2-Allylaminothiazole and 2-allylaminodihydrothiazole derivatives: Synthesis, characterization, and evaluation of bioactivity

Article abstract of DOI:10.1007/s00706-015-1539-z

Some reactions of selected chlorooxoesters and haloesters with a 1-allylthiourea under various conditions have been performed. The reactions have been performed in methanol in alkaline and neutral environment. Condensation of 1-allylthiourea with chlorooxoesters has been further led via acetal as intermediate compound. As a result, the compounds containing thiazole and a 4,5-dihydrothiazole ring with a good yield have been obtained. The structures of the compounds were verified by ¹H NMR, ¹³C NMR as well as X-ray diffraction analysis. Due to the potential biological activity of the synthesized compounds, the parameters of their bioavailability have been determined, and the probability of pharmacological action has been defined. All of the obtained compounds fulfilled the rule of five, which indicate their good absorption after oral intake. The probability of pharmacological action and potential targets calculated for the obtained compounds show that they can be potential drugs. Graphical abstract: (Equation Presented).

Full text of DOI:10.1007/s00706-015-1539-z

Monatsh Chem
DOI 10.1007/s00706-015-1539-z
ORIGINAL PAPER
2-Allylaminothiazole and 2-allylaminodihydrothiazole derivatives:
synthesis, characterization, and evaluation of bioactivity
1
2
3
2
•
Renata Studzi n´ ska
•
Aleksandra Karczmarska-W o´ dzka
•
Anna Kozakiewicz
2
•
Renata Kołodziejska
Bo z_ ena Modzelewska-Banachiewicz
1
2
1
Renata Paprocka
•
Marcin Wr o´ blewski
•
Beata Augusty n´ ska
•
Received: 7 June 2015 / Accepted: 13 July 2015
Ó The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract Some reactions of selected chlorooxoesters and
haloesters with a 1-allylthiourea under various conditions
have been performed. The reactions have been performed
in methanol in alkaline and neutral environment. Conden-
sation of 1-allylthiourea with chlorooxoesters has been
further led via acetal as intermediate compound. As a
result, the compounds containing thiazole and a 4,5-dihy-
drothiazole ring with a good yield have been obtained. The
Graphical abstract
1
13
structures of the compounds were verified by H NMR,
C
NMR as well as X-ray diffraction analysis. Due to the
potential biological activity of the synthesized compounds,
the parameters of their bioavailability have been deter-
mined, and the probability of pharmacological action has
been defined. All of the obtained compounds fulfilled the
rule of five, which indicate their good absorption after oral
intake. The probability of pharmacological action and
potential targets calculated for the obtained compounds
show that they can be potential drugs.
Keywords Heterocycles Á Thiazole derivatives Á
Organic synthesis Á Structure–activity relationships Á
X-ray structure determination
Introduction
The thiazole and 4,5-dihydrothiazole derivatives exhibit
promising biological activity. The attention should be paid
to, among others, biovitrum BVT-2733, biovitrum BVT-
1
4225 [1–4], and amgen 2922 [4–6], which are described
as inhibitors of 11b-hydroxysteroid dehydrogenase type 1
Fig. 1). 11b-Hydroxysteroid dehydrogenase type 1 regu-
(
&
Renata Studzi n´ ska
rstud@cm.umk.pl
lates glucocorticoid action, and the inhibition of this
enzyme is a viable therapeutic strategy for the treatment of
type 2 diabetes and the metabolic syndrome. Furthermore,
compounds containing a thiazole ring are used as inhibitors
of thymidylate synthase [7, 8]. Due to their biological
activity, it is worth concentrating on the efficient method of
the thiazole and dihydrothiazole ring formation.
1
Department of Organic Chemistry, Faculty of Pharmacy,
Collegium Medicum in Bydgoszcz, Nicolaus Copernicus
University in Toru n´ , Toru n´ , Poland
2
3
Department of Biochemistry, Faculty of Medicine, Collegium
Medicum in Bydgoszcz, Nicolaus Copernicus University in
Toru n´ , Toru n´ , Poland
One of the ways of forming a dihydrothiazole ring is the
reaction of thiourea or its derivatives with haloacids. Such
reactions have been described before [9, 10]. They have
Department of Crystallochemistry and Biocrystallography,
Faculty of Chemistry, Nicolaus Copernicus University in
Toru n´ , Toru n´ , Poland
123

R. Studzi n´ ska et al.
Fig. 1 11b-Hydroxysteroid dehydrogenase type 1 inhibitors containing a thiazole and dihydrothiazole ring
Table 1 The condensation reaction of 1 with 2-haloesters 2-4
1
R
a
No.
X
Procedure
Time/h
Yield of 5–7/%
M.p. of 5–7/°C
b
2
Cl
H
A
B
A
B
A
B
8
50
89–90
24
1
Trace
68
3
4
a
Br
Br
CH
3
75–76
77–78
1
47
C
2
H
5
3
65
2
40
Procedure A: MeOH, MeONa, the boiling point; procedure B: EtOH, the boiling point
b
Ref. [9] 102–103 °C
been carried out in various solvents, i.e., water, pyridine,
reaction of 1 with haloesters was carried out in methanol
with a 10 % excess of ester and a double excess of sodium
methoxide (procedure A). The products were extracted in a
yield of 50–65 %. Additionally, the analogous reactions
without the base afforded products 6 and 7 in lower yields
(40–47 %), whereas only trace amounts of product 5 were
obtained from ester 2 (procedure B). The structures of 5–7
benzene, and acetonitrile. The obtained products had the
form of hydrogen halides. To obtain dihydrothiazoles,
hydrogen halides were treated in alkaline conditions:
sodium carbonate or aqueous solution of ammonia.
Due to the previously conducted condensation reactions
of 1-allylthiourea (1) with oxoesters in alkaline conditions,
which have allowed us to obtain the N-allylthiouracil
derivatives [11, 12], we have become interested in carrying
out the reactions of haloesters with 1 in similar conditions.
Encouraged by high efficiency of the synthesized products
as well as the easiness of their extracting, we have
1
13
were verified by H and C NMR spectral data, as well as
mass spectra. The structures of 5 and 7 were also verified
by X-ray diffraction analysis (Fig. 2).
The above-mentioned highly selective reactions in a
good yield in alkaline conditions have encouraged us to
carry out the analogous reactions with the use of 1 and
chlorooxoesters. The condensation reactions of 1 with
expanded
the
conducted
synthesis
applying
chlorooxoesters.
3-oxoesters lead to the formation of 3-allyl-2-thiouracil
(Fig. 3) [13, 14]. The presence of a chlorine atom in the
Results and discussion
Chemistry
oxoester molecules 9 and 10 causes a carbonyl group and a
halogen atom to be involved in the reaction, while an ester
group is not (Fig. 3; Table 2). Furthermore, the nucle-
ophilic substitution reaction occurs on the sulfur atom, but
does not occur on the nitrogen atom, as in the case of
addition elimination reaction in the ester group of a
The condensation reactions for three different haloesters 2–
4
were carried out in alkaline conditions (Table 1). The
1
23

2
-Allylaminothiazole and 2-allylaminodihydrothiazole derivatives: synthesis…
Fig. 2 X-ray structure of 5 (left) and 7 (right)
Fig. 3 The reaction of 1 with 3-oxoesters, chlorooxoesters, and haloesters
3
-oxoester molecule. Consequently, a five (not six)-mem-
chlorooxoesters in ethanol let us obtain products 11 and 12 in
higher yields (35–42 %) (procedure B). A further increase of
a yield was obtained due to transforming a carbonyl group
into acetal, followed by the reaction of obtained acetals from
1 in acidic environment, according to the procedure descri-
bed above (procedure C) [14]. The structures of 11 and 12
bered ring containing nitrogen and sulfur atom is formed,
in the same way as while using haloesters 2–4 (Table 1).
As a result of addition of 1 to the carbonyl group of
chlorooxoester, and then the elimination of water, the
cyclic products 11, 12, containing not one but two double
bonds in the ring, were formed.
1
13
were verified by H and C NMR spectral data, mass
spectra, as well as X-ray diffraction analysis (Fig. 4).
The reaction of 1 with chlorooxoesters and haloesters
was carried out at the same alkaline conditions (procedure
A). In the first case the products were obtained with a much
lower yield (4–15 %), which is probably due to two
simultaneous condensation reactions: aldol and Claisen
condensation reaction (Table 2).
Evaluation of biological activity
Due to the biological activity of the compounds containing
thiazole and dihydrothiazole rings [1–8], we have calcu-
lated the parameters conditioning the bioavailability of the
synthesized compounds and their probable activity.
The poor yield of products 11 and 12 made us change the
conditions of conductingthe reactions. The reactionof 1with
123

R. Studzi n´ ska et al.
Table 2 The condensation reaction of 1 with chlorooxoesters
2
3
R
a
No.
R
Procedure
Time/h
Yield of 11–12/%
M.p. of 11–12/ °C
b
9
CH
CH
3
2
COOC
H
H
2 5
A
B
C
A
B
C
38
1
4
42
82
15
35
60
104–105
1
1
0
COOC
H
2 5
13
1
42–43
1
a
3 3 2 4
Procedure A: MeOH, MeONa, procedure B: EtOH, procedure C: step 1—MeOH, HC(OCH ) , step 2—EtOH, H SO
b
Ref. [15] 70–73 °C, Ref. [16] 109–110 °C
Fig. 4 X-ray structure of 11 (left) and 12 (right)
Table 3 The value of molecular weight, miLogP, hydrogen donors and acceptors, and TPSA calculated by Molinspiration program
5
6
7
11
12
Molecular weight
miLogP
156.21
0.361
1
170.24
0.724
1
184.26
1.226
1
226.30
1.527
2
226.30
2.150
1
nOHNH
nON
3
3
3
4
4
2
˚
TPSA/A
41.46
41.46
41.46
62.23
51.22
Lipinski’s rule of five describes molecular properties
important for drug pharmacokinetics in the human body,
especially their oral absorption. The rule says, that an
orally active drug must not violate more than one of the
following criteria: B5 hydrogen donors (nOHNH), B10
hydrogen acceptors (nON), MW B 500 Da, log Pcalc B5
2–4, 11, 12 fulfilled the rule of five, which indicate their
good absorption after oral intake.
Topological polar surface area (TPSA) becomes another
popular indicator of drug absorbance [19]. TPSA values
2
lower than 140 A suggest good cell membrane perme-
˚
ability of derivatives 2-4 and 11, 12. Moreover, calculated
2
TPSA values below 60 A suggest high chances to pene-
˚
[
17]. Those properties calculated with Molinspiration
program [18] are presented in the Table 3. All compounds
trate blood–brain barrier for compounds 2–4 and 12.
1
23

2
-Allylaminothiazole and 2-allylaminodihydrothiazole derivatives: synthesis…
Table 4 Probabilities of biological activity and action mechanisms for compounds 5–7, 11, 12
Pa/%
5
6
7
11
12
Pharmacological action
Antieczematic
36.6
78.5
55.6
49.9
46.1
71.0
35.0
67.1
67.7
66.6
40.2
55.7
53.7
60.1
65.7
61.8
30.4
55.2
59.4
69.3
55.6
61.6
29.8
57.2
67.4
52.0
30.9
45.5
54.3
60.7
68.5
62.5
65.9
52.9
np
89.6
83.2
75.2
66.3
21.4
np
Mucomembranous protector
Antiulcerative
Antiviral
Radioprotector
Mechanism of action
Chloride peroxidase inhibitor
Muramoyltetrapeptide carboxypeptidase inhibitor
Membrane permeability inhibitor
43.9
49.8
68.9
43.1
55.9
75.5
46.6
36.2
51.5
-
Cl -transporting ATPase inhibitor
Gastrin inhibitor
np Not predicted
The probability of pharmacological action and potential
targets for compounds 2–4 and 11, 12 were calculated by
PASS online program [20], which is based on analysis of
structure–activity relationships (SAR) of chemical compounds
and predicts over 4000 kinds of biological activities, including
pharmacological effects, mechanisms of action, toxic and
adverse effects with average accuracy above 95 % [21]. The
selected results of the predicted activities and mechanisms of
action of 2–4 and 11, 12 are presented in Table 4.
Experimental
1
13
H NMR and C NMR spectra were recorded on Bruker
300 MHz, 400 MHz, and 700 MHz apparatus (TMS as an
internal standard). MS spectra were recorded on the Fin-
nigan MAT 95. UV spectra were recorded on the
spectrophotometer Aquarius 7250 Cecil Instruments. All
chemicals and solvents were purchased commercially and
used without further purification. The progress of reactions
and also the purity of the obtained compounds were
monitored by TLC on TLC-sheets ALUGRAM SIL
G/UV254 plates with ethyl acetate as an eluent.
The best results were obtained for derivative 12, which
showed the highest probabilities for the mucomembranous
protection, antieczematic, antiulcerative, and antiviral
activity. The predictions for compounds 2–4 and 12
showed that they are also possible mucomembranous pro-
tectors. Moreover, derivatives 3, 4 may be radioprotectors
and may have antiviral activity. According to PASS cal-
culations a possible mechanism of action for compounds
General procedures for the synthesis of compounds
5–7, 11, 12
Procedure A
2
–4 and 11, 12 is enzymes inhibition: chloride peroxidase,
To a solution of sodium methoxide (prepared from 0.1 mol
3
of sodium in 60 cm anhydrous MeOH), 0.05 mol of 1 and
-
muramoyltetrapeptide carboxypeptidase, Cl -transporting
ATPase. Other mechanisms of membrane permeability and
gastrin inhibitions should be associated with mucomem-
branous protection and antiulcerative activity, respectively.
0.055 mol of ester (2–4, 9, 10) were added and refluxed
(reflux time depends on the compounds present in
Tables 1, 2). The solvent was evaporated and the residue
was dissolved in water and neutralized with HCl to pH 7–8.
The product was extracted with CHCl , dried, concen-
3
Conclusion
trated, and crystallized from diethyl ether.
In conclusion, we have successfully conducted simple
synthesis leading to the compounds containing thiazole and
Procedure B
3
To a solution of 30 cm anhydrous EtOH, 0.05 mol of 1
4
,5-dihydrothiazole ring in the reaction of 1-allylthiourea
and 0.055 mol of ester (2–4, 9, 10) were added and
refluxed (reflux time depends on the compounds present in
Tables 1, 2). The solvent was evaporated and the residue
was dissolved in water and neutralized with NaOH to pH
with haloesters and oxoesters, respectively. By changing
the reaction conditions we have managed to obtain the
products of a very good performance. The method is very
universal and can be applied for the synthesis of com-
pounds containing thiazole and dihydrothiazole rings.
7–8. The product was extracted with CHCl , dried, con-
3
centrated, and crystallized from diethyl ether.
123

R. Studzi n´ ska et al.
Procedure C
3
To a solution of 30 cm anhydrous MeOH, 0.03 mol of
Ethyl 2-(allylamino)-4-methylthiazole-5-carboxylate
(11, C H N O S)
1
0 14 2 2
triethyl orthoformate, 0.075 g p-toluenesulfonic acid and
M.p.: 104–105 °C; UV (H O ? 5 % EtOH): kmax
2
3 -1 3
0
.05 mol of chlorooxoester 9 or 10 were added and mixed
(e 9 10 ) = 216 (9.77), 308 (17.73) nm (mol
dm
3
for 24 h. Diethyl ether (30 cm ) was added to the mixture
-1
1
cm ); H NMR (CDCl ): d = 1.32 (t, J = 6.9 Hz, 3H,
3
4
OCH CH ), 1.87 (1H, NH), 2.51 (s, 3H, C –CH ), 3.88 (d,
and neutralized with sodium ethoxide to pH 7–8, then
3
0 cm distilled water was added. The product was
2
3
3
3
J = 5.2 Hz, 2H, CH =CH–CH ), 4.25 (q, J = 7.1 Hz,
2 2
extracted with diethyl ether and dried with sodium car-
2H, OCH CH ), 5.23 (dd, 1H, J = 1.5, 10.2 Hz, CH
2 3 A
bonate. The solvent was evaporated and to the residue
H =CH–CH ), 5.33 (dd, J=1.5, 17.3 Hz, 1H,
B 2
13
3
.02 mol of 1, and 0.11 cm of concentrated sulfuric acid
were added and refluxed for 1 h. The solvent was evapo-
0
CH H =CH–CH ), 5.88 (m, 1H, CH =CH–) ppm;
C
A
B
2
2
NMR (100 MHz, CDCl ): d = 171.6, 162.7, 159.4, 132.5,
3
3
rated and the residue was dissolved in 30 cm water and
117.7, 109.3, 60.4, 48.3, 17.4, 14.5 ppm; MS (CI, isobu-
?
tane): m/z (%) = 227 ([M ? 1] , 100).
neutralized with NaOH to pH 7–8. The product was
extracted with CHCl , dried, concentrated, and crystallized
3
from diethyl ether.
Ethyl 2-[2-(allylamino)thiazol-4-yl]acetate
(
12, C H N O S)
10 14 2 2
2
-(Allylamino)thiazol-4(5H)-one (5, C H N OS)
6 8 2
M.p.: 42–43 °C; UV (H O ? 5 % EtOH): kmax
(e 9 10 ) = 261 (7.55) nm (mol dm cm ); H NMR
2
M.p.: 89–90 °C; UV (H O ? 5 % EtOH):
k
2
max
-1
3
-1
3
-1
1
3
-1
3
(
e 9 10 ) = 191 (0.75), 230.5 (2.22) nm (mol dm cm );
1
(CDCl ): d = 1.28 (t, J = 6.9 Hz, 3H, OCH CH ), 1.93
3
2
3
H NMR (CDCl ): d = 3.83 (s, 2H, CH ), 3.94 (t, J = 1.4 Hz,
3
2
(1H, NH), 3.57 (d, J = 0.9 Hz, 2H, CH OCH CH ), 3.86 (d,
2 2 3
1H, NH), 3.96 (dd, J = 1.4, 5.6 Hz, 2H, CH =CH–CH ), 5.24
2 2
J = 5.2 Hz, 2H, CH =CH–CH ), 4.21 (q, J = 6.9 Hz, 2H,
2
2
(dd, J = 2.1, 10.5 Hz, 1H, CH H =CH–CH ), 5.31 (dd,
A B 2
OCH CH ), 5.20 (dd, J = 1.5, 11.1 Hz, 1H, CH H =CH–
2
3
A B
J = 2.1, 17.5 Hz, 1H, CH H =CH–CH ), 5.90 (m, 1H,
A
B
2
1
3
CH ), 5.31 (dd, J=1.5, 17.4 Hz, 1H, CH H =CH–CH ), 5.91
2 A B 2
CH =CH–) ppm; C NMR (100 MHz, CDCl ): d = 185.8,
2
3
5 13
m, 1H, CH =CH–), 6.34 (t, J = 0.9 Hz, 1H, C H) ppm; C
(
2
1
83.8, 131.7, 118.6, 47.1, 38.7 ppm; MS (CI, isobutane):
?
NMR (100 MHz, CDCl ): d = 170.5, 169.7, 145.0, 133.5,
3
m/z (%) = 157 ([M ? 1] , 100).
-(Allylamino)-5-methylthiazol-4(5H)-one
6, C H N OS)
1
17.2, 103.6, 60.9, 48.3, 37.4, 14.2 ppm; MS (70 eV):
?
m/z = 226 ([M ? 1] , 100).
2
(
7
10 2
M.p.: 75–76 °C; UV (H O ? 5 % EtOH): kmax
2
3
-1
3
X-ray diffraction study
(
e 9 10 ) = 192.5 (0.97), 231 (2.19) nm (mol
dm
-
1
1
cm ); H NMR (CDCl ): d = 1.61 (d, J = 7.0 Hz, 2H,
3
The X-ray data for reported structures were collected at
C–CH ), 3.91 (t, J = 1.4 Hz, 1H, NH), 3.93 (dd, J = 1.4,
3
293(2) K with an Oxford Sapphire CCD diffractometer
5
.6 Hz, 2H, CH =CH–CH ), 4.08 (q, J = 7.0 Hz, CH–
2 2
using MoKa radiation k = 0.71073 A and x-2h method.
The numerical absorption corrections were applied
CH ), 5.23 (dd, J = 1.4, 10.5 Hz, 1H, CH H =CH–CH ),
3
A
B
2
5
.31 (dd, J = 1.4, 17.5 Hz, 1H, CH H =CH–CH ), 5.90
A B 2
1
3
(
[
RED171 package of programs Oxford Diffraction, 2000)
(
m, 1H, CH =CH–) ppm; C NMR (100 MHz, CDCl3):
2
22]. All structures have been solved by direct methods and
d = 189.0, 182.2, 131.7, 118.5, 49.6, 47.2, 19.0 ppm; MS
2
?
refined with the full-matrix least-squares method on F
with the use of SHELX-97 program package [23]. The
hydrogen atoms have been located from the different
electron density maps and constrained during refinement.
The crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre, the CCDC
numbers: 1034864 for 5 and 1034865–1034867 for 7, 11,
and 12, respectively.
(
CI, isobutane): m/z (%) = 171 ([M ? 1] , 100).
-(Allylamino)-5-ethylthiazol-4(5H)-one
7, C H N OS)
2
(
8
12 2
M.p.: 77–78 °C; UV (H O ? 5 % EtOH): kmax
2
3
-1
3
(
e 9 10 ) = 192 (0.85), 231.5 (2.31) nm (mol
dm
-
1
1
cm ); H NMR (CDCl ): d = 0.99 (dt, J = 2.8, 7.0 Hz,
3
3
H, CH–CH –CH ), 2.00 (dq, J = 2.8, 4.2 Hz, 2H, CH–
2 3
CH –CH ), 3.95 (dd, J = 1.4, 5.6 Hz, 2H, CH =CH–CH ),
2
3
2
2
4
.09 (t, J = 1.4 Hz, 1H, NH), 4.18 (tq, J = 4.2, 7.0 Hz, CH–
Open Access This article is distributed under the terms of the
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made.
C H ), 5.23 (dd, J = 1.4, 10.5 Hz, 1H, CH H =CH–CH ),
2
2
5
A
B
5
.30 (dd, J = 1.4, 17.5 Hz, 1H, CH H =CH–CH ), 5.94 (m,
A B 2
1
H, CH =CH–) ppm; C NMR (100 MHz, CDCl3):
3
1
2
d = 188.0, 182.6, 131.8, 118.4, 57.4, 47.3, 26.2, 11.5 ppm;
MS (CI, isobutane): m/z (%) = 185 ([M ? 1] , 100).
?
1
23

2
-Allylaminothiazole and 2-allylaminodihydrothiazole derivatives: synthesis…
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