.1038/nrc1951.
Imidazole Histamine
Propylpiperazines as Non-Imidazole Histamine H
Eur. J. Med. Chem. 2005, 40, 15–23. DOI: 10.1016/j.ejmech.
004.09.010.
H
3
Ligands. Part III. New 4-n-
[
23] Paull, K. D.; Shoemaker, R. H.; Hodes, L.; Monks, A.; Scudiero,
D. A.; Rubinstein, L.; Plowman, J.; Boyd, M. R. Display and
Analysis of Patterns of Differential Activity of Drugs against
Human Tumor Cell Lines: development of Mean Graph and
COMPARE Algorithm. J. Natl. Cancer Inst. 1989, 81,
1088–1092. DOI: 10.1093/jnci/81.14.1088.
[24] Weinstein, J. N.; Myers, T. G.; O’Connor, P. M.; Friend, S. H.;
Fornace, A. J.; Kohn, K. W.; Fojo, T.; Bates, S. E.; Rubinstein,
L. V.; Anderson, N. L.; et al. An Information-Intensive
Approach to the Molecular Pharmacology of Cancer. Science
1997, 275, 343–349. DOI: 10.1126/science.275.5298.343.
3
-Antagonists.
2
[
14] Rao, A. U.; Palani, A.; Chen, X.; Huang, Y.; Aslanian, R. G.;
West, R. E.; Williams, S. M.; Wu, R. L.; Hwa, J.; Sondey, C.;
0
et al. Synthesis and Structure–Activity Relationships of 2-(1,4 -
0
Bipiperidin-1 -yl)Thiazolopyridine as H
3
Receptor Antagonists.
Bioorg. Med. Chem. Lett. 2009, 19, 6176–6180. DOI: 10.1016/j.
bmcl.2009.09.006.
[
15] Singh, B.; Bacon, E. R.; Lesher, G. Y.; Robinson, S.; Pennock,
P. O.; Bode, D. C.; Pagani, E. D.; Bentley, R. G.; Connell, M. J.;