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Synthesis and Biological Investigations of Some New Thiazolylbenzimidazoles and Benzimidazolylthiazolo[32-a]pyridines.

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325
Thiazolylbenzimidazoles
Synthesis and Biological Investigations of Some New
Thiazolylbenzimidazoles and Benzirnidazolylthiazo10[3,2-a]pyridines
S.M. Rida, N.S. Habib*, E.A.M. Badawey, and H.T.Y. Fahmy
Department of Pharmaceutical Chemistry, Faculty of Pharmacy. University of Alexandria, Alexandria, Egypt
H.A. Ghozlan
Division of Microbiology, Faculty of Science, University of Alexandria, Alexandria, Egyp
Received August 11. 1994; revised form received October 28.1994.
Synthese und bidq-sche Untersuchungen van einigen neuen Thiazdylbenzimidazolen und BenzimidazdylthiazdoI 3,2a]pyridinen
2[(4-0~0-4.5-dihydrothiazol-2-yl)rnethyl]-l
H-benzimidazol (2) w ur de
2-[(4-0xo-4,5-dihydrothiazol-2-yl)methyl]-lH-benzimidamle
(2) was prepared through the reaction of 2-cyanomethyl-1H-benzimidazole(1) with
thioglycolic acid. The syntheses of its arylidene 3 and diazo-coupled compounds 5 and the cyclization of the aforementioned thiazolylbenzimidazole
to benzimidazolylthiazolo[3.2-a]py~idines8 were also performed. The prepared compounds were screened for their in-vitro antibacterial, antifungal.
anti-HIV, and anticancer activities: they show promising antifungal activity.
Benzimidazolesexhibit antibacterial”*),antiviral3A),antifun al? and anticancer6”) activity; thiazolidinones possess antimicrobial8-”) and anticancer”’”) activity. Particular interest has been focused recent1 o n
1benzimidazolescarryingthiazoles at C-Zas bactericidesand fun ’cides’ 16).
Moreover, thiazolo[3,2-a]pyridinespossess anti-HIV activity
18
durch Reaktion von 2-Cyanomethyl-1H-benzimidazol (1) mit Thioglycolsaure hergestellt. Die synthese der entspr. Aryliden- 3 und Arylazo-Derivate
5 und die Cyclizierung des Thiazolyl-benzimidazoles2 zu Benzimidazolylthiazolo[3,2-a]pyridnen 8 wird beschrieben. Die so hergestellten Verbindungen wurden in-vitro auf antibakterielle. antimykotische. anti-HIV und
anti-Tumor-Aktiviten gepriift: sie zeigen signifikante antimykotische
Aktivitit.
Experimental Part
Melting points: Gallenkamp apparatus. uncorrected.- IR spectra (KBr):
Perkin-Elmer 1430.- ‘H-NMR: Varian EM-390 spectrometer, TMS internal
standard, 6 (ppm), [MIDMSO, unless otherwise stated, 90 MHz- Mass
spectra:MAT-71 1spectrometer.-Elemental analyses: MicroanalyticalUnit,
Faculty of Science, University of Cairo, Egypt. All values of C, H, N, and S
are within f 0.4 % of the calculated data.
As a continuation to our work on b e n ~ i m i d a z o l e s ~this
~”~)
publication deals with the synthesis of some new compounds
containing benzimidazole attached to 4-thiazolidinone
through a methylene bridge, as well as its arylidene and
H-bemimi&zole (2)
arylazo derivatives. Some novel benzimidazolylthiazolo[3,2- 2-[(4-Oxo-4,5dihydrothiazol-2-yl)methyl]-l
A
mixture
of
2-cyanomethyl-1H-benzimidazole
(1) (1.57 g, 10 mmole)
alpyridines were also described in order to study their antimiand
thioglycolic
acid
(0.92
g,
0.69
ml,
10
mmole)
was placed in an oil bath
crobial, anti-HIV, and anticancer activity.
Chemistry
The reaction of 2-cyanomethyl-1H-benzimidazole
(1)with
thioglycolic acid by fusion for a few min is a new route to
benzimidazolescarrying a thiazole moiety at C-2. Thus 2 4 4 oxo-4,5-dihydrothiazol-2-yl)methyl]-1H-benzimidazole(2)
was obtained in an excellent yield. The SchifSbases4a-c were
prepared either by condensing 2 with the appropriate aldehydes, or by the reaction of the arylidene derivatives of
cyanomethyl-lH-benzimidazoles 3a-c”) with thioglycolic
acid. Similarly, compounds 6a-d were prepared from diazocoupled cyanomethyl-lH-benzimidazolesS a d 1 ) and thioglycolic acid, whereas attempts to prepare the same
compounds from 2 and diazonium salts failed: a mixture of
products has been produced, from which no pure compound
could be isolated. The benzimidazolylthiazolo[3,2-~]pyridines 8 a d were prepared by reaction of 2 with 2-arylidene
malononitriles 7 a 4 in a 1:2 molar ratio2*’”) (Scheme).
Arch. P
h (Weinheim) 328,32%328(1995)
at 170-180 “C for 5 min during which liberation of water and formation of
a yellow product occurred. The mixture was cooled and the product was
triturated with acetone, filtered, washed with acetone, dried and recrystallized from aqueous dimethylformamide: m.p. 245-7 “C, yield 1.84 g (go%).IR: 3280 (NH); 1690 (C--O), 1610 (C=N), 1590,1480 (C=C). 1525 (6 NH).
1270-1020 an-’ (C-S-C).- ‘H-NMR (CF3COOH). 6 @pm) = 4.3 (s 2H.
thiaz. S-Hz), 6.5 (s. 2H. CH2), 7.47.8 (m. 4H. Ar-H).
Method I:
Toa solution of 2 (2.31 g, 10 mmole)and piperidine (1 ml) in absol. EtOH
(20 ml), the appropriate aldehyde (10 mmole) was added. The reaction
mixture was heated under reflux for 5 h during which an orange product
separated, and oooled. The product was filtered, washed with EtOH, dried,
and recrystallized from aqueous dimethylformamide. Yields of 80-85 % are
obtained by this method.
Method 11:
A solution of the appropriatenitrile 3n-c (10 mmole) in glacial acetic acid
(20ml) and thioglycolicacid (0.92 g. 0.69 ml. 10 mmole) was heated under
reflux for 5 h, then cooled. The product obtained after addition of water was
0 VCH Valagsgeselkchaft mbH, D-69451 Weinheim, 1995
0365-6233/95/0404-0325 S. 5.00 + .25/0
326
Rida Habib, Badawey. Fahmy.Ghozlan
5a-d
3a-c
I
I
7 a-C
1
4a-C
6a-d
Scheme
filtered,washed with EtOH. dried, and recrystallizedfromaqueous dimethylformamide. - 4a: R = H, mp. 226- 8; 4b:R = Cl,mp. 280-2; 4c R = OCH3
m.p.220-2. - IR3300(NH); 170-1690(C=O); 1640-1620(C=N); 11590, 1490 (CX); 1550 (6 NH); 1280-1250, 105&1020 m-' C-S-C).1
H-NMR (h.R = H) (CF3COOH);6 epm) = 3.8 (s, 2H. thiaz.S-Hz), 6.87.7 (m,9H, Ar-H), 7.9 (s, lH, CH=).- H-NMR (4b.R = Cl) (CF3COOH):
separated. It was then cooled and the product was filtered, washed with hot
EtOH, dried, and recrystallized from aqueous dimethylf0nnamide.- 6a: R
= H, yield 82 %, m.p. 243-5; 6b:R = Cl,yield 85 96,m.p. 2624; 6c:R = Br,
yield 85 96.mp. 270-272; 6d:R = CH3, yield 83 96,mp. 247-9.- I R 3290
(NH); 1710 (C=O); 1640-1620 (C=N); 1600, 1480 (C=C); 1560 (N=N);
1540 (6 NH); 1260,1010cm-I (C-S-C).- 'H-NMR (kR = H) 6 @pm)=
4.0 (s, 2H. thiaz. S-Hz), 6.5 (s, In H, CH), 7-7.9 (m, 9H, Ar-H), 14.0 (s,
6@pm)=3.6(~,2H,thiaz5-Hz),6.7-7.5(m,SH,Ar-H),7.8(s,lH,CH=).1
1 0 H, NH).- 'H-NMR (a,
R =a)
S (ppm) = 3.9 (s, 2H, thiaz S-Hz), 6.4
H-NMR (k,R = OCH3) (CF3COOH). 6 (ppm) = 3.6 (s. 2H, thiaz. 5-Hz).
(s, 1RH. CH), 7.2-7.8(m, SH, Ar-H), 13.9 (s, lnH,NH).- 'H-NMR(6d,
3.65 (s, 3H. OCH3). 6.7-7.5 (m. 8H, Ar-H). 7.75 (s, 1H. CH=).- ElMS (4c)
m h (96): 349 (8) M+';273 (100); 230 (81); 193 (10); 164 (15); 156.8 (40);
R = CH3): 6 @pm)= 2.3 (s, 3H, CH3). 3.9 (s, 2H, thiaz. 5-Hz). 6.4 (s, ln H,
131 (12); 121 (38).
CH), 7-7.9 (mSH, At-H), 14.0 (s, H, NH).
A suspension ofthe appropriate Sa-d (10 mmole) in glacial acetic acid (20
ml) and thioglycolicacid (0.92 g, 0.69 ml, 10mmole) was heated under reflux
for 5 h during which the starting material slowly dissolved and the product
To a solution of 2 (2.31 g, 10mmole) and piperidine (1 ml) in ahsol. &OH
(20 ml), the approfiate 2-arylidene malononitrile 7n-c (20 mmole) was
added. The reaction mixture was heated under reflux for 5 h during which
Arch Pharm (Weinheim)328 32%328(1995)
327
Thiazolylbenzimidazoles
Table 2 Anti-HIV adivity.
the product separated. It was then cooled and the product was filtered,washed
with EtOH. dried, and recrystallized from aqueous dimethylfamamide. 8a:
R = H, yield 63 %, mp. 290-2; 8b: R = CI, yield 62 %. m.p. 296-8; &: R =
OCH3. yield 65 %, mp. 255-7.
I R 3460,3310,3160 (NH); 2200-2190
(C-N); 1710-1690 (GO); 1660-1650 (C=N): 1610-1600, 1510-1500
( C S ) ; 1570-1550 (6 NH): 1260, 1040-1010 cm-' (C-S-C). - 'H-NMR
(&: R = H) 6 @pm) = 4.8 (s, lH, 7-H), 7.2-8.3 (m, 14H, Ar-H), 8.5 (s, lH,
CH=). - 'H-NMR(8b: R=Cl)S@pm)=4.8(~,lH,7-H),7.1-7.8(m, 12H,
Ar-H), 7.9 (s, lH, CH=). - 'H-NMR (8c: R = OCH3) 6 @pm) = 3.8 (s, 3H,
OCH3), 3.9 (s, 3H, OCH3). 4.8 (s, lH, 7-H), 6.9-7.9(m, 12H, Ar-H), 8.0 (s,
lH, CH=)
Compd
no.
-
2
4a
4b
4c
.
6a
6b
6d
Biological Investigation
8a
1 ) Antimicrobial Screening
8b
The test compounds were evaluated by the agar diffusion technique")
using a 1 m g h l solution in dimethylformamide.Test organisms: Staphylococcus aureus (ATCC 29523). Escherichia coli (HP 101). Proteus vulgaris
(local isolate), Candih albicans (NCTC 2708), Aspergillus niger, and
Pmicillium sp. (local isolate). Dimethylfonnamide showed no inhibition
zone. The minimum inhibitory concentration (MIC)of some of the compounds was measured using the two-fold serial dilution method. Reference
antibiotics: Strepomycin sulphate, Ampicillin,and Clotrimazole.Inhibition
zones(IZ)andMICarelistedinTable 1.Thecompounds wereweaklyactive
against the Gram positive bacterial (S. aureus) and the yeast (C. albicans)
and more active against the Gram negative bacteria (E. coli and P. vulgaris).
They were highly active against the hngi (A. niger and Pmicillium). Most
of the compounds showed IZ in the range 3 0 4 0 nun with MIC 4-25
)IB/ml.
&
Maximum
Dose
5% proteaion
(Molar)
IC50
(Molar)
27.54
55.69
10.91
10.61
7.29
26.42
22.38
7.72
14.81
10.05
3.1 10-~
2.3 x
7.5x
1.9 x lo4
4.9 x lo-'
6.5 x lod
1.0 x lod
7.0 x lo4
2.2 x lo"
5.0 x 10-~
>3.1
>2.3 x lo5
>7.5 x 10"
>2.0 x 10"
>1.6 x
>2.1 x 10-~
>LOx 10-~
>2.2 x lod
>7.1 x lod
>5.0 x 10"
.
~~
Table 3:Comparisonbetween anti-HIV activity of 4a and AZT.
Activity
parameter
4a
AZT
Maximum % protection
IC50 (molar)
EC50 (molar)
TI50 (TC/EC)
55.69
>2.30
2.10~10-~
>1.10
111.76
>Loo x 104
2.57 x
>3.89 x lo-*
Table 1: Antimicrobial activity of the prepared compounds.
Compi
no.
2
4a
4b
4c
6a
6b
6c
6d
8a
8b
&
Ampicillin
Streptomycin
Clotrimazole
E. coli
S. aureus
Iz
MIC
IZ
16
16
14
15
16
16
16
14
13
14
14
-
24
17
18
22
19
19
22
24
20
19
19
-
1
4
-
P. vulgaris
MIC
MIC
Iz
400
32
20
18
16
18
22
20
21
25
17
16
-
400
-
<loo
<loo
-
400
3
-
2) Anti-HNScreening
The test compounds were screened for their anti-HIV activity, following
the National Cancer Institute in-vitro anti-AIDSz) discovery program. The
maximum protection in term of percentage of living cells infected with the
virus and treated with the sample relative to untreated infected controls,
exerted by each compound and the corresponding concentrationand IC 50
values are listed in Table 2. Here only for 4a which showed the highest
activity among all the tested compounds,the three activity pameters IC 50,
EC 50, and TI 50 were calculated.These parameters compared to that of AZT
as the standard compound are listed in Table 3.
3) Anticancer Screening
The test compounds were screened for their in-vitro anticancer activity
against 60 human cell lines derived from 7 types of cancer (lung, colon,
melanoma renal, ovarian,brain, and 1eukemia)followingthe NCI preclinical
antitumor Drug Discovery Screenx). The 5 measures of sutqmnel selectivity
of each compound are listed in Table 4. Statistically significant values are
marked witha star. Compounds &a and 8b show a broad spectrum of activity
A K ~Phann
.
(Weirthejm) 3281 325-328(1995)
<200
-
-
<200
-
<200
-
<200
3
-
IZ
C. albicans
MIC
18
15
15
15
17
16
14
15
22
15
16
IZ
<loo
A. niger
MIC
Iz
40
40
Q5
4 5
6 0
40
40
6 0
40
60
40
35
30
32
35
30
35
35
30
31
32
30
40
-
400
-
22
39
18
20
30
30
34
40
40
<loo
38
22
<lo0
-
-
P. species
MIC
5
2
4 0
40
4 0
-
40
-
-
4 0
5
against all types of cancer except leukemia. Compound 6b achieved the
response parameter GI 50 for a specific cell line (NCI-4226 non-small cell
lung cancer) at a concentration 4 . 1 % of the mean concentration required
Table 4: Anticancer activity.
Compd
no.
Dciso
(conc.)
DKI
(conc.)
DLCSO
(conc.)
DH
(conc.)
MGDH
4a
4b
25.0w.o).
61.O(-5.0)
25.0(-4.0)
31.0(-4.0)
38.0(4.0)
32.0(4.0)
10.0(-6.0)
25.0(-6.0)
21.0(-4.0)
28.q-4.0)
37.0(-5.0)
24.0(4.0)
29.0(-4.0)
31.0(-4.0)
15.0(-4.0)
40.0(-5.0)
19.0(-5.0)
44.0(-4.0)
25.q-4.0)
26.q4.0)
12.q4.0)
11.q-4.0)
75.69(-5.oj
64.29(-4.0)
39.32(-4.0)
43.54(-4.0)
46.17(4.0)
49.54(-4.0)
67.06(-6.0)
52.98(-5.0)
45.83(-4.0)
48.24
57.53
36.20
44.53
42.17
31.76
45.83
35.81
38.52
4c
6s
6b
6d
&a
8b
8c
O.O(O.0)
O.O(O.0)
28.q-5.0)
3O.q-5.0)
22.q4.0)
328
Rida, Habib, Badawey, Fahmy, Ghozlan
for all the other cell lines. However, none of the tested compounds was
selected for further in-vivo testing.
Theauthorsaregrateful tothestaffoftheDepartmentofHealthandHuman
Services, Natimd Cancer Institute. Bethesda, Maryland, USA, foranti-Hw
and anti-cancer testing.
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Arch Pharm (Weinheim)328,32S328(1995)
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investigation, synthesis, thiazolylbenzimidazoles, benzimidazolylthiazolo, biological, pyridine, new
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