Synthesis, physicochemical characterization, cytotoxicity, antimicrobial, anti-inflammatory and psychotropic activity of new N-[1,3-(benzo)thiazol-2-yl]- ω-[3,4-dihydroisoquinolin-2(1H)-yl]alkanamides

Article abstract of DOI:10.1016/j.ejmech.2013.10.008

A series of new N-[(benzo)thiazol-2-yl]-2/3-[3,4-dihydroisoquinolin-2(1H)- yl]ethan/propanamide derivatives was synthesized and characterized by ¹H, ¹³C NMR and IR spectroscopy and mass-spectrometry. A single crystal X-ray study of N

Full text of DOI:10.1016/j.ejmech.2013.10.008

European Journal of Medicinal Chemistry 70 (2013) 846e856
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, physicochemical characterization, cytotoxicity,
antimicrobial, anti-inflammatory and psychotropic activity of new
N-[1,3-(benzo)thiazol-2-yl]-u-[3,4-dihydroisoquinolin-2(1H)-yl]
alkanamides
,
a
b
a
Alla Zablotskaya a , Izolda Segal , Athina Geronikaki , Tatiana Eremkina ,
*
Sergey Belyakova, Marina Petrova a, Irina Shestakova a, Liga Zvejniece a, Vizma Nikolajeva c
a Latvian Institute of Organic Synthesis, 21 Aizkraukles Street, Riga LV-1006, Latvia
b Aristotelian University of Thessaloniki, School of Pharmacy, Thessaloniki 54124, Greece
c University of Latvia, Biological Faculty, Kronvalda Boulv. 4, Riga LV-1586, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new N-[(benzo)thiazol-2-yl]-2/3-[3,4-dihydroisoquinolin-2(1H)-yl]ethan/propanamide de-
rivatives was synthesized and characterized by 1H, 13C NMR and IR spectroscopy and mass-spectrometry.
A single crystal X-ray study of N-(1,3-benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-yl]ethanamide
is reported to determine its conformational feature. The investigated compounds were found to be active
in psychotropic in vivo, anti-inflammatory in vivo and cytotoxicity in vitro screening. They possess
marked sedative action, reveal high anti-inflammatory activity, have selective cytotoxic effects and NO-
induction ability concerning tumour cell lines. Some of the compounds synthesized demonstrate anti-
microbial action. An attempt was made to correlate the biological results with their structural charac-
teristics and physicochemical parameters. Some specific combinations of types of activities for the
synthesized compounds have been revealed.
Received 28 December 2012
Received in revised form
30 September 2013
Accepted 3 October 2013
Available online 16 October 2013
Keywords:
Tetrahydroisoquinoline
Thiazole
Cytotoxicity
Ó 2013 Elsevier Masson SAS. All rights reserved.
Psychotropic activity
Anti-inflammatory activity
Antimicrobial activity
1. Introduction
various biological activities such as anti-inflammatory [5e7], anti-
microbial [8e12], antitubercular [13], antitumour activities [14e
Among pharmacologically important heterocyclic compounds,
thiazole and tetrahydroisoquinoline derivatives have been well
known in medicinal chemistry because of their wide spectrum of
biological activities and the presence of their structural moieties in
molecules of naturally occurring compounds.
Thiazole core is present in many biologically relevant molecules,
which are in therapeutical use, such as Sulfathiazole (antimicrobial
drug), Ritonavir (antiretroviral drug), Abafungin (antifungal drug),
Tiazofurin (antineoplastic agent), Meloxicam (non-steroidal anti-
inflammatory drug), Nitazoxanide (antiprotozoal agent) etc. Many
natural products containing thiazole ring were isolated and most of
them exhibit considerable cytotoxicity and antitumour potential
[1e4]. Thiazole and its derivatives are found to be associated with
18], enzyme inhibition [19,20] and also find application in the
drug development for the treatment of allergies [21], schizophrenia
[22] and as hypnotics [23]. Some coumarins incorporating thiazolyl
semicarbazones act as anticonvulsant agents [24]. Thiazole de-
rivatives were reported to possess antidegenerative activity and
coupling with other heterocyclic system form new biologically
active compounds [25e27].
The tetrahydroisoquinoline ring system is an important struc-
tural motif [28,29], which is commonly encountered in naturally
occurring alkaloids with interesting biological activities. Typical
examples include indenoisoquinoline (topoisomerase I inhibitor)
[30], saframycin-B [31], narciclasine [32] and ecteinascidin-743
(antitumour agents) [33]. In this regard, the tetrahydroisoquino-
line framework has become widely identified as a “privileged”
structure with representation in several medicinal agents of diverse
therapeutic action and are the potential drug candidates [34e37].
Tetrahydroisoquinoline derivatives have been discussed as affine
* Corresponding author.
E-mail address: aez@osi.lv (A. Zablotskaya).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.10.008

A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
847
R
R
N
R
N
N
N(CH2)nCONH
S
NHCO(CH2)nCl
S
NH2
S
5a-f
3a-e
1a-c
5a R=H n=1
3a R=H n=1
3b R=CH3 n=1
5b R=CH3 n=1
5c R=p-CH3OC6H4 n=1
1a R=H
1b R=CH3
.
3c R=p-CH3OC6H4 n=1
1c R=p-CH3OC6H4
5d R=p-CH3OC6H4 n=1
5e R=H n=2
HCl
i
ii
3d R=H n=2
3e R=p-CH3OC6H4 n=2
5f R=p-CH3OC6H4 n=2
X
X
X
N
N
N
N(CH2)nCONH
S
NHCO(CH2)nCl
S
S
NH2
6 a-c
2a,b
4 a-c
2a X=H
2b X=Cl
4a X=H n=1
4b X=Cl n=1
4c X=H n=2
6a X=H n=1
6b X=Cl n=1
6c X=H n=2
i: Cl(CH2)nCOCl/C6H6/80oC
ii: Et3N/C6H6/80oC (A); K2CO3/EtOH/78oC (B); [3 or 4]:[Tetrahydroisoquinoline] = 1:2.5/C6H6/80oC (C)
Scheme 1. Synthesis of N-[1,3-(benzo)thiazol-2-yl]-
u-[3,4-dihydroisoquinolin-2(1H)-yl]alkanamides (5aef and 6aec).
ligands for CNS receptors [38e41] and possess sedative [42e44]
and antitumour properties [45e47]. Besides hydrogenated quino-
line moieties are present as structural fragments in Amsacrine,
Bruneomycinum, Vincristine and Vinblastinum widely used in
oncology [14,48].
2. Results and discussion
As mentioned above, the aim of our work is to get potential dual
action prodrugs with low toxicity by combining conventional
pharmacophores in one molecule. New compounds, containing
two biologically active heterocycles (1,2,3,4-tetrahydroisoquinoline
and 1,3-thiazole), namely, 2(3)-[3,4-dihydroisoquinolin-2(1H)-yl]-
N-(1,3-thiazol-2-yl)- and -(1,3-benzothiazol-2-yl)ethan/prop-
anamides have been synthesized, characterized by various physi-
cochemical methods and evaluated for some types of biological
action.
Taking into account the importance of heterocyclic compounds
in creating drug [49], the successful application of fragment-based
analysis in the design of new biologically active substances [50]
and regarding the pharmacological properties of tetrahydroquino-
line and thiazole derivatives, it was envisaged to synthesize some
new bis-heterocyclic compounds as possible prodrugs and to eval-
uate their biological potentials. Coupling of tetrahydroquinoline and
thiazole ring in a single frame for the development of new chemical
entities, in which the one could reinforce or modify the biological
effects of the other, was carried out by using peptide link as a spacer.
This approach, called “dual action prodrug approach” or “mutual
prodrug approach” [51,52] has several advantages, such as syn-
chronous delivery of active agents, slower development of resis-
tance, improved formulation, improved chemical stability, reduced
potential steric and/or electronic issues associated with biological
target interaction and decreased toxicity [53].
2.1. Chemistry
The synthesis of the title compounds is outlined in Scheme 1.
The strategy for the synthesis of N-[1,3-(benzo)thiazol-2-yl]-u-
[3,4-dihydroisoquinolin-2(1H)-yl]alkanamides (5aef and 6aec)
involved the preparation of the ethanamido 3aee and prop-
anamido intermediates 4aec [54], which were further used as
alkylating agents in reaction with 1,2,3,4-tetrahydroisoquinoline to
afford a series of the desired compounds.
In this paper, we propose the synthesis of novel N-[(benzo)
thiazol-2-yl]-u-[3,4-dihydroisoquinolin-2(1H)-yl]alkanamide de-
Initially, three different synthetic modifications were followed
for the synthesis of 2-[3,4-dihydroisoquinolin-2(1H)-yl]-N-(1,3-
thiazol-2-yl)ethanamide (5a): interaction of equimolar amounts
of the 1,2,3,4-tetrahydroisoquinoline and 2-chloro-N-(1,3-thiazol-
2-yl)ethanamide (3a) in boiling benzene in presence of triethyl-
amine (A), alkylation of the appropriate amine in boiling alcohol in
presence of potassium carbonate with a little access of the amine
(B) and reaction between the reactants in boiling benzene using
2.5 molar excess of the amine (C). The yields of product 5a along the
methods A, B and C were 31, 24 and 44%, correspondingly. Taking
into account the possibility to recover the heterocyclic amine from
the reaction mixture, method C was the optimal alkylation proce-
dure among the examined ones. Therefore, the latter reaction
conditions were applied for the synthesis of all the other title
compounds. The yields of the synthesized N-[1,3-(benzo)thiazol-2-
rivatives, in order to generate compounds with high biological ac-
tivity and low toxicity, and evaluation of their biological action,
namely, in vitro inhibiting properties on tumour cells (human
fibrosarcoma HT-1080 and mouse hepatoma MG-22A), normal
mouse fibroblasts (NIH 3T3), bacterial (two Gram-positive, Staph-
ylococcus aureus and Bacillus cereus, and three Gram-negative,
Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis)
and fungal strains (Candida albicans and Aspergillus niger), as well as
their in vivo anti-inflammatory properties against carrageenin
mouse paw oedema and psychotropic activity along a number of
tests. In addition, we report on a single crystal X-ray study of N-(1,3-
benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-yl]ethana-
mide to understand its conformational feature and supramolecular
assembly. It helps in understanding the mechanism of action of the
drug and also in docking studies with various receptors. An attempt
was made to correlate the biological results with their structural
characteristics and physicochemical parameters.
yl]-u-[3,4-dihydroisoquinolin-2(1H)-yl]alkanamides ranged from
moderate to high (44e87%).
The structure of the compounds was confirmed by element
analysis, IR, 1H and 13C NMR spectroscopy, GC- and LC-mass-

848
A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
spectrometry and X-ray diffraction analysis (for compound 6a).
Analysis of IR spectra showed that they had absorption bands
typical for amide bond.
Benzothiazolyl compounds 6a and 6b were less active in this
respect. The only compounds strengthening the action of phen-
amine by 15e29% (synergists of phenamine) were thiazolyl etha-
namides 5b and 5c, containing 4-methyl or 4-methoxyphenyl
substituent correspondingly.
2.2. Biological activities
Study of the effect of some substances on memory processes
showed that the greatest activity was displayed by (4-
methoxyphenyl)thiazolyl propanamide (5f), which at dose of
5 mg kgꢀ1 completely (100%) prevented retrograde amnesia.
Psychotropic action of compounds 5def on the central nervous
system was also assessed by effect on motor coordination and
muscle tone along a number of tests, namely, rotating rod, tube,
traction, on body temperature, by analgetic and antispasmodic ef-
fect to electroshock (Table 2).
The biological activity of the title compounds, namely, in vivo
psychotropic action along
a number of tests, in vivo anti-
inflammatory effects using the functional model of carrageenin-
induced mouse paw oedema (CPE), antimicrobial activity against
different Gram-positive, Gram-negative and fungi strains, using the
agar dish diffusion method, and cell cytotoxicity on two monolayer
tumour cell lines (HT-1080 and MG-22A) and normal mouse fi-
broblasts NIH 3T3 have been investigated.
In in vivo acute toxicity experiments, the examined compounds
did not cause toxic effects. The acute toxicity depended on the
presence of the substituent in C4 position. The toxicity of (4-
methoxyphenyl)thiazolyl propanamide (5f) was lower at least by
twice in comparison with the analogue without 4-methoxyphenyl
substituent (5e). Depriming activity in rotating rod, tube and
traction tests was expressed weakly. However, thiazolyl prop-
anamide 5e possessed clearly expressed depriming activity and
analgetic action.
As the result of the carried out investigations a dominant display
of a definite type of neurotropic properties was shown depending
on the nature of the heterocyclic fragment (thiazolyl benzothia-
zolyl), alkyl chain length between two heterocycles and also on the
presence of a substituent in the C4 position of the molecule. Thia-
zolyl propanamides possessed tranquilizing/sedative (phenamine
antagonism), antihypoxic (increasing of lifespan under conditions
of hypoxia) and hypnotic (elongation in duration of sleep caused by
hexenal) action. Anticonvulsive effect in corazole induced convul-
sions test was mostly expressed in thiazolyl and benzothiazolyl
ethanamides without C4 substituent.
2.2.1. In vivo psychotropic activity
Psychotropic activity of the title compounds was examined on
mice under intraperitoneal administration in doses of 5 mg kgꢀ1
and the action of the substances on the CNS was evaluated on in-
dicators of phenamine hyperactivity, hypoxia, hexenal and ethanol
anaesthesia and corazole convulsions. The results of the study of
neurotropic properties are presented in Table 1.
The investigated compounds possessed marked sedative action.
The structureeactivity study was carried out comparing the influ-
ence of heterocycle nature and alkyl chain length on the psycho-
tropic activity indicators.
All of the tested compounds at dose of 5 mg kgꢀ1 are synergists
of hexenal and ethanol, reliably extending their narcotic action by
35e60% and by 22e53%, respectively. The most reliable extension
of narcotic action, by 1.6 times for hexenal was noted for thiazolyl
propanamide 5e without substituent in the C4 position of the
molecule.
All the compounds studied revealed anticonvulsive action in the
test of corazole induced convulsions (clonic and tonic) increasing
their threshold by 26e61% in the clonic and by 26e62% in the tonic
It can be concluded, that the investigated compounds possessed
marked neurotropic activity, such as antihypoxic, hypnotic and
anticonvulsive effects, and acted as phenamine antagonists. Thia-
zolyl derivatives 5aef displayed higher psychotropic activity in
comparison with benzothiazolyl analogues 6a, b.
phase.
2-[3,4-Dihydroisoquinolin-2(1H)-yl]-N-(1,3-thiazol-2-yl)
ethanamide (5a) possessed the greatest anticonvulsive activity and
was the stronger anticonvulsant in comparison with its benzo-
thiazolyl analogue 6a. The investigated substances did not display
protective properties in test of maximal electroshock.
2.2.2. In vivo anti-inflammatory activity
Almost all the investigated compounds acted as phenamine
antagonists, reducing the locomotor activity caused by adminis-
tration of phenamine by 49e59%. The greatest antagonistic
effect on interacting with phenamine was observed for thiazolyl-
(5e), (4-methoxyphenyl)thiazolyl- (5f) propanamides and (4-
methoxyphenyl)thiazolylethananamide hydrochloride (5d). In the
case of 5d the sedative action appeared later, after an hour.
The
in
vivo
anti-inflammatory
effects
of
2-[3,4-
dihydroisoquinolin-2(1H)-yl]-N-(1,3-thiazol-2-yl)ethanamide (5a),
3-[3,4-dihydroisoquinolin-2(1H)-yl]-N-(1,3-thiazol-2-yl)prop-
anamide (5e), and the corresponding 4-p-methoxyphenyl-
substituted analogues 5c and 5f were assessed by using the func-
tional model of carrageenin induced mouse paw oedema (CPE)
Table 1
In vivo neurotropic activity of compounds 5aef and 6a,b with respect to control (100%).
No.
Test, M ꢁ m, % to control (100%)
Phenamine
Phenamine
induced
Hypoxic hypoxia
Ethanol induced narcosis
Hexenal induced narcosis
Corazole
induced
Retrograde amnesia
hyperthermiaa
hyperactivity
convulsions
30 min
60 min
30 min
60 min
Clonic
Tonic
5a
5b
5c
5d
5e
5f
100.8
98.6
99.7
ꢀ0.8
ꢀ0.4
ꢀ0.7
99.8
96.7
98.5
99.8
100.6
ꢀ0.6
ꢀ0.6
ꢀ0.2
102
80
129
115
80
51*
41*
70
88
117
117
46*
49*
49*
64
n
n
n
115
105
139*
n
n
n
n
153*
105
122*
n
135*
111
86
140*
160*
100
141*
111
161*
132*
105
130*
115*
126*
127*
114
162*
116*
143*
135*
116*
124*
150*
126*
n
n
n
80
80
100*
n
6a
6b
98
95
95
n
n
n
*Differences in relation to control are statistically reliable at P < 0.05.
a
M ꢁ m, % to control (100%) for compounds 5aec and 6a,b or ꢂC for compounds 5def.

A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
849
Table 2
Effect of compounds 5def on the tone of skeletal musculature and motor coordination.
Compound
LD50, mg kgꢀ1
Test, ED50, mg kgꢀ1
Rotating rode
Tube
Rectal temperature
Narcosis
Analgesia
Traction
>250
70.8
>500
5d
5e
5f
>500
258
>500
224
>200
>500
>250
>200
>500
>250
>200
>500
>250
>200
>500
141
44.7
103
[26,55] and are presented in Table 3, as percent inhibition of
carrageenin induced mouse oedema.
were also potent against Gram-negative bacterial EC and PM and
fungal CA strains.
All the studied compounds after 3.5 h at dose of 0.2 mmol kgꢀ1
body weight exhibited high anti-inflammatory activity protecting
in vivo against the carrageenin induced paw oedema formation
(50.2%e75.8%).
3-[3,4-Dihydroisoquinolin-2(1H)-yl]-N-(1,3-benzothiazol-2-yl)
propanamide (6c), possessing weak antibacterial activity against
Gram-positive and being non active against Gram-negative bacte-
rial strains, showed strong antifungal activity for C. albicans and
very strong for A. niger with inhibition zones of 17 and 26 mm
correspondingly.
It can be concluded, that almost all synthesized compounds
showed good selective antibacterial activity against Gram-negative
P. aeruginosa, and benzothiazolyl derivative 6c e against tested
fungi.
Analyzing the data obtained it was revealed that 4-(p-methox-
yphenyl)thiazolyl propanamide (5f) provided the lowest protection
(50.2%), which was about similar one to the reference drug indo-
methacin (57.2%). In its turn, 4-(p-methoxyphenyl)thiazolyl etha-
namide (5c) caused the highest inhibition among the tested
compounds (75.8%) followed by compounds without substituent in
the C4 position e thiazolyl ethanamide 5a (70.4%) and thiazolyl
propanamide 5e (62.4%).
2.2.4. In vitro antitumour activity
It was interesting, that the distance elongation between tetra-
hydroisoquinolyl and thiazolyl moieties influenced the biological
response e compare compounds 5a and 5c (n ¼ 1) with compounds
5e and 5f (n ¼ 2). Both thiazolyl- and 4-(p-methoxyphenyl)thia-
zolyl ethanamides possessed higher inhibition in comparison with
their propanamide analogues, which was mostly expressed be-
tween C4-substituted compounds 5c and 5f, where the difference
in inhibition was about 25%.
Lipophilicity is a significant physicochemical property, deter-
mining distribution, bioavailability, metabolic activity and elimi-
nation. This parameter was theoretically calculated as clog P value
in n-octanol-buffer system [56]. Herein the role of lipophilicity is
marginal (5a > 5e, 5c > 5f), and the values could not be used as
successful indicators of the biological activity. It can be attributed to
the presence of basic nitrogen atoms in the examined compounds,
which could disturb the absorption/desorption process.
It was found that among tested compounds the alkyl chain
length between two heterocycle moieties is more essential for anti-
inflammatory display than the presence of the bulky substituent in
Cell cytotoxicity of the title compounds was tested on two
monolayer tumour cell lines: HT-1080 (human fibrosarcoma), MG-
22A (mouse hepatoma), and normal mouse fibroblasts (NIH 3T3).
The experimental evaluation of cytotoxic properties is presented in
Table 5. Analysis of structureeactivity data for the cytotoxic action
clearly indicates the influence of the heterocyclic substituent na-
ture on the in vitro toxic effect. Between thiazolyl (5a) and benzo-
thiazolyl (6a) ethanamides, 6a was more effective, exhibiting high
cytotoxic effect concerning mouse hepatoma MG-22A and the
moderate one concerning human fibrosarcoma HT-1080. Intro-
duction of bulky substituent p-CH3OeC6H4 at C4 position of thia-
zolyl ring (compounds 5c and 5f) had a positive impact on
antitumour properties of thiazolyl alkanamides in comparison with
their unsubstituted analogues (5a and 5e), which provided speci-
ficity concerning mouse hepatoma MG-22A cells, increasing the
cytotoxicity up to 8.6 times for 5c. Benzothiazolyl containing
compounds 6aec revealed high cytoxicity concerning human
fibrosarcoma HT-1080 or mouse hepatoma MG-22A. Compound 6b
possessed good cytotoxic properties, high NO-induction ability
C
4 position of thiazole ring.
It can be concluded that the studied compounds possessed high
(MG-22A
cell
line)
and
was
non-toxic
compound
(LD50 ¼ 1879 mg kgꢀ1).
anti-inflammatory activity, which in almost all cases was higher or
close to that of the reference drug indomethacin.
Table 3
In vivo anti-inflammatory activity (carrageenin mouse paw oedema inhibition, CPE)
of compounds 5a, 5c, 5e and 5f and theoretically calculated lipophilicity (clog P).
2.2.3. In vitro antimicrobial activity
The antimicrobial activity of the title compounds has been
investigated against two Gram-positive, S. aureus (SA) and B. cereus
(BC), three Gram-negative E. coli (EC), P. aeruginosa (PA) and P.
mirabilis (PM), and two fungi strains, C. albicans (CA) and A. niger
(AN), using the agar dish diffusion method [57,58] and was exam-
ined quantitatively by measuring of the inhibition zone diameter in
comparison with gentamicin and fluconazole as the reference
compounds. The investigation of antimicrobial screening (Table 4)
revealed that almost all the newly synthesized compounds (5aec,
5e,f and 6a,b) showed selective antibacterial activity against Gram-
negative P. aeruginosa with diameter of inhibition zones ranged
from 17 to 20 mm, and moderate antibacterial activities against
some other Gram-negative and Gram-positive bacteria with inhi-
bition zones of 9e15 mm. Thiazolyl derivatives were also potent
against Gram-positive SA (compounds 5a, 5c, 5e and 5f) and BC
bacteria (compounds 5b, 5c and 5e). Almost all the compounds
R
N
N(CH2)nCONH
S
5
Compound
No
clog Pa
CPE inhibition, %
n
R
5a
5c
5e
5f
1
1
2
2
H
2.543
4.659
2.777
4.894
e
70.4*
75.8*
62.4*
50.2*
57.2
p-MeOPh
H
p-MeOPh
Indomethacin
*Differences in relation to control are statistically reliable at P ꢃ 0.05.
a
Theoretically calculated values using the clog P program from Biobyte [56].

850
A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
Table 4
In vitro antibacterial and antifungal activity data of compounds 5aec, 5e, 5f and 6aec.
X
R
N
N
N(CH2)nCONH
N(CH2)nCONH
S
S
6
5
Compound
Diameter of zones showing complete inhibition of growth (mm)a
SA
BC
EC
PA
PM
CA
AN
No
n
R or X
5
10
5
10
5
10
5
10
5
10
5
10
5
10
5a
5b
5c
5e
5f
6a
6b
6c
1
1
1
2
2
1
1
2
H
Me
p-MeOPh
H
e
13
e
n
e
e
e
e
e
e
e
9
e
12
11
12
12
12
12
12
e
11
16
13
12
13
16
16
e
19
18
18
17
20
18
18
e
n
14
e
12
9
10
14
14
e
12
11
12
11
e
n
9
n
n
n
n
n
n
n
26
n
n
n
n
n
n
n
n
15
n
e
10
12
14
n
9
9
9
e
11
e
14
14
15
9
9
8
11
11
n
12
11
17
n
e
e
p-MeOPh
e
e
n
H
Cl
H
12
10
e
11
10
e
12
13
e
11
11
13
n
9
e
9
19
Gentamicin
Fluconazole
2.0 mg mlꢀ1
25
27
22
21
23
40
42
20
21
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
10
11
e
0.2 mg mlꢀ1
e
“e” ꢃ 4 mm (no inhibition).
“n” e not-determined.
a
Diameter of a ditch for substances e 7 mm.
Among the synthesized compounds, in general possessing
moderate cytotoxicity, the specific action of some ones concerning
tumour cell lines has been revealed. Thiazolyl (5c) and benzothia-
zolyl (6a) containing derivatives exhibited high cytotoxic activity
2.3. X-ray crystallographic study
X-ray diffraction study was carried out for N-(1,3-benzothiazol-
2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-yl]ethanamide (6a) to
determine its conformational feature and possibility of molecular
assembly. The crystal data and the refinement details are given in
Table 6.
against mouse hepatoma MG-22A (5/7 and 4/4
m
g mlꢀ1, CV/MTT
tests correspondingly). The elongation of alkyl chain length be-
tween tetrahydroisoquinolyl and thiazolyl moieties (n ¼ 1 for
compounds 5a and 5c; n ¼ 2 for compounds 5e and 5f) led to
Table 7 lists the values of bond lengths and principal valence
angles.
cytotoxicity decrease from 21/60 to 45/65 m
g mlꢀ1 against mouse
hepatoma MG-22A in the case of compounds 5a and 5e without
The molecular structure of compound 6a is shown in Fig. 1.
Fig. 1 shows a perspective view of the molecular structure. There
is the strong intramolecular hydrogen bond of N(14)eH/N(2) in
substituent in the C4 position, and from 5/7 to 21/50
m
g mlꢀ1 in the
case of 5c and 5f, containing bulky C4 substituent. The opposite
effect was revealed against human fibrosarcoma HT-1080 for
compounds 5a and 5e, when the cytotoxicity increased by up to 5
ꢀ
the structure. The lengths of this bond is equal to 2.599(7) A (N(2)/
ꢂ
ꢀ
H ¼ 1.85 A, angle N(2)/HeN(14) ¼ 132 ). The hydrogen bond
determines the molecular conformation: the torsion angle of N(2)e
C(11)eC(12)eN(14) is 12.3(5)ꢂ. The atomic plane of C(11), C(12),
O(13), N(14) is almost coplanar with benzothiazole system. The
conformation for heterocycle of isoquinoline system is near to en-
velope. The deviation of the atom N(2) from the mean plane of C(1),
times with alkyl chain elongation (100/24 and 100/18
MTT tests correspondingly).
m
g mlꢀ1, CV/
It can be concluded, that all the compounds, to more or less
extend, revealed selective cytotoxicity concerning examined
tumour cells lines.
ꢀ
As a result of biological investigation of the synthesized N-[1,3-
C(3), C(4), C(10), C(11) is 0.693(5) A.
(benzo)thiazol-2-yl]-
u
-[3,4-dihydroisoquinolin-2(1H)-yl]alka-
Fig. 2 illustrates the molecular packing of the crystal structure
on the crystallographic plane yz. There are no intermolecular
hydrogen bonds in the crystal structure. All the intermolecular
contacts correspond to sums of van der Waals radii.
namides it was revealed, that the synthesized compounds were
active in psychotropic in vivo, anti-inflammatory in vivo, anti-
tumour in vitro and antimicrobial in vitro screening. Generally the
high in vivo anti-inflammatory activity was combined with high
in vivo psychotropic activity. For all the tested compounds the high
in vivo anti-inflammatory activity was matched with moderate
in vitro antimicrobial activity (either antibacterial or antifungal)
3. Conclusions
The study revealed, that the synthesized N-[1,3-(benzo)thiazol-
and also with moderate (LC50 ¼ 18e21
m
g/ml) or high (LC50 ꢃ 5
m
g/
2-yl]-
u
-[3,4-dihydroisoquinolin-2(1H)-yl]alkanamides,
which
ml) selective cytotoxicity against tumour cell lines according to CV
or MTT tests. In the group of compounds, containing thiazole
combine two heterocyclic rings, tetrahydroisoquinoline and thia-
zole or benzothiazole, in one molecule were active in psychotropic
in vivo, anti-inflammatory in vivo, antitumour in vitro and antimi-
crobial in vitro screening. Both in vivo anti-inflammatory and in vivo
psychotropic activities were more expressed.
moiety, the moderate selective cytotoxicity (LC50 ¼ 18e41
mg/ml)
was combined with moderate antimicrobial activity, but for all the
compounds possessing benzothiazole residue the high selective
cytotoxicity (LC50 ¼ 2e6
m
g/ml) was accompanied by low anti-
A dominant display was shown of a definite type of neurotropic
properties depending on the nature of the heterocyclic fragment,
bacterial action and moderate or high antifungal activity.

A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
851
Table 5
In vitro antitumour activity and intracellular NO generation caused by compounds 5aef and 6aec.
X
R
N
N
N(CH2)nCONH
S
N(CH2)nCONH
S
5
6
Compound/test
HT-1080
MG-22A
LC50CVa
NIH 3T3
LC50NRd
No
n
R or X
LC50 CVa
LC50 MTTb
NO CVc
LC50MTTb
NOCVc
LD50, mg kgꢀ1
5a
5b
5c
5d
5e
5f
6a
6b
6c
1
1
1
1
2
2
1
1
2
H
Me
100
96
28
76
24
40
34
6
100
e
18
17
77
21
41
5
58
45
21
4
>100
10
60
42
7
73
65
50
4
38
54
182
23
6
133
90
n
n
158
59
n
n
n
37
600
15
948
723
n
n
n
517
1879
371
p-MeOPh
p-MeOPh, HCl
H
74
1
22
18
20
28
10
12
550
114
100
20
p-MeOPh
H
Cl
H
10
9
233
33
2
100
n e non-determined.
“e” no cytotoxic effect.
a
Concentration (
Concentration (
m
m
g/ml) providing 50% cell killing effect (CV:coloration).
g/ml) providing 50% cell killing effect (MTT:coloration).
b
c
NO concentration (CV:coloration), determined according to Ref. [59].
Concentration (mg/ml) providing 50% cell killing effect (NR:coloration).
d
alkyl chain length between two heterocycles and also on the
presence of a substituent in the C4 position of the molecule. All the
synthesized compounds revealed marked anticonvulsive proper-
ties. Antiphenamine action was mostly expressed for thiazolyl
propanamide derivatives.
4. Experimental
4.1. Chemistry
1H and 13C NMR spectra were recorded on Varian Mercury 200
or 400 (200 and 50 MHz or 400 and 100 MHz correspondingly) at
Anti-inflammatory effect of the tested compounds surpassed
the same one of indomethacin, and alkyl chain length between two
heterocycle moieties was essential for its display. The manifestation
of anti-inflammatory properties of the tested compounds was
combined with their moderate antibacterial and high antifungal
properties. It has been revealed, that 2-[3,4-dihydroisoquinolin-
2(1H)-yl]-N-[4-(p-methoxy)phenyl-1,3-thiazol-2-yl]ethanana-
mide, which possessed the highest anti-inflammatory activity
among thiazolyl derivatives, was also potent selective cytotoxic
agent against mouse hepatoma cell line. Some specific combina-
tions of types of activities for the synthesized compounds have
been revealed. The data obtained show the expediency of the
chosen approach to the construction of new biologically active
substances.
303
(HMDSO) as internal standard. Mass spectra under electron impact
conditions were recorded on Agilent Technologies mass-
K with CDCl3 as a solvent using hexamethyldisiloxane
a
spectrometer 5975C (GC 7890A, 70 eV) and on Waters mass-
spectrometer 3100 (LC Alliance Waters 2695). Infrared spectra
(films as Nujol mulls) were recorded with Shimadzu IR Prestige-21.
Table 7
ꢂ
ꢀ
The main bond lengths (A) and angles ( ) of compound 6a.
Principal valence angles (ꢂ)
ꢀ
Main bond lengths (A)
C(1)eN(2)
N(2)eC(3)
C(3)eC(4)
C(5)eC(6)
C(6)eC(7)
C(8)eC(9)
1.472(8)
N(2)eC(1)eC(9)
C(1)eN(2)eC(3)
C(1)eN(2)eC(11)
C(3)eN(2)eC(11)
N(2)eC(3)eC(4)
C(3)eC(4)eC(10)
N(2)eC(11)eC(12)
C(11)eC(12)eO(14)
O(13)eC(12)eN(14)
C(12)eN(14)eC(15)
N(14)eC(15)eS(16)
N(14)eC(15)eN(23)
S(16)eC(15)eN(23)
C(15)eS(16)eC(17)
C(15)eN(23)eC(22)
110.6(6)
110.5(5)
111.6(5)
112.6(5)
107.6(6)
112.8(6)
112.3(6)
124.4(6)
123.5(6)
128.6(5)
121.7(4)
120.2(5)
118.1(5)
87.7(3)
1.480(9)
1.532(11)
1.425(13)
1.379(13)
1.400(10)
1.515(9)
1.359(9)
1.751(6)
1.752(7)
1.394(10)
1.367(11)
1.410(10)
1.510(11)
1.463(9)
1.516(11)
1.378(11)
1.378(11)
1.408(10)
1.214(9)
1.385(8)
1.281(8)
1.382(9)
1.384(11)
1.377(10)
1.393(8)
Table 6
The main crystallographic and structure refinement data of compound 6a.
C(11)eC(12)
C(12)eN(14)
C(15)eS(16)
S(16)eC(17)
C(17)eC(22)
C(19)eC(20)
C(21)eC(22)
C(1)eC(9)
N(2)eC(11)
C(4)eC(10)
C(5)eC(10)
C(8)eC(7)
C(9)eC(10)
C(12)eO(13)
N(14)eC(15)
C(17)eC(18)
C(18)eC(19)
C(20)eC(21)
C(20)eC(21)
C(22)eN(23)
Brutto-formula
Formula weight
Crystal description
Crystal system
Space group
C18H17N3OS
323.418
Prism (0.12 ꢄ 0.17 ꢄ 0.28 mm)
Orthorhombic
P 21 n b
ꢀ
Cell dimensions [A]:
a
b
c
4.8526(2)
13.0104(5)
25.6052(12)
1616.6(1)
4
1.329
680
0.208
52.0
109.0(6)
3
ꢀ
Unit cell volume [A ]
Molecular multiplicity (Z)
Crystal density [g cmꢀ3
F(000)
]
Absorption coefficient [mmꢀ1
]
Maximum 2
q
(ꢂ)
Total number of reflections
3046
Number of reflections with I > 2
Number of refined parameters
Final R-factor
s
(I)
1736
208
0.0669

852
A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
1H, 5-CH), 7.0e7.2 (m, 4H, ArH), 7.42 (d, J ¼ 3.7 Hz, 1H, 4-CH), 10.4
(bs, 1H, NHCO). 13C NMR, ppm: 28.88 (40-CH2), 51.52, 56.02 (10,30-
d
CH2N), 60.73 (COCH2N), 113.62 (5-C), 125.91, 126.39, 126.60, 128.73
(50,60,70,80-Ar), 133.22, 133.32 (90,100-Ar), 137.51 (4-C), 157.39 (2-C),
168.47 (CO). LCeMS, m/z (%): 273 (Mþ, 20), 173 (MþethiazoleeNH,
20), 146 (MþethiazoleeNHCO (100). Anal. calcd for C14H15N3OS: C
61.51, H 5.53, N 15.37, S 11.73. Found: C 61.20, H 5.47, N 15.28, S
11.61.
(B): A mixture of 2-chloro-N-(1,3-thiazol-2-yl)ethanamide 3a
(220 mg, 1.25 mmol) and 1,2,3,4-tetrahydroisoquinoline (197 mg,
1.48 mmol) in absolute ethanol (10 ml) was heated at 70 ꢂC until
clear solution was obtained. Then anhydrous potassium carbonate
(314 mg, 2.96 mmol) was added, and the reaction mixture was
stirred under heating for 12 h, cooled to room temperature and
washed with 5% sodium bicarbonate solution (20 ml). The product
was extracted from water solution with chloroform (3 ꢄ 10 ml), and
the organic layer was dried over sodium sulphate and concentrated
under reduced pressure, and the crude product was purified by
column chromatography on silica-gel using chloroform/methanol
(100:1) as eluent to afford 5a (82 mg, 24%) as light beige powder.
(C): A mixture of 2-chloro-N-(1,3-thiazol-2-yl)ethanamide 3a
(220 mg, 1.25 mmol) and 1,2,3,4-tetrahydroisoquinoline (415 mg,
3.12 mmol) in benzene (12 ml) was heated for 8 h in a water bath.
After that, the mixture was cooled to room temperature and
filtered. The filtrate was evaporated under reduced pressure, and
the residue was treated with hexane to afford pure 5a (150 mg,
44%) as light beige powder.
Fig. 1. Molecular structure of N-(1,3-benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-
2(1H)-yl]ethanamide (6a).
Nonius KappaCCD was used for X-ray crystallographic study.
Elemental analyses (C, H, N) were performed on CARLO ERBA 1108
elemental analyzer. Melting points were determined on a Boetius
melting point apparatus and were taken uncorrected.
Analytical thin-layer chromatography was performed on 60 F254
Merck silica gel plates and MachereyeNagel silica gel plastic plates,
with visualization under UV (254 nm). Column chromatography
was performed using Merck silica gel (0.040e0.063 nm). Solvents
and reagents were purchased from Acros and SigmaeAldrich
Corporation.
4.1.3. 2-[3,4-Dihydroisoquinolin-2(1H)-yl]-N-(4-methyl-1,3-
thiazol-2-yl)ethanamide (5b)
Procedure C. Crude product was purified by column chroma-
tography using ethyl acetate as eluent to afford pure 5b. Yield 51%,
light beige crystalline powder, m.p. 128e130 ꢂC. IR,
n
cmꢀ1: 1700
d ppm: 2.10 (3H, s, 4-
(C]O), 1527 (NeH), 1263 (CeN). 1H NMR,
CH3), 2.9e3.0 (m, 4H, 30,40-CH2), 3.41 (s, 2H, COCH2N), 3.78 (s, 2H,
10-CH2N), 6.52 (s, 1H, 5-CH), 7.0e7.2 (m, 4H, ArH), 10.4 (bs, 1H,
NHCO). 13C NMR,
d
ppm: 16.97 (CH3), 26.95 (40-CH2), 51.55, 56.12
(10,30-CH2N), 60.85 (COCH2N), 108.14 (5-C), 125.97, 126.46, 126.68,
128.77 (50,60,70,80-Ar), 133.28, 133.37 (90,100-Ar), 147.23 (4-C), 156.72
(2-C), 168.50 (CO).
4.1.1. General procedure for the synthesis of 2-chloro-N-[1,3-
(benzo)thiazol-2-yl]ethanamides (3aee) and 3-chloro-N-[1,3-
(benzo)thiazol-2-yl]propanamides (4aec) [54]
To a solution of 2-aminothiazole or 2-aminobenzothiazole, 4-
substituted 2-aminothiazole or 2-aminobenzothiazole (0.025 mol)
Anal. calcd for C15H17N3OS: C 62.69, H 5.96, N 14.62, S 11.16.
Found: C 62.70, H 6.01, N 14.67, S 11.10.
in dry benzene
a
cooled solution of chloroacetyl or 3-
4.1.4. 2-[3,4-Dihydroisoquinolin-2(1H)-yl]-N-[4-(p-methoxy)
phenyl-1,3-thiazol-2-yl]ethanamide (5c)
chloropropionyl chloride (0.041 mol) in dry benzene (9 ml) was
added dropwise. The reaction mixture was stirred for 3 h at reflux
temperature, and then solvent and surplus of chloroacetyl or 3-
chloropropionyl chloride were removed in vacuum. The residue
was washed with 5% aqueous sodium bicarbonate solution followed
by cold water. The crude product was dried and crystallized from
ethanol.
Procedure C. Yield 80%, orange-coloured crystalline powder, m.p.
124e125 ꢂC. IR,
NMR,
n
cmꢀ1: 1685 (C]O), 1538 (NeH), 1249 (CeN). 1H
d
ppm: 2.9e3.0 (m, 4H, 30,40-CH2), 3.44 (s, 2H, COCH2N), 3.82
(m, 5H, OCH3 þ 10-CH2N), 6.91 (d, J ¼ 8.0 Hz, 2H, PhH), 6.99 (s,1H, 5-
CH), 7.0e7.2 (m, 4H, ArH), 7.72 (d, J ¼ 8.0 Hz, 2H, PhH), 10.4 (bs, 1H,
NHCO). 13C NMR,
d
ppm: 28.79 (40-CH2), 51.51, 55.98 (10,30-CH2N),
55.26 (OCH3), 60.71 (COCH2N), 105.96 (5-C), 113.99 (m-Ph), 125.98,
126.48, 126.65, 128.77 (50,60,70,80-Ar), 127.29 (o-Ph), 133.29, 133.37
(90,100-Ar), 149.79 (4-C), 156.89 (2-C), 159.44 (p-Ph), 168.51 (CO).
Anal. calcd for C21H21N3O2S: C 66.47, H 5.58, N 11.07, S 8.45. Found:
C 66.10, H 5.52, N 11.01, S 8.41.
4.1.2. 2-[3,4-Dihydroisoquinolin-2(1H)-yl]-N-(1,3-thiazol-2-yl)
ethanamide (5a)
Three different procedures (A, B and C) were used for the syn-
thesis of compound 5a.
(A):
A mixture of 1,2,3,4-tetrahydroisoquinoline (182 mg,
1.37 mmol), 2-chloro-N-(1,3-thiazol-2-yl)ethanamide 3a (241 mg,
1.37 mmol) and triethylamine (1 ml) in benzene (6 ml) was heated
at 65e75 ꢂC for 4 h. The formed precipitate was isolated by filtra-
tion. The solvent from filtrate was removed by distillation and the
residue was washed with hexane and dried to afford 5a (116 mg,
4.1.5. 2-[3,4-Dihydroisoquinolin-2(1H)-yl]-N-[4-(p-methoxy)
phenyl-1,3-thiazol-2-yl]ethanamide hydrochloride (5d)
The product was isolated from the reaction mixture when the
reaction was carried out analogously to procedure B without the
work up by potassium carbonate. Yield 31%, light orange-coloured
31%) as a light beige powder. M.p. 63e65 ꢂC. IR,
n
cmꢀ1: 1687 (C]
crystalline powder, m.p. 135e137 ꢂC. IR, cmꢀ1: 1684 (C]O), 1539
n
O), 1527 (NeH), 1276 (CeN). 1H NMR,
d
ppm: 2.8e3.2 (m, 4H, 30,40-
(NeH),1248 (CeN). 1H NMR, ppm: 2.9e3.0 (m, 4H, 30,40-CH2), 3.43
d
CH2), 3.42 (s, 2H, COCH2N), 3.80 (s, 2H, 10-CH2N), 6.98 (d, J ¼ 3.6 Hz,
(s, 2H, COCH2N), 3.82 (m, 5H, OCH3 þ 10-CH2N), 6.90 (d, J ¼ 8.9 Hz,

A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
853
Fig. 2. Molecular packing of the crystal structure of N-(1,3-benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-yl]ethanamide (6a).
2H, PhH), 6.99 (s, 1H, 5-CH), 7.0e7.2 (m, 4H, ArH), 7.72 (d, J ¼ 8.9 Hz,
2H, PhH), 10.4 (bs, 1H, NHCO). 13C NMR, , ppm: 28.90 (40-CH2),
5-CH), 7.0e7.2 (m, 4H, ArH), 7.36 (d, J ¼ 3.9 Hz, 1H, 4-CH), 12.3 (bs,
1H, NHCO). 13C NMR, ppm: 28.57 (40-CH2), 32.00 (COCH2), 50.39,
52.97, 54.90 (10,30,
-CH2N), 113.28 (5-C), 125.93, 126.47, 126.52,
d
d
51.55, 56.07 (10,30-CH2N), 55.25 (OCH3), 60.89 (COCH2N), 105.94 (5-
C), 113.99 (m-Ph), 125.96, 126.48, 126.62, 128.78 (50,60,70,80-Ar),
127.28 (o-Ph), 133.30, 133.45 (90,100-Ar), 149.80 (4-C), 156.86 (2-C),
159.41 (p-Ph), 168.68 (CO). Anal. calcd for C21H22ClN3O2S: C 60.64,
H 5.33, N 10.10, S 7.71. Found: C 60.97, H 5.26, N 10.17, S 7.81.
a
128.76 (50,60,70,80-Ar), 133.16, 133.74 (90,100-Ar), 137.28 (4-C), 158.24
(2-C), 169.93 (CO). Anal. calcd for C15H17N3OS: C 62.69, H 5.96, N
14.62, S 11.16. Found: C 62.41, H 5.96, N 14.53, S 11.12.
4.1.7. 3-[3,4-Dihydroisoquinolin-2(1H)-yl]-N-[4-(p-methoxy)
phenyl-1,3-thiazol-2-yl]propanamide (5f)
4.1.6. 3-[3,4-Dihydroisoquinolin-2(1H)-yl]-N-(1,3-thiazol-2-yl)
propanamide (5e)
Procedure C. Yield 52%, white crystalline powder, m.p. 125e
Procedure C. Yield 87%, light yellow powder, m.p. 125e127 ꢂC. IR,
127 ꢂC. IR, cmꢀ1: 1684 (C]O), 1539 (NeH), 1248 (CeN). 1H NMR,
n
n
cmꢀ1: 1710 (C]O), 1543 (NeH), 1280 (CeN). 1H NMR,
d
ppm: 2.73
d
ppm: 2.65 (t, J ¼ 6.0 Hz, 2H, COCH2), 2.90 (m, 4H, 30,40-CH2), 3.05
(t, J ¼ 6.3 Hz, 2H, COCH2), 2.9e3.0 (m, 4H, 30,40-CH2), 3.01 (t,
(t, J ¼ 6.0 Hz, 2H, CH2N), 3.78 (s, 2H, 10-CH2N), 3.79 (s, 3H, OCH3),
J ¼ 6.2 Hz, 2H, CH2N), 3.83 (s, 2H, 10-CH2N), 6.90 (d, J ¼ 3.8 Hz, 1H,
6.87 (d, J ¼ 8.8 Hz, 2H, PhH), 6.93 (s, 1H, 5-CH), 7.05e7.2 (m, 4H,

854
A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
ArH), 7.67 (d, J ¼ 8.8 Hz, 2H, PhH), 12.1 (bs, 1H, NHCO). 13C NMR,
“Lactamin” (Sweden). Food pellets and water were available ad
libitum during maintenance.
d
ppm: 28.73 (40-CH2), 31.82 (COCH2), 50.55, 53.06, 54.71 (10,30,
a-
CH2N), 55.25 (OCH3), 105.55 (5-C), 113.90 (m-Ph), 125.91, 126.46,
126.56, 128.72 (50,60,70,80-Ar), 127.19 (o-Ph), 133.29, 133.88 (90,100-
Ar),149.45 (4-C), 157.45 (2-C), 159.37 (p-Ph), 170.13 (CO). Anal. calcd
for C22H23N3O2S: C 67.15, H 5.89, N 10.68, S 8.15. Found: C 66.90, H
5.85, N 10.65, S 8.10.
The aqueous suspensions of tested compounds, prepared with
the addition of two drops of Twin 80, were administered intra-
peritoneally 30 min before carrying out the experiment. The same
volume of the sodium chloride isotonic solution was injected into
the control animals. Comparative assessment of the action of the
substance being investigated at a dose of 5 mg kgꢀ1 was carried out
on groups of 6 animals on indicators of hexenal narcosis, phen-
amine hyperactivity and corazole spasm.
4.1.8. N-(1,3-Benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-
yl]ethanamide (6a)
Procedure A. Yield 47%, light yellow powder, m.p. 132e134 ꢂC. IR,
The action of the substances on the central nervous system was
assessed by its effect on: a) the body temperature, (the criterion for
the test was a lowering of the temperature by 3 ꢂC and more); b)
antispasmodic activity on spasms caused by the intravenous titra-
tion with 1% corazole solution at a rate of 0.01 ml/s; c) duration of
n
cmꢀ1: 1702 (C]O),1530 (NeH), 1267 (CeN). 1H NMR,
d ppm: 2.9e
3.0 (m, 4H, 30,40-CH2), 3.47 (s, 2H, COCH2N), 3.83 (s, 2H, 10-CH2N),
7.0e7.2 (m, 4H, ArH), 7.33 (t, J ¼ 8.5 Hz, 1H, 6-H), 7.43 (t, J ¼ 8.0 Hz,
1H, 5-H), 7.74 (d, J ¼ 8.1 Hz, 1H, 7-H), 7.81 (d, J ¼ 7.8 Hz, 1H, 4-H),
10.45 (bs, 1H, NHCO). 13C NMR,
d
ppm: 28.88 (40-CH2), 51.64,
the hexenal anaesthesia (0.4% hexenal solution at 70 mg kgꢀ1
,
56.10 (10,30-CH2N), 60.85 (COCH2N), 121.03, 121.38, 123.98, 126.22
(4,5,6,7-Ar), 126.02, 126.46, 126.77, 128.79 (50,60,70,80-Ar); 132.21,
133.18 (90,100-Ar), 148.45 (8,9-Ar); 157.06 (2-C), 169.25 (CO). Anal.
calcd for C18H17N3OS: C 66.85, H 5.30, N 12.99, S 9.91. Found: C
66.52, H 5.26, N 12.91, S 9.85.
intravenously) and ethanol narcosis (4 g kgꢀ1, intraperitoneally); d)
locomotor activity and body temperature, measuring the rectal
temperature with an electric thermometer, on joined action of
amphetamine (0.4% amphetamine solution at 10 mg kgꢀ1, subcu-
taneously). The experimental data were processed statistically. The
mean values of ED50 for 12e25 observations were determined by
the express method given in Ref. [60]. For assessing the mean
duration of anaesthetic effect of hexenal, phenamine hyperactivity
and degree of hypothermia, protective action in the corasole spasm
test, the arithmetical mean values and their standard deviations
(M ꢁ m) in comparison with the appropriate control data were
calculated. Assessment of the significance of the differences be-
tween the mean values was carried out on the basis of the Student
criterion. Differences were regarded as significant at a level of
probability P ꢃ 0.5.
4.1.9. N-(4-Chloro-1,3-benzothiazol-2-yl)-2-[3,4-
dihydroisoquinolin-2(1H)-yl]ethanamide (6b)
Procedure C. Yield 63%, light beige powder, m.p. 124e126 ꢂC. IR,
n
cmꢀ1: 1686 (C]O), 1536 (NeH), 1216 (CeN). 1H NMR,
d ppm: 2.9e
3.0 (m, 4H, 30,40-CH2), 3.47 (s, 2H, COCH2N), 3.80 (s, 2H, 10-CH2N),
7.0e7.2 (m, 4H, ArH), 7.24 (t, J ¼ 8.0 Hz, 1H, 6-H), 7.45 (d, J ¼ 8.0 Hz,
1H, 5-H), 7.71 (d, J ¼ 8.5 Hz, 1H, 7-H), 10.6 (bs, 1H, NHCO). 13C NMR,
d
ppm: 28.57 (40-CH2), 51.36, 56.08 (10,30-CH2N), 60.91 (COCH2N),
119.93,124.48 (4,5,6,7-Ar),125.99, 126.42, 126.70, 128.77 (50,60,70,80-
Ar), 133.10, 133.61 (90,100-Ar), 145.58 (8,9-Ar), 157.97 (2-C), 169.74
(CO). Anal. calcd for C18H16N3ClOS: C 60.41, H 4.51, N 11.74, S 8.96.
Found: C 60.55, H 5.52, N 11.67, S 8.89.
4.2.2. In vivo anti-inflammatory activity assays
The experiment was carried out according to the carrageenin-
induced mouse paw oedema inhibition assay [26,55]. Oedema
was induced in the right hind paw of AKR or A mice (20e30 g
months old) by the intradermal injection of 0.05 ml of 2% carra-
geenin in water. Both sexes were used. Females pregnant were
excluded. Each group consisted of 10 animals. The animals, bred in
our laboratory, were housed under standard conditions and
received a diet of commercial food pellets and water ad libitum
during maintenance, but they were entirely fasted during the
experiment period. Our studies were in accordance with recog-
nized guidelines on animal experimentation. The tested com-
pounds, 0.2 mmol kgꢀ1 body weight, were diluted (HCl salt) or
suspended in water with few drops of Tween 80 and ground in a
mortar before use and were administered intraperitoneally simul-
taneously with the carrageenin injection. The mice were eutha-
nized 3.5 h after carrageenin injection. The difference between the
weight of the injected and uninjected paws was calculated for each
animal. The change in paw weight was compared with that in
control animals (treated with water) and expressed as percent in-
hibition of the oedema, CPE values % (Table 3). Indomethacin, at
0.1 mmol kgꢀ1 (57.2%) was used as a reference compound.
Assessment of the significance of the differences between the mean
values was carried out on the basis of the Student criterion. Dif-
ferences were regarded as significant at a level of probability
P ꢃ 0.5.
4.1.10. N-(1,3-Benzothiazol-2-yl)-3-[3,4-dihydroisoquinolin-2(1H)-
yl]propanamide (6c)
Procedure C. Yield 63%, light beige powder, m.p. 123e125 ꢂC. IR,
n
cmꢀ1: 1686 (C]O), 1536 (NeH), 1216 (CeN). 1H NMR,
d ppm: 2.75
(t, J ¼ 5.7 Hz, 2H, COCH2), 2.97 (m, 4H, 30,40-CH2), 3.08 (t, J ¼ 5.7 Hz,
2H, CH2N), 3.87 (s, 2H, 10-CH2N), 7.1e7.2 (m, 4H, ArH), 7.24 (t,
J ¼ 9.0 Hz, 1H, 6-H), 7.37 (t, J ¼ 9.0 Hz, 1H, 5-H), 7.71 (d, J ¼ 9.1 Hz,
1H, 7-H), 7.77 (d, J ¼ 8.6 Hz, 1H, 4-H), 10.5 (bs, 1H, NHCO). 13C NMR,
d
ppm: 28.43 (40-CH2); 31.90 (COCH2), 50.34, 52.78, 54.77 (10,30,
a-
CH2N), 121.00, 121.19, 123.57, 125.89, 126.04, 126.57, 126.61, 128.81,
132.32, 133.01, 133.82, 148.72, 157.45 (2-C), 170.75 (CO). GCeMS, m/
z (%): 205 (Mþetetrahydroisoquinoline, 9), 177 (Mþetetrahy-
droisoquinolineeCH2CH2, 9), 150 (Mþetetrahydroisoquinolinee
CH2CH2CO, 100). LCeMS, m/z (%): 338 (Mþ þ 1, 100). Anal. calcd for
C
19H19N3OS: C 67.63, H 5.68, N 12.45, S 9.50. Found: C 66.64, H 5.73,
N 12.12, S 9.32.
4.2. Biological activity assays
4.2.1. In vivo psychotropic activity assays
The neurotropic activity of the synthesized compounds was
studied in ICR female mice of 6 weeks old weighing 19e26 g in
winter season. The animals, bred in our laboratory, were housed
under standard conditions (cage size 43 ꢄ 27 ꢄ 15 cm). Our studies
were in accordance with recognized guidelines on animal experi-
mentation. The room temperature was maintained within the
limits of 22 ꢁ 2 ꢂC, relative humidity of 55 ꢁ 15%, air ventilation of
15e20 air volume change/h and 12 h (7:00e19:00) light/dark cycle.
The litter was from “Basic micro” (The Netherlands) and food from
4.2.3. In vitro antimicrobial activity assays
For the determination of antimicrobial activity several reference
microbial strains, received from the Microbial Strain Collection of
Latvia (MSCL), Riga, Latvia, were used: S. aureus MSCL 334 (SA), B.
cereus MSCL 330 (BC), P. mirabilis MSCL 590 (PM), E. coli MSCL 332
(EC), P. aeruginosa MSCL 331 (PA) and C. albicans MSCL 378 (CA) and

A. Zablotskaya et al. / European Journal of Medicinal Chemistry 70 (2013) 846e856
855
A. niger MSCL 324 (AN). All bacteria were cultivated on Plate count
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