Some reactions of 2-cyanomethyl-1,3-benzothiazole with expected biological activity

Article abstract of DOI:10.1080/10426500802590244

New pyrido[2,1-b]benzothiazoles 2a,b, 3, 2-aminoquinoline 4, coumarin 5, cyclohexane 6a,b, and 2-(1,3-benzothiazol-2-yl) methylidene 7 derivatives have been prepared via the reaction of 2-cyanomethyl-1,3-benzothiazole 1 with ,-unsaturated nitriles, α-chloro ethyl acetoacetate, 2-amino benzaldehyde, 5-chlorosalicylaldehyde, α,β-unsaturated ketone, and 2-aminobenzothiol hydrochloride. 2-Thiazole derivatives 9a,b were prepared from compound 1, which was converted to thioamide derivative 8 by reaction with HCl and thioacetamide, and cyclization of this thioamide with α-halogenated ketone gave 9a,b. Reaction of compound 1 and ethylacetate to afford ketonitrile 10. Treatment of 10 with hydrazine hydrate afforded aminopyrazole derivative 11. Substituted 4-aminothiophene 13 has been synthesized by reaction of compound 1 with p-chlorophenyl isothiocyanate. The resulting product 12 was then alkylated with phenacylbromide. Phenyl-2-yl-carbonylhydroximoyl-chloride 15 was prepared by treatment of the corresponding sulfonium bromide with sodium nitrite and hydrochloric acid in dioxane. Compound 15 reacted with α-(1,3- benzothiazol-2-yl) cinnamonitrile 14 afforded the isoxazole derivatives 16. Reaction of coumarin derivative 5 with anthranilamide, pyrimidine diamine, thiosemicarbazide, acetylacetone, and hydrazine hydrate yielded quinazoline-2-one 17, purine 18, triazole 19, 2-acetyl naphthalene-2-one 20, and N-aminoquinoline-2-one 21 derivatives.

Full text of DOI:10.1080/10426500802590244

This article was downloaded by: [Dalhousie University]
On: 09 September 2012, At: 08:21
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Some Reactions of
2-Cyanomethyl-1,3-
benzothiazole with Expected
Biological Activity
A. Y. Hassan a
a Chemistry Department, Faculty of Science (Girls),
Al-Azhar University, Nasr City, Cairo, Egypt
Version of record first published: 03 Nov 2009
To cite this article: A. Y. Hassan (2009): Some Reactions of 2-Cyanomethyl-1,3-
benzothiazole with Expected Biological Activity, Phosphorus, Sulfur, and Silicon and
the Related Elements, 184:11, 2856-2869
To link to this article: http://dx.doi.org/10.1080/10426500802590244
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable

for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 184:2856–2869, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802590244
Some Reactions of 2-Cyanomethyl-1,3-benzothiazole
with Expected Biological Activity
A. Y. Hassan
Chemistry Department, Faculty of Science (Girls), Al-Azhar University,
Nasr City, Cairo, Egypt
New pyrido[2,1-b]benzothiazoles 2a,b, 3, 2-aminoquinoline 4, coumarin 5, cy-
clohexane 6a,b, and 2-(1,3-benzothiazol-2-yl) methylidene 7 derivatives have
been prepared via the reaction of 2-cyanomethyl-1,3-benzothiazole 1 with α,β-
unsaturated nitriles, α-chloro ethyl acetoacetate, 2-amino benzaldehyde, 5-
chlorosalicylaldehyde, α,β-unsaturated ketone, and 2-aminobenzothiol hydrochlo-
ride. 2-Thiazole derivatives 9a,b were prepared from compound 1, which was con-
verted to thioamide derivative 8 by reaction with HCl and thioacetamide, and
cyclization of this thioamide with α-halogenated ketone gave 9a,b. Reaction of com-
pound 1 and ethylacetate to afford ketonitrile 10. Treatment of 10 with hydrazine
hydrate afforded aminopyrazole derivative 11. Substituted 4-aminothiophene 13
has been synthesized by reaction of compound 1 with p-chlorophenyl isothiocyanate.
The resulting product 12 was then alkylated with phenacylbromide. Phenyl-2-yl-
carbonylhydroximoyl-chloride 15 was prepared by treatment of the correspond-
ing sulfonium bromide with sodium nitrite and hydrochloric acid in dioxane.
Compound 15 reacted with α-(1,3-benzothiazol-2-yl) cinnamonitrile 14 afforded
the isoxazole derivatives 16. Reaction of coumarin derivative 5 with anthranil-
amide, pyrimidine diamine, thiosemicarbazide, acetylacetone, and hydrazine hy-
drate yielded quinazoline-2-one 17, purine 18, triazole 19, 2-acetyl naphthalene-2-
one 20, and N-aminoquinoline-2-one 21 derivatives.
Keywords Cinamonitrile; coumarin; 2-cyanomethyl-1,3-benzothiazole and its deriva-
tives; cyanothioacetamide; ketonitrile; thioamide
INTRODUCTION
Heterosulfur compounds now find a wide variety of applications rang-
ing from antitumor,1–3 bacteriostatic,4,5 antibiotic,6,7 and CNS regulant8
to high ceiling diuretics.9 These considerable biological activities have
stimulated interest in the synthesis and chemistry of a new class of
thiazole derivatives.10
Received 2 June 2008; accepted 13 October 2008.
Address correspondence to A. Y. Hassan, Chemistry Department, Faculty of Science
(Girls), Al-Azhar University, Nasr City, Cairo, Egypt. E-mail: helali aisha@yahoo.com
2856

2-Cyanomethyl-1,3-benzothiazole
2857
RESULTS AND DISCUSSION
Compound 111 reacted with α,β-unsaturated nitrile to yield 1:1 adducts,
for which structure 2a,b can be considered. Structure 2a,b could be es-
1
tablished from the H NMR spectrum, which revealed a signal at δ
4.28 ppm for pyridine (H-4). The formation of 2a,b from compound 1
and α,β-unsaturated nitrile is assumed to proceed via Michael addition
of the active methylene group to the activated double bond to yield
acyclic intermediate 2ꢀa,b, which cyclizes give 2a,b via the addition of
ring NH to the cyano group. 1-Oxo-1H-pyrido [2,1-b]-1,3-benzothiazole
3 was prepared by the reaction of compound 1 with α-chloro ethyl ace-
toacetate. 2-Aminobenzaldehyde, upon condensation with compound 1
in the presence of piperidine without any solvent at room tempera-
ture,12 resulted in the formation of 2-amino-3-(1,3-benzothiazol-2-yl)-
quinoline 4.
In addition, compound 1 reacted with 5-chlorosalicyladehyde in
ethanol piperidine13 to give the corresponding coumarin derivative 5.
1
The structures of compounds 3, 4, and 5 were established by IR, H
NMR, and mass spectrometry (cf. Scheme 2 and Table II).
The synthesis of highly substituted cyclohexanol derivatives has
been accomplished in a single step reaction14 of 2-cyanomethyl-1,3-
benzothizaole 1 and α,β-unsaturated ketones (1:2) using sodium ethox-
ide in anhydrous diethyl ether at room temperature to give 3-aroyl-
1,2,4,6-tetraaryl-4-hyroxcyclohexane carbonitrile derivatives 6a,b. The
isolated products indicated that the reaction could involve a dou-
ble Michael addition of benzothiazol-2-yl-acetonitrile carbonion to two
moles of α,β-unsaturated ketones followed by cyclization. A suggested
reaction mechanism is also outlined in that scheme in which the 1,7-
diketone 6ꢀa,b undergoes an intramolecular aldol cyclization to give
the cyclohexanol 6a,b. The structure of the products 6a,b was eluci-
1
dated on the basis of their elemental analysis, H NMR, and IR data
(cf. Table II).
2-(1,3-Benzothiazol-2-yl) methylidene-(1,3-benzothiazole) 7 was pre-
pared, albeit in low yield, from (1,3-benzothiazol-2-yl)-acetonitrile and
2-aminobenzothiol hydrochloride. The mass spectral data for this prod-
uct revealed a molecular formula (C15H10N2S2), m/z = 282 (7.92%).
Three tautomeric structures were considered. The structure of 7a was
1
readily ruled out based on the H NMR spectrum that revealed one
proton signal at δ = 5.39 ppm; this signal can only interpreted in
terms of the 7b,c. The 2-thiazole derivative target was prepared from
2-cyanomethyl-1,3-benzothiazole 1 that was converted to thioamide
8 by reaction with HCl and thioacetamide in DMF.15 Cyclization of

2858
A. Y. Hassan
TABLE I Characterization Data of Newly Synthesized Compounds
% Analysis = Calcd/found
Comp.
No.
2a∗
2b
3∗∗
4
Mp◦C Yield% Mol. Formula MW
C
H
N
S
160
220
260
310
210
>360
>360
70
75
60
62
80
85
70
75
40
75
40
45
60
30
75
90
80
30
65
40
55
40
60
C19H11ClN4S
362.5
62.89
62.50
59.84
60.00
56.83
56.70
69.31
70.00
61.24
61.00
60.58
60.55
67.63
67.30
63.82
63.90
51.92
52.00
66.23
66.12
58.53
58.61
61.11
61.00
57.39
57.50
55.89
55.80
62.40
62.60
52.31
52.30
72.25
72.30
66.74
66.60
61.93
61.50
55.35
55.50
64.49
64.50
58.62
53.80
3.03
3.00
3.93
3.14
2.55
2.10
3.97
4.00
2.55
2.73
3.58
3.13
4.00
3.85
3.54
3.50
3.84
3.80
3.89
3.90
4.06
4.00
3.70
3.30
4.34
4.40
2.91
3.00
3.46
3.50
3.26
3.50
3.66
3.84
2.90
3.00
2.58
2.58
2.44
2.58
3.39
3.30
3.05
3.00
15.44
15.70
11.02
11.00
10.20
10.50
15.16
15.35
4.46
4.70
4.56
4.80
5.09
4.93
9.92
10.00
13.46
13.00
9.09
8.82
8.80
C
19H15N3O2S2
16.79
17.00
11.65
11.80
11.55
11.90
10.20
10.75
26.05
26.80
5.81
381
C13H7ClN2OS
274.5
C
16H11N3S
277
5∗∗∗
6a
6b
7
C16H8ClNO2S
313.5
C
31H22N2O2S5
614
C
31H22N2O6S
550
6.12
C
15H10N2S2
22.69
22.20
30.76
30.35
20.77
20.80
26.01
26.50
14.81
14.21
13.91
13.50
12.22
12.50
9.10
282
C9H8N2S2
208
8
240
290
310
230
80
9a
9b
10
11
12
13
15
16
17
18
19
20
21
C
17H12N2S2
308
9.00
C
12H10N2S2
11.38
11.50
12.96
12.96
24.34
24.70
10.33
10.00
7.69
246
C
11H8N2OS
216
C
11H10N4S
230
>360
220
>360
225
>360
180
140
120
280
C
16H10ClN3S2
18.63
18.60
13.86
14.00
—
343.5
C
24H16ClN3OS2
461.5
C8H6ClNO2
183.5
7.70
9.00
7.62
7.60
7.32
19.34
19.90
—
—
8.58
8.77
9.16
9.00
9.63
—
C
23H14N2O2S
8.37
8.80
7.73
7.80
8.25
8.11
17.36
17.61
9.05
9.51
9.77
10.00
382
7.30
C
23H12ClN3OS
10.15
10.00
18.06
18.50
15.19
15.00
3.96
4.00
12.82
12.60
413.5
C
20H10ClN5S
387.5
C
17H9ClN4S2
368.5
9.80
C
19H12ClNO2S
10.04
10.15
10.83
10.90
353.5
C
16H10ClN3OS
327.5
∗Cl:Calcd = 9.79, Found = 9.80.
∗∗Cl:calcd = 12.93, Found = 13.00.
∗∗∗Cl:Calcd = 11.32, Found = 11.50.

2859

2860

2-Cyanomethyl-1,3-benzothiazole
2861
SCHEME 1
this thioamide with an phencyl bromide or chloroacetone gave the 2-
thiazolyl derivatives 9a,b.
Compound 1 was acetylated in the presence of sodium metal and
ethyl acetate16 to yield ketonitrile 10. Treatment of 10 with hydrazine
hydrate in refluxing toluene16 afforded aminopyrazole derivative 11.
The structures of the newly synthesized derivatives were established
on the basis of elemental analysis and spectral data (cf. Scheme 1
and Table II). 2-Cyanomethyl-1,3-benzothiazole 1 reacted efficiently
with p-chlorophenylisothiocyanate in dioxan17 to give compound 12.
Alkylation of compound 12 at sulfur with phencylbromide yielded 3-
aminothiophene derivative 13. However, it has been found in contrast
to the reported behavior.18 Structure 13 finds support from the MS
spectra, which revealed a molecular formula (C24H16ClN3OS2), m/e =
461 (4.11%). The 1H NMR spectra revealed one amino function at δ 6.28
ppm and a signal at δ 9.80 ppm for the NH group.
α-(1,3-Benzothiazol-2-yl)-cinnamonitrile 1419 was treated with
phenyl-1-yl-carbonyl hydroximoyl chloride 15 in toluene and triethy-
lamine at room temperature to furnish a single product identified
as 3-benzoyl-5-(1,3-benzothiazol-2-yl)-4-phenyl isoxazoline intermedi-
ate 16ꢀ, but was unsuccessful. The IR spectrum of the reaction product
was free of the nitrile absorption band and revealed only a carbonyl
band at 1700 cm−1. Its 1H NMR spectrum displayed only a multiplet in
the region δ 7.55–8.11 ppm due to aromatic protons.
The IR spectrum of compound 15 revealed a abroad band in the re-
gion of 3300–3200 cm−1 due to the hydroxyl group and a strong band at
1665 cm−1 due to the carbonyl group. Its 1H NMR spectrum displayed
also a base-broad singlet at δ 13.74 ppm and a multiplet at δ 7.42–8.11
ppm assignable to hydroxyl and aromatic protons, respectively. A

2862
A. Y. Hassan
SCHEME 2
plausible mechanism for the formation of the hdyroximoyl chloride 15
is depicted in Scheme 1.
The interaction of compound 5 with anthranilamide, pyrimidine di-
amine, and thiosemicarbazide in glacial acetic acid and in the pres-
ence of fused sodium acetate20 yielded quinazolinone 17, purine 18,
and triazole 19 derivatives, respectively. However, formation of the
quinazolinone 17 was mediated, most likely by intermediate 17ꢀ, which
could undergo cyclodehydration to afford 17. The IR spectrum of 17
exhibited bands at 1700 cm−1 (C=O) and 1630 cm−1 (C=N), and the
mass spectrum of 17 showed a molecular ion peak m/z 413 (16.31%).
The IR spectrum of compound 18 showed the absence of C=O and
the presence of C=N at 1640 cm−1. Extending the reaction to include
acetylacetone using sodium ethoxide21 as a catalyst gave 2-acetyl-8-

2-Cyanomethyl-1,3-benzothiazole
2863
SCHEME 3
(1,3-benzothiazol-2yl)-5chloro-naphthalene-1-one 20 in low yields. Con-
densation of 5 with hydrazine hydrate gave 3-(1,3-benzothiazol-2-yl)-
N-amino-4-chloro quinoline-2-one 21. The IR spectrum of 21 showed
the presence of (NH2) at 3380, 3230 cm−1 and C=O at 1680 cm−1 (cf.
Scheme 3 and Table II).
EXPERIMENTAL
All melting points were recorded on a Gallen Kamp melting apparatus
and uncorrected. The IR spectra were recorded on a pye-unicam Sp-
3–100 spectrophotometer using KBr Wafer Technique. 1H and 13C NMR
spectra were recorded on a Brucker 400 MHz with DMSO-d6 as solvent
and tetramethysilane as an internal standard; chemical shifts are as δ
units (ppm). The mass spectra were recorded on Ms-S 988 operaing at
70eV. Elemental analysis was determined using a Perkin-Elmer 240C
microanalyses. The newly synthesized compounds were screened for in
vitro antitumor activity at Cairo University, National Center Institute,
Cancer Biology Department Pharmacology unit.
Compounds 1 and 14 were prepared according to the procedure in
the literature.11,19

2864
A. Y. Hassan
1-Amino-3(p-chlorophenyl)-4-cyano-3H-pyrido[2,1-
b]benzothiazole-2-carbonitrile 2a or Ethyl-1-amino-3(2-thienyl)
4-cyano-3H-pyrido[2,1-b]benzothiazole-2-carboxylate 2b
Equimolecular amounts (0.01 mol) of 1 with the appropriate cinna-
monitrile were refluxed in ethanol (50 mL) in the presence of piperi-
dine (0.1 mL) for 3 h. The solid product so formed was filtered off and
recrystallized from ethanol.
2-Chloro-4-cyano-3-methyl-1-oxo-1H-pyrido
[2,1-b]-1,3-benzothiazole 3
A solution of 1 (0.01 mol) in ethanol (20 mL), α-chloro ethyl-acetoacetate
(0.01 mol), and piperidine (3 drops) was refluxed for 6 h. The reaction
mixture was left to cool at room temperature and recrystallized from
ethanol.
2-Amino-3-(1,3-benzothiazol-2-yl)quinoline 4
A mixture of 2-aminobenzaldehyde (0.01 mol), compound 1 (0.01 mol),
and piperidine (5 drops) was ground by pestle and mortar at room
temperature for 30 min and treated with water. The resultant product
was filtered, washed with water, and recrystallized from methanol.
6-Chloro-3-(1,3-benzothiazol-2-yl)-coumarin 5
A mixture of the appropriate 1 (0.005 mol) and 5-chloro-salicylaldehyde
(0.005 mol) in absolute ethanol (35 mL) containing piperdine (5 drops)
was refluxed for 4 h. The reaction mixture was cooled and then acidified
with dilute hydrochloric acid. The solid so formed was collected and
recrystallized from ethanol.
3-Aroyl-1-(1,3-benzothiazole)-2,4,6-triaryl-4-
hydroxycyclohexane carbonitrile 6a,b
To a suspension of sodium ethoxide (0.01 mol) in anhydrous ether (150
mL) containing compound 1 (0.01 mol), chalcone22 (0.02 mol) was added.
The mixture was stirred at room temperature for 20–24 h, the solid
formed was filtered and recrystallized from dioxan. The filtrate was
poured into water (100 mL), the organic layer was separated, dried with
sodium sulfate, and evaporated to give the crude unreacted starting
materials.

2-Cyanomethyl-1,3-benzothiazole
2865
2-(1,3-Benzothiazol-2-yl)methylidene-(1,3-benzothiazole) 7
A solution of 1 (28 mmol) and 2-aminobenzenthiol hydrochloride (5.0 g,
30 mmol) in ethanol (75 mL) was heated at reflux for 48 h. The solvent
was evaporated in vacuo, and the solid was collected and recrystallized
from cyclohexanone.
1-(Benzothiazol-2-yl)thioacetamide 8
A solution of 8 (120 mmol) and thioacetamide (40 mmol) in DMF
(75 mL) was heated in an oil bath to 90–100◦C for about 2 h, while
HCl gas was being bubbled into the reaction mixture. The solvent was
evaporated in vacuo, and the residue was triturated with acetone to
give crude product. This material was recrystallized from ethanol.
[5-(Phenylthiazol-2-yl)methyl]-2-(1,3-benzothiazol-2-yl) 9a and
[(5-Methylthiazol-2-yl) methyl]-2-(1,3-benzothiazol-2-yl) 9b
A solution of 8 (26 mmol) and phencyl bromide or chloroacetone (45.6
mmol) in ethanol (25 mL) was heated at reflux for 6 h. After the starting
material had been consumed as judged by TLC, the reaction mixture
was cooled and the crude product was collected by filtration. Chro-
matography on silica (90:9:1, CHCl3:MeOH:NH4OH) yielded a yellow
oil, which was dissolved in MeCN and treated with diethyl ether. The
solid was collected and recrystallized from ethanol.
1-Cyano-1-(1,3-benzothiazole)-propan-2-one 10
To a solution of 1 (0.22 mol) in ethyl acetate (200 mL), sodium metal
(6.43 g, 0.28 mol) was added portionwise at room temperature. Ethy-
lacetate (400 mL) was added to the reaction suspension to facilitate
stirring, and the resultant mixture was stirred at room temperature
for 48 h. The collected solid was washed with copious amounts of di-
ethyl ether and recrystallized from ethanol.
5-Amino-4-(1,3-benzothiazole)-3-methyl-pyrazole 11
A mixture of 10 (80.3 mmol), hydrazine monohydrate (120.45 mmol),
acetic acid (14.9 mL, 200.75 mmol), and toluene (300 mL) was heated
at reflux using a Dean-Stark trap for 5 h. The reaction mixture was
cooled to room temperature. The solid was collected and recrystallized
from benzene.

2866
A. Y. Hassan
1-(2-(1,3-Benzothiazole)-N-(p-chlorophenyl
cyanothioacetamide) 12
A mixture of 1 (0.01 mol), finely divided sodium metal (0.01 mol), and
p-chlorophenyl isothiocyanate (0.01 mol) was refluxed for 7 h in dry
dioxan (50 mL), then allowed to cool, poured onto cold water, and neu-
tralized with dilute HCl. The precipitated was filtered off and recrys-
tallized from ethanol.
4-Amino-5-(benzoyl)-3-(1,3-benzothiazol-2-yl)-2-p-
chlorophenyl-aminothiophene 13
A mixture of 12 (0.01 mol), sodium ethoxide (0.005 mol), and phencyl
bromide (0.01 mol) in 50 mL ethanol was heated under reflux for 22 h,
and the reaction mixture was poured into ice cold dilute HCl. The
product was crystallized from ethanol.
Phenyl-1-yl-carbonylhydroximoyl Chloride 15
To a stirred solution of the sulfonium bromide (20 mmol) and sodium
nitrite (1.4 g, 20 mmol) in dioxan (25 mL) and water (25 mL), concen-
trated hydrochloric acid (50 mL) was added portionwise over a period
of 1 h. The reaction mixture was stirred for a further 2 h at room
temperature during which the sulfonium bromide dissolved and the
precipitated which was filtered off, washed with water, dried, and re-
crystallized from AcOH.
3-Benzoyl-5-(1,3-benzothiazol-2-yl)-4-phenylisoxazole 16
A mixture of the hydroximoyl chloride 15 (2 mmol) and α-(benzothiazol-
2-yl) cinnamonitrile 14 (2 mmol) in dry toluene (15 mL) and triethy-
lamine (0.2 mL) was stirred for 6 h. The solvent was evaporated under
reduced pressure, and the residue was triturated with methanol. The
solid so formed was collected by filtration, washed with ethanol, dried,
and finally recrystallized from DMF.
Formation of Quinazolinone 17, Purine 18, and Triazole 19
Derivatives
A mixture of 5 (0.01 mol), anthranilamide, pyrimidine diamine, and/or
thiosemicarbazide (0.01 mol) and fused sodium acetate (1 g) was re-
fluxed in glacial acetic acid (25 mL) for 12 h. After cooling, the reaction
mixture was poured onto ice cold water (100 mL). The solid so formed

2-Cyanomethyl-1,3-benzothiazole
2867
was isolated, dried, and crystallized from ethanol for compound 18 and
19, but for compound 17 was recrystallized from acetic acid.
1-(1,3-Benzothizol-2-yl)-3-acetyl-6-chloro-naphthalene-2-
one 20
A mixture of 5 (0.01 mol) in sodium ethoxide (0.01 mol) and acetyl
acetone (0.01 mol) in (50 mL) ethanol was heated under reflux for 18 h.
The reaction mixture was poured into ice cold diluted HCl. The product
was crystallized from ethanol and acetic acid.
3-(1,3-Benzothiazol-2-yl)-N-amino-4-chloroquinoline-2-one 21
A solution of 5 (0.01 mol) and hydrazine hydrate (0.02 mol) in (30 mL)
ethanol was heated under reflux for 6 h. The product obtained after
cooling was crystallized from ethanol.
BIOLOGICAL RESULTS
Antitumor Activity (In Vitro Study)23
Ehrlich A sites carcinoma cells (EAC) were drawn from mice, in sterile
test tube, where 2.5 × 105 tumor cells/mL were suspended in phosphate
buffer saline at three different concentrations for each compound (25,
50, and 100 µg/mL). The 2.5 × 105 tumor cells for each test tube were
added at 37◦C for 2 h. The cells were tested for viability and contami-
nation by staining a certain cell volume of this fluid by an equal volume
of the working solution of trypan blue dye and examined under micro-
scope. The dead cells stained blue and live cells not stained were then
carried out to calculate the percentage of nonviable cells. Compounds
producing more than 70% nonviable cells are considered active (see
Table III)24:
no. of nonviable
Total No. of cell
% of non-viable cells =
× 100
Compounds 6b, 7, 11, and 13 are more effective than the positive
control (doxorubicin) and were able to reduce the magnitude of activity
to 90%. Compounds 2a,b, 4, and 9b possess moderate activity against
tumor cell lines, while compounds 16, 17, 18, 19, and 20 did not show
any activity at different concentration, probably because of a solubility
problem in the used culture media. On the basis of the structure of the
tested compounds, one can conclude structure–activity relationships
provided evidence that geometry, size, and shape of the compounds is an

2868
A. Y. Hassan
TABLE III In Vitro Cytotoxic Activity of
Synthesized Compounds
Nonviable cells (%)
concentration (µg/mL)
Compound no.
100
50
25
2a
2b
3
4
5
6a
6b
7
8
9a
9b
10
11
12
13
16
50%
50%
−ve
70%
−ve
−ve
100
90%
−ve
−ve
50%
−ve
90%
−ve
90%
−ve
−ve
−ve
−ve
−ve
100%
40%
40%
−ve
60%
−ve
−ve
100%
85%
−ve
−ve
40%
−ve
85%
−ve
80%
−ve
−ve
−ve
−ve
−ve
55%
20%
30%
−ve
55%
−ve
−ve
95%
80%
−ve
−ve
25%
−ve
70%
−ve
75%
−ve
−ve
−ve
−ve
−ve
20%
17
18
19
20
Doxorubicin25
important as their substituents. These heterocycles could be considered
as a useful template for further development and further derivatization
or modification to obtain more potent and selective antitumor agents.
REFERENCES
[1] E. Marco and F. Gago, J. Mol. Pharmacol. 68(6), 1559 (2005).
[2] A. B. Herrero, M. Castellahous, E. Marco, F. Gago, and S. Moreno, Cancer Res.,
66(16), 8155 (2006).
[3] J. Bendnarski, J. Des Pharmazie, 341(2), 121–125 (2008).
[4] M. M. Ghorab and A. Y. Hassan, Phosphous, Sulfur, and Silicon, 141, 251 (1998).
[5] S. Suzen and E. Buyukbingol, Il Farmaco, 55, 246 (2000).
[6] R. M. Harnden, S. Baiky, R. M. Boyd, R. D. Taylor, and D. N. Wright, J. Med. Chem.,
21, 82 (1977).
[7] I. Hyakawa, Y. Tanaka, and Y. Nagata; Tap, P. 77, 83, 588 (1976); Chem. Abstr., 88,
37785c (1987).
[8] A. A. Deshmukh, M. K. Mody, T. Ramalingam, and P. H. Sattur, Indian J. Chem.,
25B, 793 (1985).

2-Cyanomethyl-1,3-benzothiazole
2869
[9] A. Andereani, M. Ramboldi, A. Locattelli, and A. M. Isettam, Eur. J. Med. Chem.,
26, 335 (1991).
[10] A. A. Elagamey, F. A. El-Taweel, F. A. Amer, and H. H. Zoorob, Arch. Pharm., 320,
246 (1987).
[11] K. Saito, S. Kampe, and Y. Nanano, Synthesis, 210 (1983).
[12] K. Mogilaiah, H. Ramesh Babu, and N. V. Reddy, J. Synth. Commun., 32(15), 2377
(2002).
[13] A. O. Abd El-Hamid, Phosphorus, Sulfur, and Silicon, 88, 217 (1994).
[14] M. M. Al-Arab, B. S. Ghanem, and M. M. Olmstead, Synthesis, 1003 (1992).
[15] R. E. Boyd, J. B. Press, C. R. Ramsussen, R. B. Raffa, E. E. Cood, C. D. Connelly, D.
J. Bennet, A. L. Kirrifides, J. F. Gardocki, B. Reynolds, J. T. Hortenstein, and A. B.
Reitz, J. Med. Chem., 42, 5064 (1999).
[16] L. He, P. J. Gilligan, R. Zaczek, L. W. Fitzgerald, J. Mcelroy, H. S. L. Shen, J. A.
Saye, N. H. Kalin, S. Shelton, D. Christ, G. Trainor, and P. Hartig, J. Med. Chem.,
43, 449 (2000).
[17] F. Zaragoza, Tetrahedron Lett., 37, 6213 (1996).
[18] R. Laliberte and G. Medawar, Can. J. Chem., 48, 2704 (1970).
[19] A. M. Farag, K. M. Dawood, and A. O. Abdelhamid, Tetrahedron Lett., 53, 17461
(1997).
[20] M. M. Ghorab, O. M. Nassar, and A. Y. Hassan, Phosphorus, Sulfur, and Silicon,
134–135, 57 (1998).
[21] M. M. Hamad, S. A. Said, A. F. El-Farargy, and G. M. Gendy, Pak. J. Sci. Ind. Res.,
36(6–7), 228 (1993).
[22] N. R. E-Rayyes, J. Heterocycl. Chem., 19, 415 (1982).
[23] The method used is that of trypan blue exclusion, Mclimans et al. , J. Immunol. 79,
428 (1957).
[24] M. M. El-Merzabani, A. A. El-Aaser, A. K. El-Dueini, and A. M. Ghazal, Planta
Medica, 36, 150 (1979).
[25] F. A. Fornair, J. K. Randolph, J. C. Yalowich, M. K. Ritke, and D. A. Gewirtz, J.
Molec. Pharmacol., 456, 649 (1999).