Silyl modification of biologically active compounds. 8. Trimethylsilyl ethers of hydroxyl-containing thiazole derivatives

Article abstract of DOI:10.1023/A:1020698107686

Trimethylsilyl ethers of various hydroxyl-containing thiazole derivatives have been synthesized. The psychotropic activity (in vivo) and the cytotoxicity (in vitro on tumor cell lines HT-1080 and MG-22A) of these ethers and of their unsilylated precursors

Full text of DOI:10.1023/A:1020698107686

Chemistry of Heterocyclic Compounds, Vol. 38, No. 7, 2002
SILYL MODIFICATION OF BIOLOGICALLY
ACTIVE COMPOUNDS. 8*. TRIMETHYLSILYL
ETHERS OF HYDROXYL-CONTAINING
THIAZOLE DERIVATIVES
A. Zablotskaya1, I. Segal1, S. Germane1, I. Shestakova1, I. Domracheva1, A. Nesterova1,
A. Geronikaki2, and E. Lukevics1
Trimethylsilyl ethers of various hydroxyl-containing thiazole derivatives have been synthesized. The
psychotropic activity (in vivo) and the cytotoxicity (in vitro on tumor cell lines HT-1080 and MG-22A)
of these ethers and of their unsilylated precursors have been studied. It was discovered that the
obtained compounds possess a sedative action. A moderate cytotoxic effect was detected for piperidine-
containing thiazoles, displayed most strongly in relation to MG-22A cells.
Keywords: piperidine, silyl group, thiazole, psychotropic activity, silylation, cytotoxicity.
The role of the thiazole ring in biological processes is well known. A thiazole ring is the active part of
thiamine (vitamin B1) and thiamine pyrophosphate (cocarboxylase), which are coenzymes in the composition of
certain enzymes (dehydrogenase and transkelase of γ-hydroxyketoglutarate) or are an important group for
certain multienzymes (complexes of pyruvate dehydrogenase and -ketoglutarate). Due to the effective
α
influence on various functions of the organism and participation in metabolism and neuroregulation, thiamine
displays a positive action on various pathological processes. Thiamine and its derivatives are therefore accepted
pharmaceutical agents. In addition, compounds containing a thiazole ring possess psychotropic activity [2-7],
and a series of bisthiazolium salts have the properties of neuromuscular blocking agents [8].
One of the problems of designing new drugs is the preparation of biologically active substances with
increased lipophilicity, in order to provide penetration of the drug through the plasma membrane (lipid bilayer)
and, for substances influencing the central nervous system, passage through the blood–brain barrier. A series of
investigations has shown that silyl modification is one of the most effective means of solving this problem. Our
investigations [1,9-14] also confirm the promise of such an approach. The O(N)-silyl derivatives are inclined
towards chemical and metabolic hydrolysis with the formation of the initial compound, being so-called prodrugs
in this respect. The expected byproducts of hydrolysis (the triorganosilanols and disiloxanes) are mainly
nontoxic or weakly toxic compounds.
We have obtained trimethylsilyl ethers (2,4,6,13-15) of various hydroxyl-containing thiazoles (1,3,5,10-
12) and also a C-silyl derivative, an organosilicon salt of 2-aminothiazole (16). The psychotropic activity and
also the cytotoxicity of these compounds has been studied in comparison with their unsilylated precursors.
_______
* For Part 7 see [1].
__________________________________________________________________________________________
1
2
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: AEZ@osi.lv.
Department of
Pharmaceutical Chemistry, Aristotelian University of Thessaloniki, 54006, Greece. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 968-976, July, 2002. Original article submitted October 8, 2001.
0009-3122/02/3807-0859$27.00©2002 Plenum Publishing Corporation
859

The organosilicon derivatives of 5-(β-hydroxyethyl)-4-methylthiazole 2, and of 2-amino- and
4-hydroxymethyl-2-phenylthiazole 4 and 6 were synthesized by heating the initial thiazoles 1, 3, and 5 with
hexamethyldisilazane for several hours.
Me
Me
N
N
(CH2)2OSiMe3
(CH2)2OH
silylation by
(Me3Si)2NH
S
S
1
2
– (Me3Si)2O
CH2OH
CH2OSiMe3
chemical or
metabolic
hydrolysis
N
N
R
R
S
S
3, 5
4, 6
3, 4 R = NH2; 5, 6 R = Ph
The N-(2-thiazolyl)amides 10-12 were synthesized by the condensation of 2-aminothiazole (substituted
or unsubstituted) with the appropriate acyl chloride (chloroacetic or chloropropionic acid chlorides) and then
reaction of the obtained chloroalkylamide 7-9 with 4-hydroxypiperidine [15, 16]. Heating thiazoles 10-12 with
hexamethyldisilazane leads to the formation of the trimethylsilyl ethers 13-15.
1
1
R
R
O
N
N
Cl(CH2) COCl
n
C(CH2)
Cl
n
R2
R2
NH2
N
H
S
S
7–9
1
R
O
N
HN
OH
C(CH2)
N
OH
n
R2
N
H
S
10–12
1
R
O
N
C(CH2)
N
OSiMe3
n
2
R
N
S
H
13–15
1
2
1
2
1
2
7, 10, 13 R = R = H, n = 2; 8, 11, 14 R = Ph, R = H, n = 1;
R = Ph, R = n-C14H29, n = 1
9, 12, 15
The organosilicon salt 16 was obtained by the quaternization of 2-aminothiazole with
3-(trimethylsilyl)propyl iodide.
+
N
N(CH2)3SiMe3
I(CH2)3SiMe3
_
I
NH2
NH2
S
S
16
The neurotropic activity of the synthesized compounds was studied in a series of tests. Results of the
study of the neurotropic properties and the acute toxicity are given in Tables 1 and 2.
860

TABLE 1. Neurotropic Activity of Hydroxyl-containing Thiazoles and Their Trimethylsilyl Ethers
M ± m, % control (100%)
Test
Com-
amphetamine
hypothermia
°C (30 min)
amphetamine
hyperactivity
(30 min)
pound
corazole spasms
(clonic/tonic)
retrograde
amnesia*2
hypoxic hypoxia
hexenal narcosis
ethanol narcosis
instruction, sec*3
-0.2
-2.6*
-2.4*
-2.0*
-0.8*
0.4
-2.6*
-3.4*
0.7
-0.4
-2.8
-1.2
-0.8
16*
17*
39*
85
83*
30*
81*
65*
48*
137*
48*
99
120*
171*
152*
122*
146*
141*
152*
137*
178*
155*
162*
170*
124*
16.9
94
87
87*
97
105
121*
102
89*
150*
119
110
131*
117*
256*
172*
113
185*
172*
167*
131*
238*
108
96/117*
156*/137*
146*/129*
166*/140*
128*/130*
145*/128*
146*/109
137*/142*
144*/184*
119/116
100*
100*
60
40*
40
100*
80*
20
80*
0
143.4* ± 7.8
140.8* ± 9.3
95.2 ± 20.7
85.8 ± 18.2
51.5 ± 38.4
147.8* ± 7.1
137.0* ± 8.6
59.8 ± 1.4
128.2* ± 14.2
33.8 ± 21.9
87.4 ± 22.8
127.8* ± 8.7
161.4* ± 1.8
1
2
3
4
5
6
10
11
12
13
14
15
16
139*
156*
89
140*/144*
149*/180*
149*/130*
40
80*
100*
42*
_______
* P < 0.05.
*2 Control, %: 33.3.
*3 Control, sec: 58.1±10.9.

TABLE 2. The Effect of Hydroxyl-containing Thiazoles and Their Trimethylsilyl Ethers on the Tone of the Skeletal
Musculature and Movement Coordination
ЕD50, mg/kg
Compound
LD50, mg/kg
Test
rotating rod
>250
tubes
>250
rectal temperature
>250
analgesia
>250
narcosis
>250
pulling on a beam
>250
>1000
>250
>1000
1
2
3
355
137
224
129
(61-202)
>250
346
(120-662)
>250
(249-461)
(50-262)
(144-285)
>1000
>400
>250
>250
>250
65
51
>250
>250
>250
>250
>250
>250
>250
>250
>250
>25
4
(37-100)
(29-79)
69
274
45
355
274
5
(24-130)
(99-524)
(31-60)
(249-461)
(99-524)
258
>250
>250
>250
141
>250
>250
>250
>250
6
(108-357)
(92-209)
815
87
172
69
10
13
11
14
12
15
16
(567-1110)
(73-332)
(24-130)
>250
>1000
>250
>250
258
>250
(168-357)
89
69
41
205
87
(63-120)
(24-130)
(27-55)
(146-288)
(30-165)
>250
>224
45
204
>250
>250
>250
(144-285)
(31-60)
(144-285)
>500
>250
>250
>250
69
141
(24-130)
(68-209)
>1000
69
41
51
(24-130)
(27-55)
(36-69)
51.5
28.2
28.2
28.2
25.8
28.2
(36.2-69.2)
(18.3-37.2)
(18.3-37.2)
(18.3-37.2)
(16.8-35.7)
(18.3-37.2)

All the compounds investigated possess antihypoxic properties and prolong the life of mice under
conditions of hypoxia by 20-78%. The silylated and unsilylated compounds in the majority of cases display
antihypoxic activity of the same order, in individual cases the activity grew by 25-51% (see 1 and 2, 11 and 14)
on introducing the trimethylsilyl group.
The most active antihypoxic agents were the piperidine-containing thiazoles 12 and 15, prolonging the
life of mice by 78 and 70% respectively.
The action of the synthesized compounds at a dose of 5 mg/kg on the prolongation of hexenal narcosis
varied. The piperidine-containing thiazole 10 prolonged narcosis by 21%, and its trimethylsilyl ether 13 by 50%.
The prolongation of narcosis was reduced insignificantly under the influence of trimethylsilyl ether 4 and the
piperidine-containing thiazole 12.
In the case of ethanol narcosis the action of the synthesized compounds was more marked. They almost
all prolonged the action of ethanol narcosis (by 17-156%), while the silylated and unsilylated compounds
displayed activity of the same order (117-238 and 139-256% respectively). The most reliable prolongation of
narcosis (by 129%) on introducing the trimethylsilyl substituent was noted in the case of 5-(β-hydroxyethyl)-4-
methylthiazole (1) and its trimethylsilyl ether 2.
Almost all of the compounds studied possess an antispasmic action on corazole spasms (clonic and
tonic). They increased the threshold of corazole spasms by 28-66% in the tonic and 17-84% in the clonic phase.
In several cases in this test the trimethylsilyl ethers were stronger anticonvulsants (see 1 and 2, 3 and 4, 5 and 6,
11 and 14). The strongest anticonvulsive action was possessed by the piperidine-containing thiazole 12 and its
trimethylsilyl ether 15 (133/184 and 149/180% respectively).
The substances investigated did not display protective properties in the maximal electroshock test.
The majority of the compounds investigated act as amphetamine antagonists, reducing locomotor
activity caused by the administration of amphetamine by 17-84%.
The greatest effect on the interaction with amphetamine was observed for compound 1 and its
trimethylsilyl ether 2 which significantly reduced locomotor activity (by 85-84%) for 30 min. The most reliable
strengthening of the antagonistic properties in relation to amphetamine on introducing a trimethylsilyl group (by
53%) was noted on comparing 4-hydroxymethyl-2-phenylthiazole 5 and its silyl ether 6.
Study of the influence of the substances investigated on memory processes showed that for a series of
compounds retrograde amnesia was prevented (100%), and also the latent period of instruction was increased.
The most active on these processes proved to be trimethyl ether 6, which at a dose of 5 mg/kg completely
prevented retrograde amnesia.
All of the compounds had almost no effect on the tone of the skeletal musculature and movement
coordination (Table 2).
Hypothermic action, like the analgesic action, was also expressed extremely weakly in the compounds
studied.
According to the results of investigating the neurotropic activity of 2-amino-3-(γ-
trimethylsilyl)propylthiazolium iodide (16), this organosilicon salt shows neurotropic action in several tests of
the same order as the remaining compounds. Its greatest effect might be expected on memory processes.
The cytotoxic ptoperties (in vitro) of the compounds synthesized were also studied in relation to two
lines of tumor cells, HT-1080 (human lung fibrosarcoma) and MG-22A (mouse hepatoma) (see Table 3).
A large proportion of the compounds studied, mainly the piperidine-containing derivatives 10-12, 13-15,
possess low cytotoxicity in relation to cell line HT-1080 and moderate in relation to MG-22A. Compounds 1-4
were not cytotoxic, and the cytotoxic effect of compounds 5 and 6 was low. The strongest cytotoxic action on
tumor cells (MG-22A) was possessed by the piperidine derivative of thiazole 11 and its trimethylsilyl ether 14.
The introduction of the trimethylsilyl group was clearly followed by a strengthening of the cytotoxic effect in
both tests. The organosilicon salt 16 displayed the greatest activity in relation to HT-1080 cells among all the
compounds studied.
863

TABLE 3. Cytotoxic Activity in vitro TD50 and NO of Hydroxyl- and
Silicon-containing Thiazoles*
Cell line
HT 1080
TD50, µg/ml
MTT
MG 22-A
TD50, µg/ml
Compound
NO, %
CV
NO, %
CV
CV
CV
MTT
No activity
4
5
3
5
9
4
200
27
350
250
40
250
275
No activity
4
9
6
6
6
10
200
300
350
200
150
200
550
1
No activity
No activity
No activity
No activity
No activity
No activity
2
3
4
76
75
100
69
35
15
8
No activity
5
No activity
80
27
24
57
45
12
59
23
6
48
59
34
44
51
77
22
48
84
61
56
65
76
14
10
11
12
13
14
15
16
44
5.3
37
46
_______
* TD50 is the concentration causing 50% death of cells; CV is staining with
crystal violet; MTT is staining with 3-(4,5-dimethyl-2-thiazolyl)-2,5-
diphenyltetrazolium bromide.
The greatest level of NO generation was detected for the hydroxypiperidine-containing thiazoles 11 (up
to 300% on line MG-22A) and 12 (up to 350% on both lines), and also for the organosilicon salt 16, particularly
on line MG-22A (up to 550%).
It was established from the investigations carried out that all the substances synthesized possess a
sedative action. The greatest effect was noted in the tests of hypoxic hypoxia, ethanol narcosis, corazole spasm,
and in tests reflecting the effect of substances on memory processes. The compounds studied are amphetamine
antagonists. The greatest depriming type of activity was displayed by (hydroxyethyl)-thiazole 1 and its
trimethylsilyl ether 2, and also by the trimethylsilyl ether of 4-hydroxymethyl-2-phenylthiazole (6).
In several cases an increase of activity was observed on introducing the trimethylsilyl substituent into
the molecule of thiazole derivative, although on the whole the trimethylsilyl ethers of thiazoles and their
unsilylated precursors displayed psychotropic activity of the same order. The greatest cytotoxic effect on
MG-22A cells was observed in the case of trimethylsilyl ether 14.
EXPERIMENTAL
1
The H NMR spectra were taken on a Varian Mercury 200 (200 MHz) spectrometer in CDCl3, internal
standard for the unsilylated compounds was hexamethyldisiloxane (HMDS), the organosilicon compounds were
measured relative to the signal of the solvent (7.25 ppm). Elemental analyses were carried out with a Carlo Erba
1108 analyzer. The GLC analysis was effected on a Chrom-5 (Czech Republic) chromatograph with a flame
ionization detector. A glass column (1.2 m × 3 mm) was used packed with 5% OV-17 on Chromosorb W-HP
(80-100 mesh) as carrier.
4-Methyl-5-(β-trimethylsilyloxyethyl)thiazole (2). A mixture of 5-(β-hydroxyethyl)-4-methylthiazole
1 (715 mg, 5 mmol) and hexamethyldisilazane (7 ml) was heated with stirring for several hours. The progress of
the reaction was followed by GLC. At the end of the reaction the excess of hexamethyldisilazane was removed
864

in vacuum on a rotary evaporator. The residue was purified on a chromatographic column (support was Acros
silica gel 0.060-0.0200 mm, pore diameter 6 nm, eluent benzene). Compound 2 (570 mg, 53%) was obtained.
1H NMR spectrum, , ppm: 8.56 (1H, d, 2-H); 3.73 (2H, t, CH2O); 2.96 (2H, t, CH2C); 2.39 (3H, s, CH3); 0.08
δ
[9H, s, Si(CH3)3]. Found, %: C 49.97; H 7.90; N 6.42; S 14.55. C9H17NOSSi. Calculated, %: C 50.16; H 7.95;
N 6.50; S 14.88.
2-Amino-4-(trimethylsilyloxymethyl)thiazole (4) was obtained by the procedure described above from
2-amino-4-hydroxymethylthiazole 3 (650 mg, 5 mmol) in 54% yield (545 mg); mp 74-75°C. 1H NMR spectrum.
, ppm: 6.38 (1H, s, 5-H); 4.98 (2H, br s, NH2); 4.55 (2H, s, CH2); 0.15 [9H, s, Si(CH3)3]. Found. %: C 41.87;
δ
H 7.03; N 13.99; S 15.86. C7H14N2OSSi. Calculated, %: C 41.56; H 6.97; N 13.84; S 15.85.
2-Phenyl-4-trimethylsilyloxymethylthiazole (6) was obtained analogously from 4-hydroxymethyl-2-
phenylthiazole 5 (764 mg, 4 mmol) in 49% yield (515 mg); mp 74-75°C. 1H NMR spectrum, , ppm: 7.86-7.97
δ
and 7.36-7.46 (5H, m, C6H5); 7.17 (1H, d, 5-H); 4.85 (2H, d, CH2); 0.19 [9H, s, Si(CH3)3]. Found, %: C 60.03;
H 6.38; N 5.22; S 12.52. C13H17NOSSi. Calculated, %: C 59.27; H 6.50; N 5.32; S 12.17.
N-(2-Thiazolyl)-3-chloropropionamide (7), N-(4-Phenyl-2-thiazolyl)-2-chloroacetamide (8), and
N-(4-Phenyl-5-tetradecyl-2-thiazolyl)-2-chloroacetamide (9) were obtained by the procedure given in [15].
N-(2-Thiazolyl)-3-(4-hydroxypiperidino)propionamide (10), N-(4-Phenyl-2-thiazolyl)-2-(4-
hydroxypiperidino)acetamide (11), and N-(4-Phenyl-5-tetradecyl-2-thiazolyl)-2-(4-hydroxypiperidino)-
acetamide (12) were synthesized by the procedure given in [15,16].
N-(2-Thiazolyl)-3-(4-trimethylsilyloxypiperidino)propionamide (13) was obtained by the procedure
given above from compound 10 (765 mg, 3 mmol) in 49% yield (480 mg); mp 87°C. 1H NMR spectrum, , ppm:
δ
12.80 (1H, s, NH); 7.42 (1H, d, 4-H); 6.91 (1H, d, 5-H); 3.80 (1H, m, CHcyclO); 2.85, 2.38, and 1.81 (8H, m + t + t,
CH2cycl); 2.71 and 2.58 (4H, t + t, CCH2N + COCH2C); 0.12 [9H, s, Si(CH3)3]. Found, %: C 51.62; H 7.73;
N 12.85; S 9.79. C14H25N3O2SSi. Calculated, %: C 51.34; H 7.69; N 12.83; S 9.79.
N-(4-Phenyl-2-thiazolyl)-2-(4-trimethylsilyloxypiperidino)acetamide (14) was obtained by an
1
analogous method from compound 11 (792 mg, 2.5 mmol) in 51% yield (492 mg); mp 115-118°C. H NMR
spectrum, , ppm: 7.27-7.90 (5H, m, C6H5); 7.15 (1H, s, 5-H); 3.75 (1H, m, CHcyclO); 3.23 (2H, s, COCH2N);
δ
2.82, 2.42, and 1.75 (4H + 2H + 2H, m + m + m, (CH2cycl); 0.12, [9H, m, Si(CH3)2]. Found, %: C 58.71; H 7.08;
N 10.39; S 8.09. C19H27N3O2SSi. Calculated, %: C 58.58; H 6.99; N 10.79; S 8.22.
N-(5-Tetradecyl-4-phenyl-2-thiazolyl)-2-(4-trimethylsilyloxypiperidino)acetamide
(15)
was
1
obtained analogously from compound 12 (770 mg, 1.5 mmol) in 45% yield (395 mg); mp 77-80°C. H NMR
spectrum, , ppm: 7.28-7.60 (5H, m, C6H5); 3.76 (1H, m, CHcyclOSi); 3.21 (2H, d, COCH2N); 2.85, 2.39, and
δ
1.92 (4H + 2H +2H, m + m + m, CH2cycl); 1.65 and 1.23 (4H + 22H, m + m, CH2); 0.90 (3H, s, CH3); 0.12 [9H,
s, Si(CH3)3]. Found, %: C 67.68; H 9.39; N 7.19; S 5.40. C33H55N3O2SSi. Calculated, %: C 67.64; H 9.46;
N 7.17, S 5.47.
2-Amino-3-(γ-trimethylsilylpropyl)thiazolium Iodide (16). A mixture of 2-aminothiazole (325 mg,
3.25 mmol), 3-iodopropyltrimethylsilane (784 mg, 3.24 mmol), and acetonitrile (2 ml) was heated at ~45°C for
10 h. The solution obtained was filtered, and evaporated to an oil. The oil was triturated with absolute ether
1
until a bright yellow solid was obtained. The yield of compound 16 was 642 mg (58%), mp 66-69°C. H NMR
spectrum, , ppm: 9.07 (2H, s, NH2); 6.85 (1H, d, 4-H); 6.77 (1H, d, 5-H); 4.30 (2H, t, N+CH2); 1.79 (2H, m,
δ
CCH2C); 0.60 (2H, m, CCH2Si); -0.02 [9H, s, Si(CH3)3]. Found, %: C 31.18; H 5.39; N 8.19; S 9.30.
C9H19IN2SSi. Calculated, %: C 31.58; H 5.59; N 8.18; S 9.37.
Biological Section. Neurotropic activity was studied in BALB/c strain mice and random-bred male
rats. An oil solution of the substance being studied was introduced intraperitoneally 30 min before beginning the
test.
The action of a substance on the central nervous system was assessed by 1) the effect on movement
coordination and muscular tone (tests were "rotating rod", "tubes", "pulling on a beam"), 2) body temperature,
3) analgesic effect (test "hot plate"), 4) antispasmic activity (tests were maximal electroshock and corazole
865

spasm), 5) duration of hexenal and ethanol narcosis, 6) lifespan under conditions of hypoxic hypoxia, 7)
locomotor activity and body temperature under joint action of amphetamine, 8) unavoidable stress situation and
influence on processes of memory and retrograde amnesia.
The experimental data were processed statistically. Mean values of LD50 and ED50 were found from
12-20 observations using the express method of [17]. Assessment of the significance of differences between
mean values (M + m) was carried out by the Student criteria. Differences were considered significant at a
probability level of P 0.05.
≤
Investigation of cytotoxicity on tumor cell lines HT-1080 and MG-22A were carried out in 96-well
panels [18,19]. Optical density in the biological tests was determined with a Tetertek Multiscan MCC/340
horizontal spectrophotometer.
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