Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues

Article abstract of DOI:10.1002/jhet.3524

On the pharmaceutical account of the reported anticancer activity of benzothiazole derivatives, differently substituted benzothiazole derivatives 2a–c to 34a,b, attached at 2-position to different heterocyclic moieties, were synthesized via different chemical reactions. Thirteen of the newly synthesized compounds were selected by the National Cancer Institute, Bethesda, Maryland, USA, and evaluated for their in vitro antitumor activity against 60 human tumor cell lines in a one-dose screening panel among which two compounds 4 and 17 showed high activity and were selected for further evaluation in the five-dose full panel assay, in which compound 4 exerted powerful growth inhibitory activity against all cell lines with GI₅₀ ranging from 0.683 to 4.66?μM/L in addition to excellent lethal activity against most of the cell lines.

Full text of DOI:10.1002/jhet.3524

Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole
Analogues
a
Marwa T. Sarg,b*
b
Aisha Y. Hassan,
and Ebtehal M. Hussein
a
Department of Chemistry, Faculty of Science (Girls), Al-Azhar University, Cairo, Egypt
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
b
*
E-mail: m.t.sarg@hotmail.com
Received October 29, 2018
DOI 10.1002/jhet.3524
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
On the pharmaceutical account of the reported anticancer activity of benzothiazole derivatives, differently
substituted benzothiazole derivatives 2a–c to 34a,b, attached at 2-position to different heterocyclic moieties,
were synthesized via different chemical reactions. Thirteen of the newly synthesized compounds were se-
lected by the National Cancer Institute, Bethesda, Maryland, USA, and evaluated for their in vitro antitumor
activity against 60 human tumor cell lines in a one-dose screening panel among which two compounds 4 and
1
7 showed high activity and were selected for further evaluation in the five-dose full panel assay, in which
compound 4 exerted powerful growth inhibitory activity against all cell lines with GI50 ranging from 0.683
to 4.66 μM/L in addition to excellent lethal activity against most of the cell lines.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
DISCUSSION
Benzothiazole derivatives represent an important class
of biologically active molecules having diverse
pharmacological activities including anticancer [1–3],
antimicrobial [4,5], anti-inflammaotory [6], antiviral [7],
antioxidant [8], antitubercular [9], anticonvulsant [10],
antimalarial [11], and antileshmanial [12] activities.
Besides, many benzothiazole derivatives were found to
be responsible for inhibition of topoisomerase II [13–15]
and tyrosine kinase histone deacetylase [16] enzymes.
Therefore, it was aimed to synthesize novel compounds
comprising a benzothiazole moiety attached at the 2-
position to various substituted heterocyclic rings such as
thiazole, thiazinane, pyrazole, thiophene, pyrrole,
thienopyrimidine, indole, furan, pyridine, chromen,
quinoline, triazoloquinoline, and triazepinoquinoline
rings, in which benzothiazol-2-acetonitrile was an
excellent synthone for these syntheses. The newly
synthesized heterocyclic compounds possessed variable
substituents, which were designed to fulfill the objectives
of the target anticancer activity.
Chemistry. 2-(Benzo[d]thiazol-2-yl)acetonitrile 1 was
synthesized adopting the reported method [17]
(Scheme 1). However, the base-catalyzed reaction of
active methylene bearing compounds with phenyl
isothiocyanate was reported to yield their corresponding
ketene N,S-acetals that were further subjected to
cyclization via their reaction with alkylating agent.
Therefore, compound
1 was reacted with phenyl
isothiocyanate in the presence of finely powdered
potassium hydroxide and dimethyl formamide that was
followed by addition of chloroacetyl chloride, 1,3-
dichloropropane, or ethyl bromoacetate to afford the
thiazolidinone 2a, thiazinane 2b, or the open-chain ester
derivative 2c, respectively.
1
H NMR spectrum of compound 2a revealed a singlet
integrated for two protons at δ 4.17 ppm corresponding
to thiazolidinone–CH
protons. While compound 2b
2
showed a multiplet and two triplets each integrated for
two protons at δ 3.22–3.29 ppm and 3.59 and 3.97 ppm
assigned for thiazinane–C , C , and C –H, respectively,
5 4 6
©
2019 Wiley Periodicals, Inc.

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
Scheme 1. Reagents and conditions: (i) phenyl isothiocyanate/KOH/DMF/0°C, chloroacetyl chloride or 1,3-dichloropropane or ethyl bromoacetate/0°C/
RT; (ii) phenyl isothiocyanate/KOH/DMF/RT, ethyl iodide; (iii) hydrazine hydrate 99%/absolute ethanol/reflux; (iv) carbon disulfide/KOH/DMF/10°C,
dimethyl sulfate; (v) 4-X-C H -CHO/absolute ethanol/TEA/reflux.
6 4
1
compound 2c revealed a deuterium oxide exchangeable
singlet signal at δ 10.12 ppm attributed to NH proton.
Aminopyrazoles have been widely reported to be
synthesized via several methods [21–28]. Therefore,
compound 1 was reacted with phenyl isothiocyanate/ethyl
iodide, carbon disulfide/dimethyl sulfate, or differently 4-
substituted benzaldehyde derivatives to afford the
corresponding acrylonitrile derivatives 3, 5, and 7a–c,
respectively, which were further subjected to
hydrazinolysis through their reaction with hydrazine
hydrate 99% in ethanol to yield the target aminopyrazole
derivatives 4, 6, and 8, respectively. It is worth mentioning
that compounds 7b and 7c upon hydrazinolysis failed to
yield the target aminopyrazole derivatives.
H NMR spectrum of compound 10 showed three
dueterium oxide exchangeable singlet signals at δ 4.74,
7.18 and 9.66 ppm attributed to NH , NH–NH , and NH
protons, respectively.
The reaction of acetonitrile derivatives with
chloroacetamide analogues was reported to afford the
corresponding aminopyrrolone derivatives [30]. However,
2
2
2-(benzo[d]thiazol-2-yl)acetonitrile derivative
1 upon
reaction with chloroacetamide in ethanol containing a
catalytic amount of potassium carbonate yielded both the
alkylated β-cyanoamide derivative 11 and the cyclic
aminopyrrolone derivative 12.
1
H NMR spectrum of compounds 11 revealed one
deuterium oxide exchangeable singlet signal in
compound 11 at δ 7.26 ppm integrated for two protons
corresponding to NH2 protons, while the spectrum of
compound 12 showed two deuterium oxide exchangeable
singlet signals at δ 4.10 and 7.68 ppm assigned for NH2
and NH protons, respectively.
It is well documented that Gewald multicomponent
reaction of activated nitriles with ketones and elemental
sulfur in the presence of a basic catalyst led to the
synthesis of the corresponding aminothiophene
derivatives [31–35] through the formation of non-isolated
acrylonitrile intermediate [31,35].
1
H NMR spectra of compounds 4 and 6 revealed two
deuterium oxide exchangeable singlet signals at δ 6.86–
6.16 and 9.36–11.45 ppm attributed to NH2 and
pyrazole-NH protons, respectively.
It is to be noted that C-acylation [29] of compound 1 was
achieved via reaction with benzoyl chloride in toluene
containing a catalytic amount of triethyl amine to yield the
target compound 9 (Scheme 2). Also, compound 1 upon
heating under reflux with thiosemicarbazide in glacial
acetic acid yielded unexpectedly the acyclic hydrazinyl
acrylonitrile derivative 10.
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Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
Scheme 2. Reagents and conditions: (i) benzoyl chloride/toluene/TEA/reflux; (ii) thiosemicarbazide, glacial acetic acid/reflux; (iii) chloroacetamide/
CO /absolute ethanol/reflux; (iv) 1-tetralone/sulfur, absolute ethanol/TEA/reflux; (v) 4-nitroacetophenone/NH OAc/fusion at 160–170°C; (vi)
K
2
3
4
malononitrile/absolute ethanol/TEA/reflux.
One pot reaction of 2-(benzo[d]thiazol-2-yl)acetonitrile
, 1-tetralone, and elemental sulfur in ethanol containing
a catalytic amount of triethyl amine was carried out to
derivative that upon cyclization with phenacyl halide
yielded their corresponding thiophene derivative [21,38]
(Scheme 3). Compound 1 was stirred with phenyl
isothiocyanate in dimethyl formamide containing
potassium hydroxide at room temperature followed by
treatment with 4-chlorophenacyl bromide to provide the
1
afford the acrylonitrile intermediate 13 and the cyclic
1
aminothiophene derivative 14. H NMR spectra of
compounds 13 and 14 revealed multiplet signals at δ
.80–1.40 and 2.60–2.77 ppm due to dihydronaphthyl
1
0
corresponding thiophene derivative 17. H NMR spectrum
and dihydronapthothiophene protons, respectively, in
addition to a triplet signal in compound 13 at δ 4.12 ppm
corresponding to dihydronaphthyl–C –CH protons.
Besides, H NMR spectrum of compound 14 showed a
deuterium oxide exchangeable singlet signal at δ
of compound 17 showed two deuterium oxide
exchangeable singlet signals at δ 8.54 and 10.42 ppm
assigned for NH and NH protons, respectively.
2
2
2
1
Furthermore, the reaction of active methylene moiety in
cyanomethyl containing compounds with electrophilic
reagents such as carbon disulfide yielded ketene-acetal
intermediates, which were cyclized with haloesters to
afford their corresponding thiophene derivatives [39]. So
compound 1 was stirred with carbon disulfide in dimethyl
formamide containing potassium hydroxide at 10°C
followed by addition of ethyl chloroacetate to form the
corresponding 2-aminoester derivative 18 that was
subjected to hydrazinolysis via refluxing with hydrazine
7.50 ppm integrated for two protons corresponding to
NH protons.
2
Treatment of activated nitriles with different ketones in
basic medium was reported to afford alkylidene
Knoevenagel condensation products [36,37] that were
cyclized via their reaction with malononitrile [36].
Consequently, compound 1 was condensed with 4-
nitroacetophenone by fusion in ammonium acetate at
1
160–170°C to yield the corresponding benzylidene
hydrate to yield the acid hydrazide analogue 19. H NMR
derivative 15 that was cyclized with malononitrile via
heating under reflux in ethanol in the presence of
triethylamine as a base adopting the reported procedure.
spectrum of compound 18 showed a triplet signal at δ
1.13 ppm and a quartet signal at δ 4.04 ppm due to ester
1
methyl and methylene protons, respectively, while
H
[
36] The electron impact mass spectrum of compound 16
NMR spectrum of compound 19 lacked the triplet and
quartet signals characteristic to ester ethyl protons and
revealed three dueterium oxide exchangeable singlet
signals at δ 5.01, 5.79, and 11.86 ppm assigned for acid
hydrazide NH , thiophene–C –NH , and NH protons,
revealed the molecular ion peak at 387 (1.37), while the
base peak appeared at 95 (100).
Base-catalyzed reactions of active methylene bearing
compounds with phenyl isothiocyanate were reported to
afford the corresponding potassium salt of thiocarbamoyl
2
3
2
respectively.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
Scheme 3. Reagents and conditions: (i) phenyl isothiocyanate/KOH/DMF/0°C/4-chlorophenacyl bromide; (ii) carbon disulfide/KOH/DMF/10°C, ethyl
chloroacetate; (iii) hydrazine hydrate 99%/absolute ethanol/reflux; (iv) phthalic anhydride/gl. AcOH/reflux; (v) gl. AcOH/Ac O/reflux.
2
Condensation of acid hydrazide analogue 19 with either
phthalic anhydride or glacial acetic acid/acetic anhydride
mixture yielded the corresponding carboxamide
derivatives 20 and acetamide derivative 21, respectively.
Electron impact mass spectra of compounds 20 and 21
revealed their molecular ion peaks at m/z (%) 452 (3.73)
and 388 (7.71), while their base peaks appeared at m/z (%)
exchangeable singlet signal at δ 7.83 ppm integrated for
two protons assigned for NH protons.
2
Elzahabi [40] documented that the reaction of
2-(benzo[d]thiazol-2-yl)acetonitrile with benzylidene
malononitrile afforded the corresponding aminopyridine
carbonitrile analogue. Therefore, compound 1 was
heated under reflux with 2-(2,4-dimethoxybenzylidene)
malononitrile 23 [41] in absolute ethanol containing a
catalytic amount of piperidine to provide the
aminopyridine carbonitrile derivative 24. The reaction
was suggested to proceed via Michael addition of the
active methylene to the arylidene double bond followed
by the nucleophilic addition of exocyclic NH on the
cyano function to yield the target aminopyridine
derivative.
248 (100) and 91 (100), respectively.
Compound 1 was stirred with ethyl 2-chloro-3-
oxobutanoate in sodium ethoxide solution at room
temperature to yield the corresponding furan-3-
carboxylate derivative 22 (Scheme 4). This reaction is
postulated to proceed via nucleophilic substitution
reaction with removal of hydrogen chloride molecule
followed by subsequent addition of tautomeric OH group
on the cyano function.
1
H NMR spectrum of compound 24 revealed two singlet
1
H NMR spectrum of compound 22 revealed a triplet
signals at δ 3.91 and 3.97 ppm corresponding to two
methoxy protons, in addition to a deuterium oxide
exchangeable singlet signal at δ 6.81 ppm due to NH2
protons.
and
corresponding to ester methyl and methylene protons,
respectively, in addition to deuterium oxide
a quartet signal at δ 1.35 and 4.34 ppm
a
Scheme 4. Reagents and conditions: (i) ethyl 2-chloro-3-oxobutanoate/NaOEt/RT; (ii) 2-(2,4-dimethoxybenzylidene)malononitrile 23/absolute ethanol/
piperidine/reflux; (iii) 5-bromosalicylaldehyde/absolute ethanol/piperidine/reflux; (iv) hydrazine hydrate 99%/absolute ethanol/reflux.
Journal of Heterocyclic Chemistry
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Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
Moreover, cyclocondensation of compound 1 with 5-
bromosalicylaldehyde in absolute ethanol containing a
catalytic amount of piperidine yielded the corresponding
chromen-2-imine derivative 25. The reaction was
assumed to proceed through condensation of
salicylaldehyde with activated nitrile with subsequent
intramolecular cyclization through addition of phenolic
hydroxyl function on the triple bond of cyano group.
Such chromen-2-imine derivative was subjected to
hydrazinolysis via heating under reflux with hydrazine
hydrate in absolute ethanol to afford the corresponding
iminoquinolinamine derivative 26.
initial reaction of 4-chlorobenzaldehyde with compound 1
to yield the benzylidine derivative, which reacted with
compound 26 via Michael addition of amino group to the
benzylidene double bond followed by intramolecular
cyclization through addition of imino NH on the cyano
1
function. H NMR spectrum of compound 28 revealed a
deuterium oxide exchangeable singlet signal at δ
11.11 ppm integrated for two protons assigned for NH2
protons.
Also, compound 26 was heated with 1-tetralone and 2,4-
dichlorobenzaldehyde in dioxane containing a catalytic
amount of p-toluene sulfonic acid to afford the
corresponding triazepine derivative 29. The reaction was
suggested to proceed through the reaction of 1-tetralone
with the aldehyde to yield the arylidine intermediate that
was subjected to Michael addition of imino NH to the
arylidene double bond with subsequent cyclocondensation.
However, the 2-iminoquinoline-1-amine derivative 26
was further utilized for the synthesis of different
triazine and triazepine derivatives (Scheme 5). In which
compound 26 was reacted with ethyl 2-chloro-3-
oxobutanoate to yield the target triazin-6-one derivative
1
1
2
7. H NMR spectrum of compound 27 revealed two
H NMR spectrum of compound 29 revealed two triplet
singlet signals at δ 2.30 and 3.57 ppm assigned for
signals at
δ
2.03 and 2.59 ppm attributed to
CH and triazine-C protons, respectively, in addition to
tetrahydronaphthyl–C and C –CH protons, respectively.
3
3
4
3
2
a deuterium oxide exchangeable singlet signal at δ
Besides, a singlet signal at δ 4.56 ppm integrated for one
8.15 ppm attributed to NH proton.
proton assigned for triazepine–C proton.
5
It is to be noted that multicomponent reaction of
Furthermore, the reaction of compound 26 with the
reagents of either 23 and 30[41] was carried out via
heating under reflux in absolute ethanol containing a
catalytic amount of piperidine to yield the target
compound 26 with compound 1 and 4-chorobenzaldehyde
in dioxane afforded the corresponding aminotriazepine
analogue 28. The reaction was suggested to proceed via
Scheme 5. Reagents and conditions: (i) ethyl 2-chloro-3-oxobutanoate/fusion at 180–190°C; (ii) 2-(benzo[d]thiazol-2-yl)acetonitrile 1/
-chlorobenzaldehyde/dioxane/ reflux; (iii) 1-tetralone/2,4-dichlorobenzaldehyde/p-toluene sulfonic acid/dioxane/reflux; (iv) 2-(2,4-
4
dimethoxybenzylidene)malononitrile 23 or ethyl 2-cyano-3-(2,4-dimethoxyphenyl)acrylate 30/absolute ethanol/piperidine/reflux; (v) 2-(bis(methylthio)-
methylene) malononitrile 32 or ethyl 2-cyano-3,3-bis(methylthio)acrylate 33/DMF/TEA/reflux.
Journal of Heterocyclic Chemistry
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A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
Table 1
The mean growth percent, delta values, the percent growth inhibition, and the lethality percent against some subpanel cell lines of the selected compounds
of Scheme 1.
Comp. no.
NSC-number)
Subpanel cell
lines (lethality
percent)
Mean growth
percent
(
Panel: Subpanel cell lines (growth inhibition percent)
Leukemia: MOLT-4 (19.40), SR (16.52).
2b
89.94
(790032)
(31.26)
Non-Small Cell Lung Cancer: HOP-92 (24.08), NCI-H226 (27.48), NCI-H23
(
16.90), NCI-H522 (41.32).
Colon Cancer: HCT-116 (19.25).
CNS Cancer: SNB-75 (18.28).
Melanoma: UACC-62 (39.54).
Ovarian Cancer: IGROV1 (31.48), OVCAR-4 (23.11).
Renal Cancer: UO-31 (37.94).
Breast Cancer: MDA-MB-231/ATCC (22.45), T-47D (37.20).
3
83.86
(43.20)
Leukemia CCRF-CEM (20.16), K-562 (15.37), MOLT-4 (26.29), RPMI-8226
(34.62),
(790038)
Non-Small Cell Lung Cancer: A549/ATCC (15.04), HOP-62 (18.00), HOP-
9
2 (57.51), NCI-H226 (20.56), NCI-H522 (24.98).
Colon Cancer: HCT-116 (40.42), HCT-15 (17.00), HT29 (19.48), KM12
20.09).
(
CNS Cancer: SNB-19 (16.75), SNB-75 (23.70), U251 (15.56).
Melanoma: UACC-62 (50.91).
Ovarian Cancer: IGROV1 (29.88), OVCAR-4 (28.67), SK-OV-3 (22.35).
Renal Cancer: ACHN (20.13), CAKI-1 (15.31), SN12C (18.34), UO-31
(
37.45).
Prostate Cancer: PC-3 (27.03).
Breast Cancer: MCF7 (34.58), MDA-MB-231/ATCC (29.61), BT-549
(
17.63), T-47D (59.34), MDA-MB-468 (31.89).
4
23.76
(102.88)
Leukemia CCRF-CEM (91.55), HL-60 (TB) (83.39), K-562 (95.17), MOLT-4
(95.94), RPMI-8226 (76.03), SR (86.39).
(790039)
Non-Small Cell Lung Cancer A549/ATCC (80.01), EKVX (80.98), HOP-62
HOP-92 (15.78),
NCI-H522
(
71.35),
NCI-H226 (42.68), NCI-H23 (75.84), NCI-H322M (62.38), NCI-H460
94.06).
Colon Cancer Colo 205 (35.78), HCC-2998 (81.72), HCT-116 (96.27), HCT-15
88.91), HT29 (41.52), KM12 (84.38), SW-620 (84.53).
(44.56).
(
(
CNS Cancer SF-268 (68.96), SF-295 (71.37), SF-539 (44.88), SNB-19 (65.95),
SNB-75 (55.84), U251 (77.97).
Melanoma: MALME-3 M (16.62), M14 (93.59), MDA-MB-435 (77.20), SK-
MEL-2 (73.22), SK-MEL-28 (64.59), SK-MEL-5 (42.35), UACC-257 (49.36),
UACC-62 (72.77).
LOX IMVI
(79.12).
Ovarian Cancer: IGROV1 (71.54), OVCAR-3 (74.66), OVCAR-4 (70.46),
OVCAR-5 (65.52), OVCAR-8 (61.61), NCI/ADR-RES (69.96), SK-OV-3
(
51.23).
Renal Cancer 786–0 (89.83), A498 (53.24), ACHN (84.50), CAKI-1 (74.88),
RXF 393 (63.74), SN12C (65.80), TK-10 (77.05), UO-31 (81.24).
Prostate Cancer PC-3 (85.06), DU-145 (72.18).
Breast Cancer MCF7 (87.57), HS 578 T (57.76), BT-549 (61.86), T-47D
MDA-MB-231/
ATCC (16.96).
(
97.10), MDA-MB-468 (82.47).
5
57.78
(70.63)
Leukemia: CCRF-CEM (75.29), HL-60 (TB) (55.41), K-562 (52.57), MOLT-4
(36.37), RPMI-8226 (74.96), SR (18.78).
(790035)
Non-Small Cell Lung Cancer: A549/ATCC (25.24), EKVX (25.75), HOP-62
HOP-92 (12.85).
(
(
27.49), NCI-H226 (41.01), NCI-H23 (41.74), NCI-H322M (20.56), NCI-H460
42.27), NCI-H522 (93.73).
Colon Cancer: HCC-2998 (17.82), HCT-116 (85.75), HCT-15 (38.17),
KM12 (41.73), SW-620 (18.47).
CNS Cancer: SF-268 (44.93), SF-539 (39.83), SNB-19 (33.10), SNB-75
(
25.72), U251 (23.48).
Melanoma: LOX IMVI (15.85), MALME-3 M (32.05), M14 (51.92), MDA-
MB-435 (23.52), SK-MEL-2 (59.99), SK-MEL-28 (61.21), SK-MEL-5
(
72.14), UACC-257 (46.00), UACC-62 (90.56).
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
Table 1
(
Continued)
Comp. no.
Subpanel cell
lines (lethality
percent)
Mean growth
percent
(NSC-number)
Panel: Subpanel cell lines (growth inhibition percent)
Ovarian Cancer: IGROV1 (50.70), OVCAR-3 (29.99), OVCAR-4 (31.88),
OVCAR-5 (27.51), OVCAR-8 (29.84), NCI/ADR-RES (23.34), SK-OV-3
(
80.37).
Renal Cancer: 786–0 (38.16), A498 (50.08), ACHN (37.55), CAKI-1
44.20), SN12C (65.05), UO-31 (48.21).
(
Prostate Cancer: PC-3 (69.96).
Breast Cancer: MCF7 (52.70), MDA-MB-231/ATCC (47.07), HS 578 T
(
22.94), BT-549 (86.91), T-47D (66.82), MDA-MB-468 (56.23).
8
99.42
(20.81)
Non-Small Cell Lung Cancer: NCI-H322M (15.38).
Melanoma: MALME-3 M (21.39).
(790023)
Ovarian Cancer: IGROV1 (21.24).
Renal Cancer: UO-31 (17.70).
Breast Cancer: MDA-MB-231/ATCC (15.23).
Table 2
The mean growth percent, delta values, the percent growth inhibition, and the lethality percent against some subpanel cell lines of the selected compounds
of Schemes 2 and 3.
Comp. no.
NSC-number)
Mean growth
percent (Delta)
Subpanel cell lines
(lethality percent)
(
Panel: Subpanel cell lines (growth inhibition percent)
LEUKEMIA: CCRF-CEM (16.58), MOLT-4 (20.27).
12
85.16
(790028)
(37.09)
NON-SMALL CELL LUNG CANCER: A549/ATCC (21.15), HOP-92 (20.68),
NCI-H226 (18.70), NCI-H23 (15.96), NCI-H322M (16.63), NCI-H460 (20.93),
NCI-H522 (35.24).
COLON CANCER: HCT-116 (15.92), HT29 (17.05), KM12 (18.92), SW-
6
20 (16.66).
CNS CANCER: SF-268 (18.35), SNB-19 (22.52), SNB-75 (21.67), U251
16.35).
MELANOMA: SK-MEL-2 (25.67), SK-MEL-28 (15.41), UACC-62
30.91).
(
(
Ovarian Cancer: IGROV1 (32.97).
RENAL CANCER: A498 (27.15), ACHN (15.03), UO-31 (29.92).
Prostate Cancer: PC-3 (23.97).
BREAST CANCER: MCF7 (51.93), MDA-MB-231/ATCC (16.22), T-47D
(
38.14), MDA-MB-468 (31.75).
1
7
29.23
(53.64)
Leukemia: CCRF-CEM (39.74), HL-60 (TB) (30.41), K-562 (44.79), MOLT-4
(23.53), RPMI-8226 (71.68), SR (66.85).
(790031)
Non-Small Cell Lung Cancer: A549/ATCC (82.20), EKVX (40.09), NCI-H226
HOP-62 (7.72),
HOP-92
(
50.11), NCI-H23 (82.96), NCI-H322M (69.47), NCI-H522 (92.62).
(18.74), NCI-
H460 (0.30).
Colon Cancer: COLO 205 (48.64), HCC-2998 (32.48), HCT-116 (86.05), HCT-
1
5 (60.25), HT29 (82.07), KM12 (83.91), SW-620 (60.70).
CNS Cancer: SF-268 (54.53), SF-539 (56.77), SNB-19 (37.93), SNB-75
81.88), U251 (95.06).
SF-295 (24.41).
(
Melanoma: LOX IMVI (82.17), MALME-3 M (79.34), M14 (69.40), MDA-
MB-435 (83.26), SK-MEL-2 (61.47), SK-MEL-28 (57.40), SK-MEL-5 (44.90),
UACC-257 (41.20), UACC-62 (92.12).
Ovarian Cancer: IGROV1 (70.92), OVCAR-3 (95.90), OVCAR-5 (53.64),
OVCAR-8 (77.00), NCI/ADR-RES (81.21).
Renal Cancer: 786–0 (91.90), A498 (53.85), ACHN (73.76), CAKI-1 (74.80),
RXF 393 (27.24), SN12C (17.44), UO-31 (80.66).
OVCAR-4 (9.61),
SK-OV-3 (0.59).
TK-10 (13.30).
Prostate Cancer: PC-3 (89.72), DU-145 (74.54).
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
Table 2
(
Continued)
Comp. no.
NSC-number)
Mean growth
percent (Delta)
Subpanel cell lines
(lethality percent)
(
Panel: Subpanel cell lines (growth inhibition percent)
Breast Cancer: MCF7 (56.06), MDA-MB-231/ATCC (81.18), HS 578 T
(
67.57), BT-549 (44.80), T-47D (88.22), MDA-MB-468 (85.30).
20
95.06
Non-Small Cell Lung Cancer: NCI-H226 (19.48), NCI-H522 (28.63).
(790059)
(26.28)
Melanoma: UACC-62 (23.84).
Ovarian Cancer: IGROV1 (25.68), SK-OV-3 (23.08).
Renal Cancer: UO-31 (26.80).
Prostate Cancer: PC-3 (17.60).
Breast Cancer: MCF7 (19.39), MDA-MB-231/ATCC (16.26), T-47D
(
31.22).
Table 3
The mean growth percent, delta values, and the percent growth inhibition against some subpanel cell lines of the selected compounds of Schemes 4 and 5.
:
Comp. no.
Mean
growth
percent
(Delta)
(
NSC-number)
Panel: Subpanel cell lines (growth inhibition percent)
Leukemia: HL-60(TB) (26.25).
2
4
97.94
(790020)
(24.19)
Renal Cancer: A498 (21.91).
Breast Cancer: MDA-MB-231/ATCC (21.02).
2
9
62.06
(50.81)
Leukemia: CCRF-CEM (70.09), HL-60 (TB) (44.28), K-562 (83.78), MOLT-4 (76.97), RPMI-8226 (62.21),
SR (69.02).
(790050)
Non-Small Cell Lung Cancer: A549/ATCC (27.46), EKVX (33.08), HOP-62 (32.44), HOP-92 (56.79), NCI-
H226 (31.02), NCI-H23 (40.18), NCI-H460 (22.49), NCI-H522 (57.47).
Colon Cancer: COLO 205 (18.88), HCC-2998 (37.26), HCT-116 (55.16), HCT-15 (40.11), HT29
(30.54), KM12 (48.75), SW-620 (58.91).
CNS Cancer: SF-268 (29.97), SF-295 (19.12), SNB-19 (32.90), SNB-75 (27.90), U251 (28.76).
Melanoma: LOX IMVI (40.81), MALME-3 M (28.73), M14 (33.39), MDA-MB-435 (88.75), SK-MEL-
2
(27.93), SK-MEL-28 (22.74), SK-MEL-5 (30.83), UACC-257 (26.99), UACC-62 (57.54).
Ovarian Cancer: IGROV1 (55.96), OVCAR-3 (35.83), OVCAR-4 (40.90), OVCAR-5 (20.43), OVCAR-
(26.58), NCI/ADR-RES (29.26), SK-OV-3 (36.27).
Renal Cancer: A498 (27.04), ACHN (19.71), CAKI-1 (20.70), RXF 393 (16.89), SN12C (36.98), UO-31
60.30).
8
(
Prostate Cancer: PC-3 (48.25).
Breast Cancer: MCF7 (76.56), MDA-MB-231/ATCC (42.32), HS 578 T (23.05), T-47D (74.92), MDA-
MB-468 (72.01).
31a
88.68
Leukemia: CCRF-CEM (27.03), RPMI-8226 (17.00).
(790036)
(40.33)
Non-Small Cell Lung Cancer: A549/ATCC (17.66), HOP-62 (15.93), HOP-92 (26.64), NCI-H226 (16.10),
NCI-H522 (31.06).
Melanoma: LOX IMVI (15.57), SK-MEL-2 (15.32), SK-MEL-28 (22.91), UACC-257 (16.32), UACC-
62 (36.32).
Ovarian Cancer: OVCAR-5 (15.17), SK-OV-3 (28.25).
Renal Cancer: A498 (25.70), ACHN (17.98), UO-31 (34.97).
Prostate Cancer: PC-3 (31.05).
Breast Cancer: MCF7 (37.76), MDA-MB-231/ATCC (29.21), BT-549 (17.75), T-47D (51.65).
Leukemia: CCRF-CEM (23.57), MOLT-4 (17.11), SR (15.56).
34a
89.45
(790029)
(33.62)
Non-Small Cell Lung Cancer: HOP-62 (22.06), HOP-92 (26.33), NCI-H226 (24.07).
CNS Cancer: SNB-75 (18.24).
Melanoma: LOX IMVI (16.02), UACC-62 (21.78).
Ovarian Cancer: IGROV1 (35.38), OVCAR-5 (18.30), SK-OV-3 (16.77).
Renal Cancer: ACHN (15.00), UO-31 (44.17).
Prostate Cancer: PC-3 (31.83).
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
Table 3
(
Continued)
Comp. no.
Mean
growth
percent
(Delta)
(NSC-number)
Panel: Subpanel cell lines (growth inhibition percent)
Breast Cancer: MCF7 (27.54), MDA-MB-231/ATCC (27.87), BT-549 (17.10), T-47D (41.02).
Leukemia: MOLT-4 (15.86), SR (24.63).
34b
92.45
(790030)
(30.77)
Non-Small Cell Lung Cancer: HOP-62 (17.14), HOP-92 (19.41), NCI-H226 (18.22), NCI-H522 (15.34).
CNS Cancer: SNB-75 (22.53).
Melanoma: UACC-62 (23.34).
Ovarian Cancer: IGROV1 (32.35).
Renal Cancer: UO-31 (38.32).
Prostate Cancer: PC-3 (23.87).
Breast Cancer: MCF7 (35.65), MDA-MB-231/ATCC (21.71), T-47D (36.33).
1
triazepine carbonitrile derivative 31a,b, respectively. H
NMR spectra of compound 31a,b revealed two singlet
signals at δ 2.73–3.90 ppm attributed to two methoxy
protons.
Finally, 2-iminoquinoline-1-amine derivative 26 was
heated under reflux with either 2-[bis(methylthio)
methylene]malononitrile 32[42] or ethyl 2-cyano-3,3-
bis(methylthio)acrylate 33[42] in dimethyl formamide
containing a catalytic amount of triethylamine to give the
Table 4
GI50, TGI, and LC50 of five-dose screening of compound 4.
Panel/cell line
GI50
TGI
LC50
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
0.911
2.61
1.88
0.683
2.24
1.84
9.61
7.00
7.81
7.81
6.65
8.02
>100
42.7
>100
84.3
67.5
>100
corresponding
4-amino-2-methylsulfanyl-3-carbonitrile
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon cancer
Colo 205
HCC-2998
HCT-116
HCT-15
derivative 34a or 4-amino-2-methylsulfanyl-3-carboxylate
2.69
1.26
2.08
1.40
3.71
1.73
2.20
1.94
1.58
11.9
4.28
5.87
3.77
17.00
5.04
11.7
4.17
3.63
50.0
22.0
28.1
10.6
72.7
23.2
39.6
1
analogue 34b, respectively.
H NMR spectra of
compound 34a,b revealed singlet signals at δ 2.89 ppm
1
assigned for S–CH protons, while H NMR spectrum of
3
compound 34b showed a triplet and a multiplet signal at
δ 1.06 and δ 3.38–3.50 ppm attributed to ester methyl
and methylene protons, respectively.
8.97
8.31
Anticancer screening.
Thirteen of the newly
synthesized compounds, 2b, 3, 4, 5, 8, 12, 17, 20, 24, 29,
1a, 34a, and 34b, were selected by Developmental
1.89
1.88
1.29
1.18
3.39
1.61
2.58
3.92
4.21
2.71
3.04
11.5
3.60
7.29
8.15
9.41
5.70
7.86
37.9
8.07
28.3
3
Therapeutic Program, Division of Cancer Treatment and
Diagnosis, National Cancer Institute (NCI), Bethesda,
Maryland, USA, to be evaluated in vitro in a single high
dose (10 μmol) against 60 human tumor cell lines for their
primary anticancer activity [45]. Among which two
compounds 4 and 17 showed strong anticancer activity
against various cell lines as they fulfilled the criteria
required to be further evaluated by the NCI in the five-
dose full panel assay. The one-dose screening results of
the selected compounds are represented as the mean
growth inhibition percent, delta values, and percent
growth inhibition against some subpanel cell lines in
HT29
KM12
SW-620
CNS cancer
SF-268
SF-295
SF-539
SNB-19
2.36
1.56
1.68
2.08
2.39
2.26
8.83
3.27
3.34
4.56
10.9
5.50
43.6
6.84
6.64
10.1
43.6
20.7
SNB-75
U251
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
1.59
2.79
1.55
1.94
2.77
2.06
4.66
2.97
8.58
3.58
4.89
8.90
4.29
15.8
5.53
42.8
8.29
15.9
34.1
(Tables 1, 2, and 3), while the results of the five-dose full
panel assay of compounds 4 and 17 are presented in
Tables 4 and 5), respectively.
However, Figures 1 and 2 represent the dose–response
curves of compounds 4 and 17 against various cancer cell
8.93
41.4
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
Table 4
Table 5
(
Continued)
(Continued)
Panel/cell line
GI50
1.40
TGI
2.96
LC50
Panel/cell line
GI50
TGI
3.19
—
>100
LC50
UACC-62
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
6.27
SF-295
SF-539
SNB-19
SNB-75
U251
1.32
1.68
3.49
1.87
1.88
—
>100
>100
>100
—
2.58
1.70
2.19
2.26
2.36
2.11
4.63
8.88
3.76
11.8
8.77
5.98
6.64
15.7
42.3
8.34
6.92
—
55.0
46.6
31.3
31.5
39.6
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-62
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
Renal cancer
786–0
2.22
0.782
1.77
—
2.48
—
—
—
>100
—
>100
>100
>100
>100
>100
>100
>100
—
Renal cancer
786-0
1.34
1.69
2.08
1.58
3.02
1.33
3.08
4.01
6.27
3.25
9.10
7.16
7.11
9.51
23.2
6.65
32.1
34.9
6.92
—
—
A498
ACHN
SN12C
TK10
UO-31
Prostate cancer
PC-3
DU-145
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578T
BT-549
T-47D
MDA-MB-468
1.66
1.29
3.47
1.72
1.02
0.217
—
1.92
4.25
2.14
>100
—
>100
—
1.58
3.02
3.39
11.6
7.27
39.5
—
—
>100
>100
>100
>100
>100
>100
>100
2.26
1.59
2.53
1.52
2.20
2.23
8.68
3.75
9.86
3.34
11.2
5.98
45.8
8.83
60.9
7.34
55.0
47.6
10.8
1.41
1.81
1.41
4.08
1.91
1.66
3.34
5.17
—
—
>100
>100
>100
>100
>100
A498
ACHN
SN 12C
TK-10
>100
4.58
UO-31
—
Prostate cancer
PC-3
DU-145
Table 5
0.759
—
—
>100
>100
>100
GI50, TGI, and LC50 of five-dose screening of compound 17.
Breast cancer
MCF7
MDA-MB-231/ATCC
HS 578 T
BT-549
Panel/cell line
GI50
TGI
LC50
1.94
1.35
0.561
2.29
1.40
1.37
>100
>100
>100
>100
>100
>100
—
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
—
6.69
>100
>100
>100
>100
80.3
>100
>100
>100
>100
>100
>100
>100
>100
7.87
19.5
>100
3.30
2.13
8.41
1.64
0.523
T-47D
MDA-MB-468
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon cancer
Colo 205
HCC-2998
HCT-116
HCT-15
—
—
>100
—
>100
>100
>100
lines, while Table 6 shows the MG-MID and the selectivity
ratio of compound 4 toward different cancer cell lines.
As revealed from one-dose screening results presented
in Tables 1–3 and in a trial to shed more light on the
SAR of compounds bearing benzothiazole, it is evident
that the presence of arylidene nitrile at 2-position of
benzothiazole as in compounds 2b and 3 bearing
thiazinane and aminophenyl exhibited weak to moderate
growth inhibitory activity against several cancer cell
lines. However, replacement of arylidene moiety by two
S-methyl functions as in compound 5 resulted in marked
increase in growth inhibitory activity against many cell
lines.
1.61
0.875
1.19
2.29
1.67
—
0.402
3.22
4.72
—
—
43.0
>100
>100
>100
>100
>100
>100
—
>100
—
>100
>100
—
>100
>100
—
>100
>100
>100
>100
>100
>100
>100
>100
0.724
2.40
HT29
KM12
SW-620
CNS cancer
SF-268
—
0.615
0.55
>100
It is to be noted that the conversion of arylidene moiety
into amino pyrazole nucleus as in compound 4 containing
phenylamino side chain resulted in powerful anticancer
activity against all cell lines. However, replacement of
0.928
>100
>100
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
Figure 1. Dose–response curves of compound 4 against variable cancer cell lines. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
Figure 2. Dose–response curves of compound 17 against variable cell lines. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
Table 6
The MG-MID (GI50) μM/L and the selectivity ratio of compound 4.
Subpanel tumor cell lines GI50 MG-MID (μM/L) (SI)
Full Panel GI50 MG-MID (μM/L)
I
II
III
IV
V
VI
VII
VIII
IX
2.10
1.694
2.095
(1.00)
1.974
(1.06)
2.055
(1.02)
2.345
(0.89)
2.547
(0.82)
1.84
(1.14)
2.3
(0.91)
2.055
(1.02)
(
1.24)
I, leukemia; ΙΙ, non-small cell lung cancer; ΙΙΙ, colon cancer; ΙV, CNS cancer; V, melanoma; VΙ, ovarian cancer; VΙΙ, renal cancer; VΙΙΙ, prostate cancer;
IX, breast cancer. SI, selectivity index.
phenylamino side chain of aminopyrazole ring in
compound 4 with 4-bromophenyl moiety in compound 8
diminished the anticancer activity.
ovarian cancer OVCAR-4, prostate cancer PC-3, and
breast cancer HS578T.
In a trial to investigate the effect of linkage of different
heterocyclic rings to the benzothiazole backbone, it was
found that attachment of aminopyrrolone ring to the
benzothiazole nucleus as in compound 12 exhibited weak
to moderate anticancer activity against most of the cell
lines. However, it showed promising growth inhibition
activity against breast cancer MDA-MB-468 cell line.
Also, attachment of 3-amino-5-(phenylamino)thiophen-
CONCLUSION
It can be concluded that attachment of different
heterocyclic moieties to the biologically active
benzothiazole backbone resulted in variable anticancer
activities upon screening in the single-dose 60 cell line
panel assay performed by the NCI, Bethesda, Maryland,
USA. Among which compounds 4 and 17, bearing 3-
amino-5-phenylaminopyrazole and 3-amino-5-phenylami
nothiophen-2-yl-(4-chlorophenyl)methanone, respectively,
attached to the 2-position of benzothiazole exhibited
powerful anticancer activity in the five-dose full panel
screening assay exerting highly potent growth inhibitory
activity against all cell lines as well as strong lethal
activity against many cell lines.
2-yl-(4-chlorophenyl)methanone to the benzothiazole
backbone as in compound 17 resulted in strong growth
inhibitory activity and lethal effect toward all of the
cancer cell lines.
Furthermore, replacement of 4-chlorophenylmethanone
and 5-phenylamino moieties in compound 17 by
dioxoisoindolin amide moiety and mercapto function,
respectively, as in compound 20 diminished the
anticancer activity. Also, attachment of 2-aminopyridine
ring to the benzothiazole nucleus as in compound 24
resulted in weak anticancer activity.
MATERIALS AND METHODS
Moreover, attachment of triazepinoquinoline to the
benzothiazole backbone as in compounds 29, 31a, 34a,
and 34b resulted in variable activities in which only
compound 29 bearing 2,4-dichlorophenyl moiety at C5
and fused dihydronaphthyl nucleus at C6 and C7 showed
moderate to strong anticancer activity against various
cancer cell lines.
All melting points were measured on Electro thermal LA
9000 SERIS, Digital Melting point Apparatus, and are
uncorrected. IR spectra were recorded, for potassium
bromide discs, on
a Perkin-Elmer 1430 Infrared
spectrophotometer at IR analytical unit, Faculty of
1
13
Pharmacy, Cairo University. H NMR and
C NMR
The five-dose screen results of compounds 4 and 17
presented in Tables 4 and 5 revealed that compound 4
exhibited powerful growth inhibitory activity against all
cell lines exerting GI50 ranging from 0.683 to 4.66 μM/L
and TGI ranging from 2.97 to 17 μM/L, and it exerted
lethal effect against many cell lines. However, it was
non-selective showing selectivity index less than 3 as
presented in Table 6.
It is to be noted that the five-dose screening results of
compound 17 revealed potent growth inhibitory activity
with GI50 less than 1 μM/L against many cell lines
including leukemia SR, non-small cell lung cancer HOP-
spectra were recorded in DMSO-d at 300 MHz on a
6
Varian Gemini NMR spectrometer (δ, ppm) using TMS as
an internal standard at Microanalytical Research Center,
Chemical Warfare Department, Ministry of Defense. Mass
spectra were carried out using a Schimadzu GCMS-QP-
1000EX mass spectrometer at 70 ev at Regional Center for
Mycology and Biotechnology, Al-Azhar University.
Elemental analyses were performed on Elementar Vario EI
III CHN analyzer at the microanalytical unit, Regional
center for Mycology and Biotechnology, Al-Azhar
University. Reactions were monitored by thin-layer
chromatography on silica gel (60 GF 254, Merck), using
glass plates. The spots were visualized by exposure to
UV-lamp at λ 254 nm for few seconds.
62 and NCI-H460, colon cancer HCT-116, KM12 and
SW-620, CNS cancer SF-268, melanoma MALME-3M,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
General procedure for the synthesis of compounds (2a–c).
(C H –C ); 122.64 (C H –C ); 124.59 (C H –C ); 125.85
6 5 2 6 5 6 6 5 4
To a well-stirred and ice-cooled suspension of compound
(benzothiazole–C ); 126.35 (benzothiazole–C ); 127.11
4 6
1
[17] (0.35 g, 2 mmol) and finely powdered potassium
hydroxide (0.22 g, 4 mmol) in dry dimethyl formamide
6 mL), phenyl isothiocyanate (0.27 g, 0.24 mL,
mmol) was added portion wise. After complete
addition, stirring was continued at room temperature for
h. The reaction mixture was cooled to 0°C, treated
with equimolar amounts of chloroacetyl chloride (0.22 g,
(benzothiazole–C ); 127.68 (benzothiazole–C ); 128.67
7 5
(C H –C ); 129.74 (benzothiazole–C ); 138.84 (C H –
6
5
3,5
1a
6 5
(
2
C ); 140.60 (benzothiazole–C ); 169.06 (benzothiazole–
1 3a
C ); 187.13 (thiazinane–C ). Anal. Calcd (%) for
2 2
C H N S : C, 65.30; H, 4.33; N, 12.02. Found: C,
19 15 3 2
3
65.49; H, 4.41; N, 12.21.
Ethyl 2-(2-(benzo[d]thiazol-2-yl)-2-cyano-1-(phenylamino)
0
0
0
.16 mL,
2
mmol), 1,3-dichloropropane (0.23 g,
vinyl thio)acetate (2c).
Dark gray powder; crystallized
.19 mL, 2 mmol), or ethyl bromoacetate (0.33 g,
.22 mL, 2 mmol), and stirring was continued for
from ethanol; yield 0.55 g (69%); mp 142–144°C. IR
ꢀ
1
(KBr, ν cm ): 3313 (NH); 3055, 3028 (CH–Ar); 2900,
2866 (CH–aliph.); 2198 (CꢁN); 1725 (ester C¼O); 1597
additional 6 h at room temperature then poured onto ice-
cold water. The obtained precipitate was filtered, washed
with water, and dried and crystallized from the
appropriate solvent to afford compounds 2a, 2b, and 2c,
respectively.
(C¼N); 1573 (C¼C); 1288, 1068 (C–S–C); 1230, 1053
1
(C–O–C). H NMR (DMSO-d
, δ ppm): 1.23 (t, 3H,
6
J = 7.2 Hz, CH
J = 7.2 Hz, CH
H); 7.21–7.32 (m, 2H, C H –C2,6–H); 7.33–7.40 (m, 2H,
CH
2
); 2.87 (s, 2H, S-CH
3
); 4.18 (q, 2H,
–C –
4
2
CH
); 7.07 (t, 1H, J = 7.6 Hz, C
H
2
3
6
5
2
-(Benzo[d]thiazol-2-yl)-2-(5-oxo-3-phenylthiazolidin-2-
6 5
ylidene)acetonitrile (2a).
crystallized from toluene; yield 0.4 g (57%); mp 214–
Bright light brown crystals;
C
C
6
H
5
–C3,5–H); 7.91 (d, 1H, J = 8.4 Hz, benzothiazole–
–H); 8.05–8.18 (m, 3H, benzothiazole–C5,6,7–H);
O exchangeable). Anal. Calcd (%)
: C, 60.74; H, 4.33; N, 10.62. Found:
4
ꢀ
1
216°C. IR (KBr, ν cm ): 3083 (CH–Ar); 2914 (CH–
10.12 (s, 1H, NH, D
for C20
2
aliph.); 2187 (CꢁN); 1720 (C¼O); 1589 (C¼N); 1520
H N O S
17 3 2 2
1
(
C¼C); 1245, 1004 (C–S–C). H NMR (DMSO-d , δ
C, 60.98; H, 4.39; N, 10.91.
6
ppm): 4.17 (s, 2H, thiazolidinone–CH ); 7.17–7.22 (m,
2-(Benzo[d]thiazol-2-yl)-3-(ethylthio)-3-(phenylamino)
2
1
H, C H –C –H); 7.25–7.43 (m, 2H, C H –C , –H);
acrylonitrile (3).
To a stirred solution of potassium
6
5
4
6
4
2 6
7
.51–7.54 (m, 2H, C H –C , –H); 7.67 (d, 1H,
hydroxide (0.11 g, 2 mmol) in dimethyl formamide
(10 mL), compound 1 was added (0.35 g, 2 mmol). After
stirring for 30 min, phenyl isothiocyanate (0.27 g,
0.24 mL, 2 mmol) was added to the resulting mixture,
and stirring was continued for further 6 h at room
temperature, then ethyl iodide (0.31 g, 0.16 mL, 2 mmol)
was added, and the reaction mixture was stirred
overnight, diluted with cold water (5 mL), and the solid
precipitate was collected, filtered, washed with water,
dried and crystallized from hexane.
6
4
3 5
J = 8.1 Hz, benzothiazole–C –H); 7.84–7.91 (m, 1H,
benzothiazole–C –H); 7.92–7.95 (m, 1H, benzothiazole–
4
6
C –H); 8.06 (d, 1H, J = 8.1 Hz, benzothiazole–C –H).
5
7
1
3
C NMR (DMSO-d , δ ppm): 79.29 (thiazolidinone–C );
6
4
1
1
14.84 (C–CN); 122.08 (CꢁN); 122.58 (C H –C , );
6
5
2 6
25.38 (C H –C ); 125.85 (benzothiazole–C ); 127.23
6
5
4
4
(
(
benzothiazole–C ); 128.66 (benzothiazole–C ); 129.96
6 7
benzothiazole–C ); 130.13 (C H –C ); 131.15 (C H -
5
6
5
3
6 5
C ); 133.27 (benzothiazole–C ); 135.30 (C H –C );
5
1a
6
5
1
1
1
53.44 (thiazolidinone–C ); 164.37 (benzothiazole–C );
Lemon yellow powder; yield 0.5 g (74%); mp 134–
135°C. IR (KBr, cm ): 3394 (NH); 3059 (CH-Ar);
2
3a
ꢀ
1
65.01 (benzothiazole–C ); 173.65 (C¼O). Anal. Calcd
2
(%) for C H N OS : C, 61.87; H, 3.17; N, 12.03.
2868, 2854 (CH–aliph.); 2194 (CꢁN); 1593 (C¼N);
18
11
3
2
1
Found: C, 62.03; H, 3.20; N, 12.17.
1494 (C¼C); 1278, 1085 (C–S–C). H NMR (DMSO-
2
-(Benzo[d]thiazol-2-yl)-2-(3-phenyl-1,3-thiazinan-2-
d , δ ppm): 1.15 (t, 3H, J = 7.5 Hz, CH CH ); 2.65 (q,
6 2 3
ylidene)acetonitrile (2b). Light orange powder; crystallized
from ethanol; yield 0.38 g (54%); mp 208–210°C. IR (KBr,
ν cm ): 3091, 3055 (CH–Ar); 2899, 2866 (CH–aliph.);
2
2H, J = 7.5 Hz, CH CH ); 7.32–7.44 (m, 5H, C H );
2 3 6 5
7.47–7.50 (m, 2H, benzothiazole–C5,6–H); 7.92 (d, 1H,
8.1 Hz, benzothiazole–C –H); 8.07 (d, 1H,
ꢀ
1
J =
4
187 (CꢁN); 1591 (C¼N); 1537 (C¼C); 1282, 1070 (C–
J = 8.1 Hz, benzothiazole–C –H); 12.37 (s, 1H, NH,
7
1
S–C). H NMR (DMSO-d , δ ppm): 3.22–3.29 (m, 2H,
D O exchangeable). Anal. Calcd (%) for C H N S : C,
6
2
18 15 3 2
thiazinane–C –CH ); 3.59 (t, 2H, J = 6.8 Hz, thiazinane–
64.06; H, 4.48; N, 12.45. Found: C, 64.24; H, 4.53; N,
12.69.
4-(Benzo[d]thiazol-2-yl)-N -phenyl-1H-pyrazole-3,5-diamine
5
2
C –CH ); 3.97 (t, 2H, J = 6.8 Hz, thiazinane–C –CH );
4
2
6
2
5
7
.18 (t, 1H, J = 7.5 Hz, C H –C –H); 7.33–7.39 (m, 2H,
6 5 4
C H –C –H); 7.42–7.49 (m, 2H, C H –C3,5–H); 7.67 (d,
(4). A mixture of compound 3 (0.34 g, 1 mmol) and
hydrazine hydrate 99% (0.1 g, 0.1 mL, 2 mmol) in
absolute ethanol (10 mL) was heated under reflux for 6 h.
The reaction mixture was allowed to cool, and the solid
crystals were filtered, washed with ethanol, then dried
and recrystallized from ethanol.
6
5
2,6
6 4
1
H, J = 7.7 Hz, benzothiazole–C –H); 7.82–7.96 (m, 2H,
4
benzothiazole–C5,6–H); 8.06 (d, 1H, J = 7.7 Hz,
1
3
benzothiazole–C –H). C NMR (DMSO-d , δ ppm):
7
6
3
1.32 (thiazinane–C ); 32.08 (thiazinane–C ); 43.74
5 6
(
thiazinane–C ); 78.12 (C–CN); 114.06 (CꢁN); 122.51
4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
Anal. Calcd (%) for C H N S : C, 50.36; H, 3.84; N,
Creamy white crystals; yield 0.2 g (65%); mp 181–
11 10 4 2
ꢀ
1
1
3
1
83°C. IR (KBr, ν cm ): 3360, 3186, 3136 (NH , NH);
21.36. Found: C, 50.53; H, 3.88; N, 21.51.
2
089, 3051 (CH–Ar); 1616, 1593 (C¼N); 1550 (C¼C);
General procedure for the synthesis of 2-(benzo[d]thiazol-2-
1
290, 1090 (C–S–C). H NMR (DMSO-d , δ ppm): 6.16
yl)-3-(4-substituted
phenyl)acrylonitriles
(7a–c).
An
6
(
s, 2H, NH , D O exchangeable); 6.76 (t, 1H, J = 7.5 Hz,
equimolar mixture of compound 1 (0.35 g, 2 mmol) and
the appropriate 4-substituted benzaldehyde (2 mmol),
namely, 4-bromobenzaldehyde, 4-chlorobenzaldehde, and
4-dimethylaminobenzaldehde, was heated under reflux for
4–6 h in absolute ethanol (10 mL) containing few drops
of triethyl amine The reaction mixture was concentrated,
and the obtained solid product was filtered, washed with
2
2
C H –C –H); 7.17–7.29 (m, 4H, C H –C2,3,5,6–H); 7.43
6
5
4
6 5
(t, 2H, J = 8.1 Hz, benzothiazole–C5,6–H); 7.91 (d, 1H,
J
=
8.1 Hz, benzothiazole–C –H); 7.96 (d, 1H,
4
J = 8.1 Hz, benzothiazole–C –H); 8.73 (s, 1H, NH–
phenyl, D O exchangeable); 11.45 (s, 1H, pyrazole-NH,
D O exchangeable). C NMR (DMSO-d , δ ppm): 70.03
7
2
1
3
2
6
(
(
(
(
(
(
(
(
pyrazole–C4);
115.83
(C H –C2,6);
119.17
ethanol, dried and recrystallized from ethanol.
6
5
benzothiazole–C ); 121.00 (benzothiazole–C ); 121.93
2-(Benzo[d]thiazol-2-yl)-3-(4-bromophenyl)acrylonitrile
4
7
(
7a). Greenish yellow crystals; yield 0.51 g (74%); mp
C H –C );
123.73
(benzothiazole–C6);
126.43
132.24
148.83
6
5
4
1
46–148°C as reported [44].
benzothiazole–C5);
benzothiazole–C );
129.28
144.24
(C H –C3,5);
6 5
2
-(Benzo[d]thiazol-2-yl)-3-(4-chlorophenyl)acrylonitrile
7b). Creamy white crystals; yield 0.5 g (84%); mp 154–
56°C as reported [44].
(C H –C );
1a
6
5
1
(
pyrazole–C3); 149.01 (benzothiazole–C2); 152.54
pyrazole–C ); 161.74 (benzothiazole–C ). Anal. Calcd
1
5
3a
2
-(Benzo[d]thiazol-2-yl)-3-(4-(dimethylamino)phenyl)
%) for C H N S: C, 62.52; H, 4.26; N, 22.78. Found:
16 13 5
acrylonitrile (7c). Red crystals; yield 0.45 g (73%); mp
C, 62.67; H, 4.34; N, 22.95.
ꢀ1
2
37–238°C. IR (KBr, ν cm ): 3051, 3005 (CH–Ar);
2
-(Benzo[d]thiazol-2-yl)-3,3-bis(methylthio)acrylonitrile
To a stirred suspension of finely powdered
2
920, 2854 (CH–aliph.); 2214 (CꢁN); 1612 (C¼N); 1566
(5).
1
(C¼C); 1280, 1060 (C–S–C). H NMR (DMSO-d , δ
6
potassium hydroxide (0.22 g, 4 mmol) in dry DMF
10 mL), compound 1 (0.35 g, 2 mmol) was added, and
ppm): 3.09 (s, 6H, two CH ); 6.87 (d, 2H, J = 9 Hz, 4-N
3
(
(
CH ) -C H –C3,5–H); 7.43 (t, 1H, J = 7.5 Hz,
3 2 6 4
the reaction mixture was stirred at 10°C in an ice bath,
then carbon disulfide (0.15 g, 0.12 mL, 2 mmol) was
added slowly, and stirring was continued for 6 h. Then,
dimethylsulfate (0.25 g, 0.19 mL, 2 mmol) was added to
the reaction mixture, and stirring was continued for
additional 3 h. The reaction mixture was poured onto
crushed ice and neutralized with 10% HCl, and the
obtained precipitate was filtered, washed with water,
dried and crystallized from ethanol.
benzothiazole–C –H); 7.53 (t, 1H,
J
=
7.5 Hz,
6
benzothiazole–C –H); 7.95–8.04 (m, 2H, 4-N (CH ) –
5
3 2
C H –C2,6–H); 8.10 (d, 2H, J = 7.5 Hz, benzothiazole–
6
4
C4,7–H); 8.14 (s, 1H, arylidene–H). Anal. Calcd (%) for
C H N S: C, 70.79; H, 4.95; N, 13.76. Found: C, 71.03;
18 15 3
H, 4.99; N, 13.98.
4
-(Benzo[d]thiazol-2-yl)-3-(4-bromophenyl)-1H-pyrazol-5-
amine (8).
Hydrazine hydrate 99% (0.5 g, 0.49 mL,
10 mmol) was added to a solution of compound 7a
(0.34 g, 1 mmol) in absolute ethanol (10 mL). The
reaction mixture was heated under reflux for 12 h then
concentrated and left to cool. The obtained solid
precipitate was filtered, washed with ethanol, dried and
recrystallized from ethanol.
Orange powder; yield 0.51 g (91%); mp 118–120°C as
ꢀ
1
reported [43]. IR (KBr, ν cm ): 3050 (CH-Ar); 2870
CH–aliph.); 2220 (CꢁN); 1620 (C¼N); 1506 (C¼C);
232, 1060 (C–S–C).
(
1
4
6).
-(Benzo[d]thiazol-2-yl)-5-(methylthio)-1H-pyrazol-3-amine
An equimolar mixture of compound 5 (0.56 g,
(
Yellow crystals; yield 0.16 g (43%); mp 225–227°C.
ꢀ
1
2
2
mmol) and hydrazine hydrate 99% (0.1 g, 0.1 mL,
mmol) was heated under reflux for 8 h in absolute
IR (KBr, ν cm ): 3262 (broad NH , NH); 3056 (CH–
2
Ar); 1616 (C¼N); 1576 (C¼C); 1250, 1060 (C–S–C).
+
ethanol (15 mL). The reaction mixture was concentrated
and allowed to cool, and the obtained precipitate was
filtered, washed with ethanol, left to dry then crystallized
from DMF.
EI-MS: m/z (%): 373 (M + 2, 0.76); 371 (M , 1.31);
104 (C H N, 100). Anal. Calcd (%) for C H BrN S:
7
6
16 11
4
C, 51.76; H, 2.99; N, 15.09 Found (%): C, 51.94; H,
3.04; N, 15.32.
Brown powder; yield 0.32 g (61%); mp >300°C. IR
2-(Benzo[d]thiazol-2-yl)-3-oxo-3-phenylpropanenitrile (9).
To a solution of compound 1 (0.35 g, 2 mmol) in
ꢀ
1
(
KBr, ν cm ): 3290, 3163, 3151 (NH , NH); 3012 (CH–
2
Ar); 2856 (CH–aliph.); 1620, 1583 (C¼N); 1541 (C¼C);
toluene (10 mL), benzoyl chloride (0.42 g, 0.35 mL,
3 mmol) was added, and the reaction mixture was
heated under reflux for 12 h in the presence of triethyl
amine (three drops). The reaction mixture was then
concentrated and left to cool, and the desired product
was filtered, washed with toluene, dried and crystallized
from acetone.
1
1
270, 1070 (C–S–C). H NMR (DMSO-d , δ ppm): 2.55
6
(
s, 3H, SCH ); 6.86 (s, 2H, NH , D O exchangeable);
3 2 2
6
1
.87–7.03 (m, 1H, benzothiazole–C –H); 7.20–7.60 (m,
6
H, benzothiazole–C –H); 7.73 (d, 1H, J = 7.5 Hz,
5
benzothiazole–C –H); 7.94–8.08 (m, 1H, benzothiazole–
4
C –H); 9.36 (s, 1H, pyrazole–N H, D O exchangeable).
7
1
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
Reddish brown powder; yield 0.36 g (64%); mp 288–
90°C. IR (KBr, ν cm ): 3412, 3387 (broad tautomeric
3305, 3248 (NH , NH); 3059 (CH–Ar); 2926 (CH–
2
ꢀ
1
2
aliph.); 1678 (C¼O); 1645 (C¼N); 1543 (C¼C); 1282,
1
OH); 3057 (CH–Ar); 2929 (CH–aliph.); 2194 (CꢁN);
1087 (C–S–C). H NMR (DMSO-d , δ ppm): 2.73 (s,
6
1
685 (C¼O); 1624 (C¼N); 1545 (C¼C); 1274, 1076 (C–
2H, CH ); 4.10 (s, 2H, NH , D O exchangeable); 7.47–
2
2
2
1
S–C). H NMR (DMSO-d , δ ppm): 2.06 (s, 1H, CH–
7.55 (m, 2H, benzothiazole–C5,6–H); 7.68 (s, 1H, NH,
6
CN); 7.29–7.34 (m, 2H, benzothiazole–C5,6–H); 7.40–
D O exchangeable); 7.94–8.01 (m, 1H, benzothiazole–
2
7
.42 (m, 3H, C H –C3,4,5–H); 7.48 (d, 2H, J = 8.4 Hz,
C –H); 8.05–8.10 (m, 1H, benzothiazole–C –H). MS: m/z
6
5
4
7
+
C H –C2,6–H); 7.59 (d, 1H, J = 7.8 Hz, benzothiazole–
(%): 231 (M , 9.60); 83 (C H NO, 100). Anal. Calcd (%)
6
5
4 5
C –H); 7.92 (d, 1H, J = 7.8 Hz, benzothiazole–C –H).
for C H N OS: C, 57.13; H, 3.92; N, 18.17. Found: C,
11 9 3
4
7
Anal. Calcd (%) for C H N OS: C, 69.04; H, 3.62; N,
57.28; H, 3.96; N, 18.41.
1
6 10 2
2
-(Benzo[d]thiazol-2-yl)-2-(3,4-dihydronaphthalen-1(2H)-
ylidene) acetonitrile (13) and 1-(benzo[d]thiazol-2-yl)-4,5-
dihydronaphtho[2,1-b]thiophen-2-amine (14). An
1
0.06. Found: C, 69.31; H, 3.68; N, 10.29.
3
-Amino-2-(benzo[d]thiazol-2-yl)-3-hydrazinylacrylonitrile
(10).
An equimolar mixture of compound 1 (0.35 g,
2
mmol) and thiosemicarbazide (0.18 g, 2 mmol) was
equimolar mixture of compound 1 (0.35 g, 2 mmol),
elemental sulfur (0.06 g, 2 mmol), and 1-tetralone (0.29 g,
0.27 mL, 2 mmol) in absolute ethanol (10 mL) containing
triethyl amine (0.5 mL) was heated under reflux for 12 h.
The reaction mixture was filtered while hot, and the
obtained solid precipitate was crystallized from toluene to
afford two products. The insoluble part in boiling toluene
was filtered, dried to give the cyclic compound 14, while
the filtrate was concentrated and allowed to cool to yield
the open-chain derivative 13.
heated under reflux for 20 h in glacial acetic acid
10 mL). The reaction mixture was concentrated and
(
cooled, and the desired precipitate was filtered, washed
with ethanol, dried and crystallized from toluene.
Pale brown powder; yield 0.26 g (56%); mp 270–272°C.
ꢀ
1
IR (KBr, ν cm ): 3385, 3278, 3215 (NH , NH); 3061
2
(
1
CH–Ar); 2206 (CꢁN); 1618 (C¼N); 1533 (C¼C); 1255,
1
083 (C–S–C). H NMR (DMSO-d , δ ppm): 4.74 (s,
6
2H, NH , D O exchangeable); 7.18 (s, 2H, NHNH , D O
2
2
2
2
2
-(Benzo[d]thiazol-2-yl)-2-(3,4-dihydronaphthalen-1(2H)-
exchangeable); 7.35–7.60 (m, 1H, benzothiazole–C –H);
6
ylidene)acetonitrile (13). Green powder; crystallized from
7.94–8.03 (m, 1H, benzothiazole–C –H); 8.08 (d, 1H,
5
toluene; yield 0.2 g (33%); mp 125–127°C. IR (KBr, ν
J = 8 Hz, benzothiazole–C –H); 8.27 (d, 1H, J = 8 Hz,
benzothiazole–C –H); 9.66 (s, 1H, NHNH2, D O
exchangeable). Anal. Calcd (%) for C H N S: C, 51.93;
H, 3.92; N, 30.28. Found: C, 52.14; H, 3.94; N, 30.45.
4
ꢀ
1
cm ): 3057, 3032 (CH–Ar); 2926, 2858 (CH–aliph.);
206 (CꢁN); 1577 (C¼N); 1533 (C¼C); 1271, 1055
7
2
2
1
0 9 5
1
(C–S–C). H NMR (DMSO-d , δ ppm): 0.80–0.90 (m,
6
2
H, dihydronaphthyl–C –CH ); 1.20–1.40 (m, 2H, dihy
3 2
3
-(Benzo[d]thiazol-2-yl)-3-cyanopropanamide
(11)
and
5
A
-amino-4-(benzo[d]thiazol-2-yl)-1H-pyrrol-2(3H)-one (12).
dronaphthyl–C
dronaphthyl–C
4
–CH
–CH
2
); 4.12 (t, 2H, J = 5.2 Hz, dihy
); 7.19–7.36 (m, 1H, dihydronap
mixture of compound 1 (0.35 g, 2 mmol),
2
2
chloroacetamide (0.19 g, 2 mmol), and finely divided
potassium carbonate (0.35 g, 2.5 mmol) in absolute
ethanol (10 mL) was heated under reflux for 6 h. The
reaction mixture was then cooled, triturated with water,
hthyl–C
H); 7.55–7.68 (m, 1H, benzothiazole–C
(m, 1H, benzothiazole–C –H); 7.94 (d, 1H, J = 7.6 Hz,
6
–H); 7.42–7.52 (m, 1H, dihydronaphthyl–C
7
–
–H); 7.69–7.70
6
5
dihydronaphthyl–C
–H); 8.01 (d, 1H, J = 7.6 Hz,
–H); 8.07 (d, 1H, J = 7.6 Hz,
5
filtered, washed with excessive amount of H O, dried,
dihydronaphthyl–C
8
2
and crystallized from ethanol, in which the insoluble part
in boiling ethanol was filtered to give the cyclic
compound 12, while the filtrate was concentrated and
allowed to cool to afford the open-chain derivative 11.
benzothiazole–C
benzothiazole–C
4
–H); 8.25 (d, 1H, J
=
7.6 Hz,
S:
–H). Anal. Calcd (%) for C19
7
H N
14 2
C, 75.47; H, 4.67; N, 9.26. Found: C, 75.52; H, 4.70;
N, 9.26.
1
-(Benzo[d]thiazol-2-yl)-4,5-dihydronaphtho[2,1-b]thiophen-
3
-(Benzo[d]thiazol-2-yl)-3-cyanopropanamide (11). Green
2
-amine (14).
Dark olive green powder; washed with
powder; crystallized from ethanol; yield 0.32 g (69%); mp
ꢀ
1
boiling solvents; yield 0.3 g (45%); mp >300°C. IR (KBr,
2
53–255°C. IR (KBr, ν cm ): 3383, 3360 (NH ); 3059
2
ꢀ
1
ν cm ): 3385, 3107 (NH ); 3057 (CH–Ar); 2924 (CH–
(
1
CH–Ar); 2927 (CH–aliph.); 2198 (CꢁN); 1660 (C¼O);
2
1
aliph.); 1560 (C¼N); 1508 (C¼C); 1247, 1093 (C–S–C).
614 (C¼N); 1556 (C¼C); 1280, 1089 (C–S–C).
H
1
H NMR (DMSO-d , δ ppm): 2.60–2.65 (m, 2H,
NMR (DMSO-d , δ ppm): 1.88–1.91 (m, 1H, CHCN);
6
6
dihydronaphthothiophene–C –CH ); 2.72–2.77 (m, 2H,
dihydronaphthothiophene–C –CH ); 7.32–7.35 (m, 2H,
2
.69–2.73 (m, 1H, CH CO); 2.86–2.89 (m, 1H, CH CO);
5
2
2
2
7
.26 (s, 2H, NH , D O exchangeable); 7.35–7.74 (m, 2H,
4
2
2
2
dihydronaphthothiophene–C7,8–H); 7.50 (s, 2H, NH2,
benzothiazole–C5,6–H); 8.03–8.15 (m, 2H, benzothiazole–
C4,7–H). Anal. Calcd (%) for C H N OS: C, 57.13; H,
D O exchangeable); 7.69–7.73 (m, 2H, dihydronap
2
11
9 3
hthothiophene–C6,9–H); 7.91–8.23 (m, 2H, benzo
thiazole–C5,6–H); 8.28–8.35 (m, 2H, benzothiazole–C4,7
3
.92; N, 18.17. Found: C, 57.34; H, 3.90; N, 18.39.
–
5
-Amino-4-(benzo[d]thiazol-2-yl)-1H-pyrrol-2(3H)-one
(
12). Dark green powder; washed with boiling solvents;
H). Anal. Calcd (%) for C H N S : C, 68.23; H, 4.22;
N, 8.38. Found: C, 68.37; H, 4.29; N, 8.54.
19 14 2 2
ꢀ
1
yield 0.1 g (22%); mp >300°C. IR (KBr, ν cm ): 3388,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
1
2
15).
-(Benzo[d]thiazol-2-yl)-3-(4-nitrophenyl)but-2-enenitrile
(C¼N); 1571 (C¼C); 1265, 1050 (C–S–C). H NMR
(
2
An equimolar mixture of compound 1 (0.35 g,
(
DMSO-d , δ ppm): 7.08–7.18 (m, 1H, C H –C –H);
6 6 5 4
mmol), 4-nitroacetophenone (0.33 g, 2 mmol), and
7
.36–7.45 (m, 2H, C H –C2,6–H); 7.47–7.51 (m, 2H,
6 5
ammonium acetate (0.15 g, 2 mmol) was fused in an oil
bath at 160–170°C for 2 h. The resulted mass was
triturated with ethanol, and the obtained precipitate was
filtered, washed with ethanol, dried and crystallized from
ethanol.
C H –C –H); 7.53–7.60 (m, 4H, 4–Cl–C H –C3,5–H &
6 5 3,5 6 4
benzothiazole–C5,6–H); 7.68 (d, 2H, J = 8.4 Hz, 4–Cl–
C H –C2,6–H); 8.04–8.18 (m, 2H, benzothiazole–C4,7
–
6
4
H); 8.54 (s, 2H, NH , D O exchangeable); 10.42 (s, 1H,
2
2
NH, D O exchangeable). Anal. Calcd (%) for
2
Pale brown powder; yield 0.41 g (64%); mp 153–
55°C. IR (KBr, ν cm ): 3071 (CH–Ar); 2855 (CH–
C H ClN OS : C, 62.40; H, 3.49; N, 9.10. Found (%):
C, 62.53; H, 3.57; N, 9.15.
24
16
3
2
ꢀ
1
1
aliph.); 2227 (CꢁN); 1583 (C¼N); 1516, 1335 (NO );
Ethyl
3-amino-4-(benzo[d]thiazol-2-yl)-5-
2
1
1
450 (C¼C); 1230, 1013 (C–S–C). H NMR (DMSO-
mercaptothiophene-2-carboxylate (18).
An equimolar
d , δ ppm): 2.84 (s, 3H, CH ); 7.42–7.55 (m, 1H,
mixture of compound 1 (0.35 g, 2 mmol) and finely
powdered potassium hydroxide (0.22 g, 4 mmol) in dry
DMF (10 mL) was cooled at 10°C in an ice bath, then
carbon disulfide (0.15 g, 0.12 mL, 2 mmol) was added
slowly over a period of 10 min, and stirring was
6
3
benzothiazole–C –H); 7.58–7.67 (m, 1H, benzothiazole–
6
C –H); 7.76 (d, 1H, J = 7.8 Hz, benzothiazole–C –H);
5
4
7
.95 (d, 1H, J = 7.8 Hz, benzothiazole–C –H); 8.03 (d,
7
1
H, J = 8 Hz, 4–NO –C H –C –H); 8.16 (d, 1H,
2
6
4
2
J = 8 Hz, 4–NO –C H –C –H); 8.25 (d, 1H, J = 8 Hz,
continued for 6 h. Ethyl chloroacetate (0.25 g,
2
6
4
6
4
–NO –C H –C –H); 8.36 (d, 1H, J = 8 Hz, 4–NO –
0.21 mL, 2 mmol) was added to the reaction mixture,
then stirring was continued for another 3 h. The
reaction mixture was poured onto crushed ice and
neutralized with 10% HCl. The obtained precipitate was
filtered, washed with water, dried and crystallized from
ethyl acetate.
2
6
4
3
2
C H –C –H). Anal. Calcd (%) for C H N O S: C,
6
4
5
17 11 3 2
6
3
3.54; H, 3.45; N, 13.08. Found (%): C, 63.70; H,
.48; N, 13.21.
0
3
,5-Diamino-2-(benzo[d]thiazol-2-yl)-4 -nitrobiphenyl-4-
carbonitrile (16). An equimolar mixture of compound 15
0.32 g, 1 mmol) and malononitrile (0.07 g, 1 mmol) in
(
Shiny orange powder; yield 0.55 g (81%); mp 169–
ꢀ
1
absolute ethanol (10 mL) containing three drops of
triethyl amine was heated under reflux for 50 h. The
reaction mixture was concentrated and cooled, and the
resulted precipitate was filtered, washed with ethanol,
dried and crystallized from DMF.
1
71°C. IR (KBr, ν cm ): 3446, 3421 (NH ); 3040 (CH–
2
Ar); 2924 (CH–aliph.); 1735 (C¼O); 1600 (C¼N); 1510
1
(
C¼C); 1292, 1023 (C–S–C); 1232, 1008 (C–O–C). H
NMR (DMSO-d , δ ppm): 1.13 (t, 3H, J = 6.6 Hz,
6
CH CH ); 1.99 (s, 1H, SH, D O exchangeable); 4.04 (q,
2
3
2
Brown powder; yield 0.16 g (41%); mp > 300°C. IR
2H, J = 6.6 Hz, CH CH ); 4.25 (s, 2H, NH , D O
exchangeable); 7.59 (t, 1H, J = 7.7 Hz, benzothiazole–C6–
2 3 2 2
ꢀ
1
(
(
1
9
6
1
KBr, ν cm ): 3385, 3246 (NH ); 3057 (CH-Ar); 2200
2
CꢁN); 1597 (C¼N); 1516, 1340 (NO ); 1445 (C¼C);
H); 7.68 (t, 1H, J = 7.7 Hz, benzothiazole–C –H); 8.13 (d,
2
5
+
290, 1090 (C–S–C). EI-MS: m/z (%): 387 (M , 1.37);
1H, J = 7.7 Hz, benzothiazole–C –H); 8.27 (d, 1H,
4
5 (C H N , 100). Anal. Calcd (%) for C H N O S: C,
J = 7.7 Hz, benzothiazole–C –H). Anal. Calcd (%) for
4
5
3
20 13
5
2
7
2.00; H, 3.38; N, 18.08. Found: C, 62.24; H, 3.36; N,
8.19.
C H N O S : C, 49.98; H, 3.59; N, 8.33. Found: C,
14 12 2 2 3
50.16; H, 3.64; N, 8.49.
(
3-Amino-4-(benzo[d]thiazol-2-yl)-5-(phenylamino)thiophen-
3-Amino-4-(benzo[d]thiazol-2-yl)-5-mercaptothiophene-2-
2-yl)(4-chlorophenyl)-methanone (17).
To a well-stirred,
carbohydrazide (19). To a suspension of compound 18
ice-cold suspension of finely powdered potassium
hydroxide (0.22 g, 4 mmol) and compound 1 (0.35 g,
(0.67 g, 2 mmol) in absolute ethanol (10 mL), hydrazine
hydrate 99% (1 g, 0.97 mL, 20 mmol) was added, and
the reaction mixture was heated under reflux for 5 h. The
reaction mixture was concentrated and cooled, and the
obtained precipitate was filtered, washed with ethanol,
left to dry then crystallized from dioxane.
2
mmol) in dry dimethyl formamide (10 mL), phenyl
isothiocyanate (0.27 g, 0.24 mL, 2 mmol) was added
portion wise. After complete addition, stirring was
continued at room temperature for 3 h. Then the reaction
0
mixture was cooled to 0°C and treated with 2-bromo-4 -
Brown powder; yield 0.3 g (47%); mp > 300°C. IR
ꢀ
1
chloroacetophenone (0.47 g, 2 mmol), and stirring was
continued for another 6 h. The reaction mixture was then
poured onto ice-cold water, and the obtained precipitate
was filtered, washed with water, dried and crystallized
from ethanol.
(
KBr, ν cm ): 3304, 3116 (NH , NH); 3040 (CH–Ar);
2
1
660 (C¼O); 1581 (C¼N); 1544 (C¼C); 1282, 1095
1
(C–S–C). H NMR (DMSO-d , δ ppm): 4.48 (s, 1H,
6
SH, D O exchangeable); 5.01 (br. s, 2H, NHNH , D O
2
2
2
exchangeable); 5.79 (s, 2H, NH , D O exchangeable);
2
2
Pale orange powder; yield 0.62 g (67%); mp 225–
27°C. IR (KBr, ν cm ): 3404, 3282, 3267, 3221
7.23 (t, 1H, J = 7.7 Hz, benzothiazole–C –H); 7.39 (t,
6
ꢀ
1
2
1H, J = 7.7 Hz, benzothiazole–C –H); 7.70 (d, 1H,
5
(
NH , NH); 3057, 3026 (CH–Ar); 1665 (C¼O); 1645
J
=
7.7 Hz, benzothiazole–C –H); 7.96 (d, 1H,
2
4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
J = 7.7 Hz, benzothiazole–C –H); 11.86 (s, 1H, NH, D O benzothiazole–C –H); 7.94 (d, 1H, J
Vol 000
7.8 Hz,
=
7
2
4
13
exchangeable). Anal. Calcd (%) for C H N OS : C,
benzothiazole–C –H). C NMR (DMSO-d , δ ppm):
1
2
10
4
3
7
6
4
1
4.70; H, 3.13; N, 17.38. Found: C, 44.98; H, 3.17; N,
7.57.
13.96 (CH ); 14.59 (CH CH ); 60.82 (CH CH ); 88.92
3 2 3 2 3
(furan–C3);
111.18
(benzothiazole–C4);
120.79
3
-Amino-4-(benzo[d]thiazol-2-yl)-N-(1,3-dioxoisoindolin-2-
(
(
(
(
(
benzothiazole–C ); 121.59 (benzothiazole–C ); 123.59
7
6
yl)-5-mercaptothiophene-2-carboxamide (20). An equimolar
mixture of compound 19 (0.32 g, 1 mmol) and phthalic
anhydride (0.15 g, 1 mmol) in glacial acetic acid (10 mL)
was heated under reflux for 12 h. The reaction mixture
was concentrated and cooled, and the obtained product
was filtered, washed with ethanol, dried and crystallized
from methanol.
benzothiazole–C5);
126.19
149.29
(furan–C4);
(furan–C5);
133.43
152.37
benzothiazole–C );
1a
benzothiazole–C ); 158.79 (benzothiazole–C ); 162.20
2
3a
furan–C2); 163.82 (C¼O). Anal. Calcd (%) for
C H N O S: C, 59.59; H, 4.67; N, 9.27. Found: C,
15 14 2 3
5
9.75; H, 4.74; N, 9.45.
6-Amino-5-(benzo[d]thiazol-2-yl)-4-(2,4-imethoxyphenyl)
Dark green powder; yield 0.35 g (78%); mp 188–190°C.
nicotinonitrile (24). A mixture of compound 1 (0.35 g,
ꢀ
1
2
mmol), 2-(2,4-dimethoxybenzylidene)malononitrile
IR (KBr, ν cm ): 3383, 3367, 3213 (NH , NH); 3095
2
2
3[41] (0.43 g, 2 mmol), and piperidine (0.1 mL) in
(
(
(
(
CH–Ar); 1732 (cyclic C¼O); 1685 (C¼O); 1585
C¼N); 1543 (C¼C); 1280, 1072 (C–S–C). EI-MS: m/z
absolute ethanol (20 mL) was heated under reflux for 2 h.
The formed needle crystals were filtered, washed with
ethanol, dried and recrystallized from acetone.
+
%): 452 (M , 3.73); 248 (C H NS , 100). Anal. Calcd
1
1
6
3
%) for C H N O S : C, 53.08; H, 2.67; N, 12.38.
20 12 4 3 3
Light orange crystals; yield 0.71 g (91%); mp 175–
Found: C, 53.24; H, 2.69; N, 12.52.
N-(7-(Benzo[d]thiazol-2-yl)-6-mercapto-2-methyl-4-
ꢀ
1
177°C. IR (KBr, ν cm ): 3310 (NH ); 3095 (CH–Ar);
2
oxothieno[3,2-d]pyrimidin-3(4H)-yl)acetamide
(21).
2930 (CH–aliph.); 2217 (CꢁN); 1566 (C¼N); 1460
1
Compound 19 (0.32 g, 1 mmol) was heated under
reflux in a mixture of glacial acetic acid (5 mL) and
acetic anhydride (5 mL) for 12 h. The reaction mixture
was allowed to cool, and the obtained precipitate was
filtered, washed with dioxane, dried and crystallized
from dioxane.
(C¼C); 1278, 1025 (C–S–C); 1211, 1010 (C–O–C). H
NMR (DMSO-d , δ ppm): 3.91 (s, 3H, 2,4–(OCH ) –
6
3 2
C H –C –OCH ); 3.97 (s, 3H, 2,4–(OCH ) –C H –C –
6
3
4
3
3 2
6
3
2
OCH ); 6.70–6.80 (m, 2H, 2,4–(OCH ) –C H –C3,5–H);
3
3 2
6 3
6.81 (s, 2H, NH , D O exchangeable); 7.49 (t, 1H,
2
2
J
J
=
=
7.8 Hz, benzothiazole–C –H); 7.57 (t, 1H,
6
Dark brown powder; yield 0.28 g (73%); mp >300°C.
7.8 Hz, benzothiazole–C –H); 8.06 (d, 1H,
5
ꢀ
1
IR (KBr, ν cm ): 3410 (tautomeric OH); 2924 (CH–Ar);
J = 8.1 Hz, 2,4–(OCH ) –C H –C –H); 8.14 (d, 1H,
3 2 6 3 6
2
854 (CH–aliph.); 1680 (cyclic C¼O); 1660 (amidic
J = 7.8 Hz, benzothiazole–C –H); 8.24 (d, 1H,
4
C¼O); 1600 (C¼N); 1543 (C¼C); 1246, 1041 (C–S–
J = 7.8 Hz, benzothiazole–C –H); 8.50 (s, 1H, pyridine–
7
+
13
C). EI-MS: m/z (%): 389 (M + H, 1.81); 388 (M ,
C –H). C NMR (DMSO-d , δ ppm): 56.34 (C –OCH );
2
6
4
3
7
.17); 91 (C H N, 100). Anal. Calcd (%) for
56.79 (C –OCH ); 98.89 (pyridine–C ); 101.49 (2,4–
6
5
2 3 5
C H N O S : C, 49.47; H, 3.11; N, 14.42. Found: C,
(OCH ) –C H –C ); 107.50 (CꢁN); 114.08 (pyridine–
1
6
12
4
2
3
3 2
6
3
5
4
9.68; H, 3.17; N, 14.60.
C );
3
117.38
(2,4–(OCH ) –C H –C );
122.83
3 2
6
3
1
Ethyl
5-amino-4-(benzo[d]thiazol-2-yl)-2-methylfuran-3-
(
benzothiazole–C ); 123.31 (benzothiazole–C ); 126.34
4
7
carboxylate (22).
A solution of compound 1 (0.35 g,
mmol) and ethyl 2-chloro-3-oxobutanoate (0.33 g,
.28 mL, 2 mmol) in absolute ethanol (10 mL) was
(
benzothiazole–C ); 127.34 (benzothiazole–C ); 130.03
6
5
2
0
(
2,4–(OCH ) –C H –C ); 134.43 (benzothiazole–C1a);
3 2 6 3 6
1
41.56 (pyridine–C6); 151.92 (benzothiazole–C2 &
added drop wise at room temperature to a solution of
sodium ethoxide [prepared from sodium metal (0.05 g,
pyridine–C4); 153.52 (benzothiazole–C3a); 161.11
(
(
pyridine–C2 & 2,4–(OCH ) –C H –C ); 164.27 (2,4–
3 2 6 3 2
2
mmol) in absolute ethanol (10 mL)]. The reaction
OCH ) –C H –C ); 165.39 (2,4–(OCH ) –C H –C ).
3
2
6
3
4
3 2
6
3
3
mixture was stirred at room temperature for 2 h during
which a white precipitate separated out. The obtained
product was filtered, washed several times with water,
Anal. Calcd (%) for C H N O S: C, 64.93; H, 4.15; N,
21 16 4 2
1
4.42. Found: C, 65.12; H, 4.19; N, 14.58.
3
-(Benzo[d]thiazol-2-yl)-6-bromo-2H-chromen-2-imine
dried and crystallized from ethanol.
(25).
An equimolar mixture of compound 1 (0.35 g,
Pale yellow powder; yield 0.5 g (82%); mp 179–180°C.
2
mmol) and 5-bromosalicylaldehyde (0.4 g, 2 mmol)
ꢀ
1
IR (KBr, ν cm ): 3392, 3288 (NH ); 3066 (CH–Ar);
was heated under reflux in absolute ethanol (15 mL)
containing a catalytic amount of piperidine (five drops)
for 1 h. A yellow precipitate was separated out, which
was filtered, washed with ethanol, left to dry and
2
2
(
924, 2900 (CH–aliph.); 1697 (C¼O); 1624 (C¼N); 1500
1
C¼C); 1271, 1089 (C–S–C); 1240, 1030 (C–O–C). H
NMR (DMSO-d , δ ppm): 1.35 (t, 3H, J = 7.2 Hz,
6
CH CH ); 2.46 (s, 3H, CH ); 4.34 (q, 2H, J = 7.2 Hz,
2
3
3
crystallized from methanol.
CH CH ); 7.25 (t, 1H, J = 7.8 Hz, benzothiazole–C –H);
Yellow powder; yield 0.6 g (84%); mp 250–251°C. IR
2
3
6
ꢀ
1
7
.40 (t, 1H, J = 7.8 Hz, benzothiazole–C –H); 7.83 (s, 2H,
(KBr, ν cm ): 3249 (NH); 3048 (CH–Ar); 1659 (C¼N);
1544 (C¼C); 1225, 1061 (C–S–C); 1210, 1061 (C–O–
5
NH , D O exchangeable); 7.84 (d, 1H, J = 7.8 Hz,
2
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Design, Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues
1
C). H NMR (DMSO-d , δ ppm): 7.21 (d, 1H, J = 8 Hz,
precipitate was filtered, washed with dioxane, dried and
crystallized from methanol.
6
chromen–C –H); 7.47 (t, 1H, J = 7.7 Hz, benzothiazole–
8
C –H); 7.57 (t, 1H, J = 7.7 Hz, benzothiazole–C –H);
Brown powder; yield 0.42 g (63%); mp 118–120°C. IR
6
5
ꢀ
1
7
.68 (d, 1H, J = 8 Hz, chromen–C –H); 8.05–8.18 (m,
(KBr, ν cm ): 3398, 3385 (NH
(C¼N); 1560 (C¼C); 1269, 1087 (C–S–C). H NMR
(DMSO-d , δ ppm): 6.95 (d, 1H, J = 7.8 Hz,
quinolinine–C –H); 7.19–7.80 (m, 4H, two
benzothiazole–C5,6–H); 7.89 (d, 1H, J = 7.8 Hz,
quinoline–C –H); 8.13–8.22 (m, 2H, 4–Cl–C
H); 8.28–8.39 (m, 2H, 4–Cl–C H –C3,5–H); 8.70 (s, 1H,
2
); 3057 (CH–Ar); 1624
7
1
2H, benzothiazole–C4,7–H); 8.47 (s, 1H, chromen–C5–
H); 8.73 (s, 1H, chromen–C –H) 9.23 (s, 1H, imino
6
4
NH, D O exchangeable). Anal. Calcd (%) for
8
2
C H BrN OS: C, 53.80; H, 2.54; N, 7.84. Found: C,
1
6
9
2
5
4.03; H, 2.57; N, 7.95.
7
H –C2,6–
6 4
3
-(Benzo[d]thiazol-2-yl)-6-bromo-2-iminoquinolin-1(2H)-
6
4
amine (26). To a suspension of compound 25 (0.71 g,
quinoline–C –H); 8.80 (s, 1H, quinoline–C –H); 8.90 (d,
5
4
2
9
mmol) in absolute ethanol (20 mL), hydrazine hydrate
9% (0.1 g, 0.09 mL, 2 mmol) was added, and the
4
2
H, J = 11.7 Hz, two benzothiazole–C4,7–H); 11.11 (s,
H, NH , D O exchangeable). Anal. Calcd (%) for
2
2
reaction mixture was heated under reflux for 8 h. It was
then left to cool, and the reaction mixture was diluted
with water and neutralized with 10% HCl. The obtained
product was filtered, washed with water, dried and
crystallized from toluene.
C H BrClN S : C, 57.71; H, 2.72; N, 12.62. Found: C,
32
18
6 2
5
7.89; H, 2.70; N, 12.81.
6-(Benzo[d]thiazol-2-yl)-9-bromo-4-(2,4-dichlorophenyl)-
0
0
0
0
1,4-dihydro-3 ,4 -dihydronaphthyl[1 ,2 :6,7][1,2,4]
triazepino[2,3-a]quinoline (29).
Equimolar amounts of
compound 26 (0.37 g, 1 mmol), 1-tetralone (0.15 g,
Dark yellow powder; yield 0.45 g (61%); mp 295–
ꢀ
1
0
.13 mL, 1 mmol), and 2,4-dichlorobenzaldehyde
2
96°C. IR (KBr, ν cm ): 3419, 3387 (NH , NH); 3068
2
(
(
0.18 g, 1 mmol) were heated under reflux in dioxane
10 mL) containing a catalytic amount of p-toluene
(
CH–Ar); 1625 (C¼N); 1564 (C¼C); 1267, 1078 (C–S–
1
C). H NMR (DMSO-d , δ ppm): 6.95 (d, 1H,
6
sulfonic acid for 35 h. The reaction mixture was then
cooled, and the solid product was filtered, washed with
dioxane, dried and crystallized from benzene.
J = 8.7 Hz, quinoline–C –H); 7.52–7.55 (m, 3H,
8
quinoline–C –H & benzothiazole–C5,6–H); 7.87–7.97 (m,
7
3
H, quinoline–C –H & benzothiazole–C4,7–H); 8.90–8.95
5
Dark brown powder; yield 0.33 g (50%); mp 88–90°C.
(
m, 2H, quinoline–C –H & imino NH); 11.12 (s, 2H,
4
ꢀ
1
IR (KBr, ν cm ): 3170 (NH); 3066, 3035 (CH–Ar);
NH2, D O exchangeable). Anal. Calcd (%) for
2
2
1
927, 2870 (CH–aliph.); 1597 (C¼N); 1477 (C¼C);
C H BrN S: C, 51.76; H, 2.99; N, 15.09. Found (%):
1
6
11
4
1
284, 1080 (C–S–C). H NMR (DMSO-d , δ ppm):
C, 51.98; H, 3.04; N, 15.34.
6
3
-Acetyl-5-(benzo[d]thiazol-2-yl)-8-bromo-1H-[1,2,4]
2.03 (t, 2H, J = 5.7 Hz, tetrahydronaphthyl–C –CH );
4 2
triazino[2,3-a]quinolin-2(3H)-one (27).
Equimolar
amounts of compound 26 (0.37 g, 1 mmol) and ethyl
-chloro-3-oxobutanoate (0.16 g, 0.14 mL, 1 mmol)
2
4
.59 (t, 2H, J = 5.7 Hz, tetrahydronaphthyl–C –CH );
3 2
.56 (s, 1H, triazepine–C –H); 6.94 (d, 1H, J = 7.2 Hz,
5
2
quinoline–C –H); 7.10 (d, 2H, J = 6.6 Hz, 2,4–(Cl) –
8
2
were fused at 170–180°C for 27 h. The reaction
mixture was filtered, and the solid product was washed
with ethanol, dried and boiled with ethanol, benzene,
dioxane and DMF.
C H –C –H); 7.24 (s, 1H, 2,4–(Cl) –C H –C –H);
6
3
5,6
2
6
3
3
7
.34 (d, 1H, J = 7.2 Hz, quinoline–C –H); 7.42–7.63
7
(m, 4H, tetrahydronaphthyl–C5,6,7,8–H); 7.62 (s, 1H,
quinoline–C –H); 7.68–7.82 (m, 2H, benzothiazole–
5
Reddish brown powder; yield 0.37 g (82%); mp
C5,6–H); 7.84–8.00 (m, 2H, benzothiazole–C4,7–H);
ꢀ
1
>
300°C. IR (KBr, ν cm ): 3437 (tautomeric OH); 3090
8
.93 (s, 1H, quinoline–C –H); 11.12 (s, 1H, NH, D O
4 2
(
(
(
CH–Ar); 2870 (CH–aliph.); 1728 (broad C¼O); 1616
exchangeable). Anal. Calcd (%) for C H BrCl N S:
33
21
2 4
1
C¼N); 1556 (C¼C); 1260, 1095 (C–S–C). H NMR
C, 60.38; H, 3.22; N, 8.54. Found: C, 60.64; H, 3.20;
N, 8.70.
4-Amino-6-(benzo[d]thiazol-2-yl)-9-bromo-2-(2,4-
dimethoxyphenyl)[1,2,4]triazepino-[2,3-a]quinoline-3-
carbonitrile (31a) and 6-(benzo[d]thiazol-2-yl)-9-bromo-2-(2,4-
dimethoxyphenyl)-4-hydroxy-[1,2,4]triazepino[2,3-a]quinoline-
DMSO-d , δ ppm): 2.30 (s, 3H, CH ); 3.57 (s, 1H,
6
3
triazine–C –H); 7.15–7.21 (m, 4H, quinoline–C4,5,7,8–H);
3
7.22–7.27 (m, 4H, benzothiazole–C4,5,6,7–H); 8.15 (s, 1H,
NH, D O exchangeable). MS: m/z (%): 454 (M + H,
2
1
.16); 105 (C H N, 100). Anal. Calcd (%) for
7 7
3
-carbonitrile (31b). An equimolar mixture of compound
C H BrN O S: C, 52.99; H, 2.89; N, 12.36. Found: C,
2
0
13
4 2
2
1
6 (0.37 g, 1 mmol) and compound 23 (41) (0.21 g,
mmol) or compound 30[41] (0.26 g, 1 mmol) was
5
3.00; H, 2.91; N, 12.37.
3
,6-Di(benzo[d]thiazol-2-yl)-9-bromo-2-(4-chlorophenyl)-
[
2
1,2,4]triazepino[2,3-a]quinolin-4-amine (28).
Compound
6 (0.37 g, 1 mmol) was added to an equimolar mixture
of compound (0.17 g, mmol) and 4-
heated under reflux in absolute ethanol (20 mL)
containing a catalytic amount of piperidine (0.5 mL) for
35 h. The reaction mixture was concentrated and cooled,
and the solid product was filtered, washed with ethanol,
dried and crystallized from ethanol to yield compounds
31a and 31b, respectively.
1
1
chlorobenzaldehyde (0.14 g, 1 mmol) in dioxane (10 mL)
as solvent. The reaction mixture was heated under reflux
for 54 h, then concentrated and cooled, and the obtained
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Y. Hassan, M. T. Sarg, and E. M. Hussein
Vol 000
4
-Amino-6-(benzo[d]thiazol-2-yl)-9-bromo-2-(2,4-
dimethoxyphenyl)[1,2,4]triazepino-[2,3-a]quinoline-3-
carbonitrile (31a).
for C H BrN S : C, 51.12; H, 2.66; N, 17.03. Found
21 13 6 2
(%): C, 51.30; H, 2.63; N, 17.19.
Light orange crystals; yield 0.24 g
Ethyl
4-amino-6-(benzo[d]thiazol-2-yl)-9-bromo-2-
ꢀ
1
(
41%); mp 264–266°C. IR (KBr, ν cm ): 3400 (NH2);
(methylthio)[1,2,4]triazepino[2,3-a]quinoline-3-carboxylate
3
005 (CH–Ar); 2927, 2852 (CH–aliph.); 2195
(34b).
Brown powder; yield 0.27 g (50%); mp 280–
ꢀ
1
(
1
CꢁN); 1616, 1602 (C¼N); 1541 (C¼C); 1269,
282°C. IR (KBr, ν cm ): 3421 (NH ); 3068 (CH–Ar);
2
1
099 (C–S–C); 1234, 1074 (C–O–C). H NMR (DMSO-
2924, 2868 (CH–aliph.); 1710 (C¼O); 1624 (C¼N);
d , δ ppm): 3.86, 3.90 (two s, 6H, two OCH ); 6.61 (s,
1475 (C¼C); 1267, 1078 (C–S–C); 1234, 1078 (C–O–C).
6
3
I
1
2
H, 2,4–(OCH ) –C H –C –H); 6.66 (d, 1H, J = 8.3 Hz,
H NMR (DMSO-d , δ ppm): 1.06 (t, 3H, J = 6.9 Hz,
6
3
2
6
3
3
CH CH ); 2.89 (s, 3H, S–CH ); 3.38–3.50 (m, 2H,
,4–(OCH ) –C H –C –H); 6.95 (d, 1H, J = 8.3 Hz, 2,4–
2
3
3
3
2
6
3
5
CH CH ); 6.95 (d, 2H, J = 9 Hz, quinoline–C7,8–H);
(OCH ) –C H –C –H); 7.44–7.60 (m, 2H, quinoline–
2
3
3
2
6
3
6
7
.50–7.60 (m, 4H, benzothiazole–C4,5,6,7–H); 7.89 (s, 1H,
C7,8–H); 7.83–7.93 (m, 2H, benzothiazole–C5,6–H); 8.81
s, 1H, quinoline–C –H); 8.86 (d, 2H, J = 7.8 Hz,
quinoline–C –H); 8.93 (s, 1H, quinoline–C –H); 11.10
5
4
(
5
(
s, 2H, NH , D O exchangeable). Anal. Calcd (%) for
2 2
benzothiazole–C4,7–H); 8.93 (s, 1H, quinoline–C –H);
1
for C H BrN O S: C, 57.64; H, 3.28; N, 14.40. Found:
4
C H BrN O S : C, 51.11; H, 3.36; N, 12.96. Found: C,
23
18
5 2 2
1.10 (s, 2H, NH , D O exchangeable). Anal. Calcd (%)
2 2
5
1.23; H, 3.35; N, 13.14.
28
19
6 2
C, 57.89; H, 3.25; N, 14.62.
6
-(Benzo[d]thiazol-2-yl)-9-bromo-2-(2,4-dimethoxyphenyl)-
-hydroxy-[1,2,4]triazepino[2,3-a]quinoline-3-carbonitrile
31b). Pale brown powder; yield 0.26 g (45%); mp 218–
Acknowledgments. We would like to thank the National Cancer
Institute (NCI), Bethesda, Maryland, USA, for performing the
anticancer screening of the newly synthesized compounds.
4
(
ꢀ
1
2
20°C. IR (KBr, ν cm ): 3446, 3421 (broad OH); 3095
(
CH–Ar); 2929, 2854 (CH–aliph.); 2220 (CꢁN); 1624
(C¼N); 1560 (C¼C); 1267, 1074 (C–S–C & C–O–C).
1
REFERENCES AND NOTES
H NMR (DMSO-d , δ ppm): 2.73, 2.89 (two s, 6H,
6
two OCH ); 6.91–7.00 (m, 3H, 2,4–(OCH ) –C H –
3
3 2
6
3
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[
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1
(
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[
I
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Journal of Heterocyclic Chemistry
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet