Substituted thiazoles V. Synthesis and antitumor activity of novel thiazolo[2,3-b]quinazoline and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine analogues

Article abstract of DOI:10.1016/j.ejmech.2011.10.023

A novel series of thiazolo[2,3-b]quinazoline (14-23, 26 and 27), and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine (34-43, 45 and 46) analogues were designed and synthesized. The obtained compounds were evaluated for their in-vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 22, 38, 40 and 41 showed remarkable broad-spectrum antitumor activity. Compounds 22 and 38 are almost nine fold more active than 5-FU, with GI₅₀, TGI, and LC₅₀ values of 2.5, >100, >100; and 2.4, 9.1, 36.2 μM, respectively; while 40 and 41 are almost seven fold more active than 5-FU, with GI₅₀, TGI, and LC₅₀ values of 2.9, 12.4, 46.6 and 3.0, 16.3, 54.0 μM, respectively.

Full text of DOI:10.1016/j.ejmech.2011.10.023

European Journal of Medicinal Chemistry 47 (2012) 65e72
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Substituted thiazoles V. Synthesis and antitumor activity of novel thiazolo[2,3-b]
quinazoline and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine analogues
,
,
Fatmah A.M. Al-Omary a, Ghada S. Hassan a b, Shahenda M. El-Messery c, Hussein I. El-Subbagh d
*
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
b Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt
c Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt
d Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, 12311 Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of thiazolo[2,3-b]quinazoline (14e23, 26 and 27), and pyrido[4,3-d]thiazolo[3,2-a]
pyrimidine (34e43, 45 and 46) analogues were designed and synthesized. The obtained compounds
were evaluated for their in-vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines
panel assay. Compounds 22, 38, 40 and 41 showed remarkable broad-spectrum antitumor activity.
Compounds 22 and 38 are almost nine fold more active than 5-FU, with GI50, TGI, and LC50 values of 2.5,
Received 26 July 2011
Received in revised form
9 October 2011
Accepted 11 October 2011
Available online 20 October 2011
>100, >100; and 2.4, 9.1, 36.2
5-FU, with GI50, TGI, and LC50 values of 2.9, 12.4, 46.6 and 3.0, 16.3, 54.0
m
M, respectively; while 40 and 41 are almost seven fold more active than
M, respectively.
m
Keywords:
Ó 2011 Elsevier Masson SAS. All rights reserved.
Thiazolo[2,3-b]quinazoline and pyrido[4,3-
d]thiazolo[3,2-a]pyrimidine
Antitumor activity
1. Introduction
earned valued places in chemotherapy as effective agents. Various
literature reports displayed numerous fused pyrimidine ring systems
and their chemotherapeutic activities as anticancer [7], antibacterial
[8], antifungal [9], and antiviral [10] agents. Also, substituted thiazolo-
pyrimidine ring systems were reported to possess antitumor activity
[11]. Literature survey has pointed out the inherited antitumor potency
Cancer is a disease characterized by a shift in the controlled
mechanisms that govern cell proliferation and differentiation [1].
Malignancy is caused byabnormalities in cells, which might be due to
inherited genes or caused by outside exposure of the body to chem-
icals, radiation, or even infectious agents [2,3]. Several techniques
were adopted for the treatment and eradication of cancerous cells.
These techniques involved surgery, radiation, immunotherapy,
chemotherapy and chemoprevention. Ideal anticancer drugs would
eradicate cancercells without harming normaltissues. Unfortunately,
no currently available agents meet this criterion and clinical use of
drugs involves a weighing of benefits against toxicity in a search of
favorable therapeutic index [4]. Many of chemotherapeutic agents
currently used in cancer therapy are agents which inhibit tumor
growth by inhibiting the replication and transcription of DNA.
The wide occurrence of the heterocycles in bioactive natural
products made them important synthetic targets. Thiazoles represent
a class of heterocyclic compounds of great importance in biological
chemistry. They exist in many condensed fused systems that were
found to possess a wide range of activity [5,6]. Moreover, fused
pyrimidines have drawn the attention of medicinal chemists as
chemotherapeutic agents, where several members of this class have
in compounds containing
a,b-unsaturated ketone [12e15], fused
pyridine [14e16], condensed pyrimidine and fused quinazoline moie-
ties [17e24]. The reported significance of such synthons generated the
interest to exploit this valuable structure in the designing and the
synthesis of new thiazolopyrimidines analogues as antitumor agents.
In continuation to our previous efforts [25e28], new derivatives
of thiazolo[3,2-a]pyrimidine and thiazolo[2,3-b]quinazoline
analogues were designed, and synthesized. The new compounds
were screened for their in-vitro antitumor activity using the NCI’s
disease-oriented human cell lines assay. The full NCI 60 cell lines
panel assay includes nine tumor subpanels namely; leukemia, non-
small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and
breast cancer cells [29e31].
2. Results and discussion
2.1. Chemistry
The synthetic strategy to prepare the target compounds 14e23,
26, 27, 34e43, 45 and 46 is illustrated in schemes 1 and 2. The
* Corresponding author. Tel.: þ20 2 26186100; fax: þ20 2 26186111.
E-mail address: subbagh@yahoo.com (H.I. El-Subbagh).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.10.023

66
F.A.M. Al-Omary et al. / European Journal of Medicinal Chemistry 47 (2012) 65e72
Scheme 1. Synthesis of the target compounds 14e23, 26 and 27.
reported diarylidene derivatives 7e11 and 29e33 [12e14,32] as
well as the new analogues 25 and 44 were prepared by reacting
either cyclohexanone (1) or N-ethyl-piperidone (28) with various
benzaldehyde analogues (2e6) and 2-thiophen-carboxaldehyde
(24) in ethanolic solution of sodium hydroxide. The aforemen-
tioned target compounds were obtained by reacting 2-amino-
and presented as percentage growth inhibition (GI%). The obtained
results of the tested thiazolo[2,3-b]quinazoline and pyrido[4,3-d]
thiazolo[3,2-a]pyrimidine analogues showed distinctive potential
pattern of selectivity, as well as broad-spectrum antitumor activity
(Tables 2 and 3).
Regarding the activity towards individual cell lines; the tested
6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazoline derivatives showed
selective potency against non-small cell lung NCI-H226, CNS cancer
SNB-75, and renal cancer UO-31 cell lines. Compounds 15, 18, 21, and
22 showed GI values of 11.2, 21.6,10.5 and 100% against non-small cell
lung NCI-H226, respectively; while compounds 15, 20, 22, 26 and 27
showed GI values of 13.3, 12.4, 65, 10.4 and 16.6% against CNS cancer
SNB-75, respectively. Renal cancer cell line UO-31 proved to be
selectively sensitive to compounds 14, 15, 18, 19, 20, 22, 23, 26 and 27
with GI values of 21.4, 28.8, 32.0, 23.3, 27.9, 100, 20.0, 28.7, 24.5%,
respectively (Table 2). The tested 6,7,8,9-tetrahydro-5H-pyrido[4,3-d]
thiazolo[3,2-a]pyrimidine analogues showed selectivity toward non-
small cell lung EKVX, CNS cancer SNB-75, and renal cancer A498
andUO-31celllines. Compounds38, 40, 41 and46 showedGIvaluesof
51.9, 27.1, 37.5 and 17.7% against non-small cell lung EKVX,
thiazole (12) or 2-amino-4-methyl-thiazole (13) with the
a,b-
unsaturated ketones 7e11, 25, 29e33 and 44 in glacial acetic acid
(schemes 1 and 2, Table 1).
2.2. Preliminary in-vitro antitumor screening
The synthesized compounds 14, 15, 18e23, 26, 27, 38e41, 45 and
46 were subjected to the NCI’s disease-oriented human cell lines
screening assay to be evaluated for their in-vitro antitumor activity.
A single dose (100 mM) of the test compounds were used in the full
NCI 60 cell lines panel assay which includes nine tumor subpanels
namely; leukemia, non-small cell lung, colon, CNS, melanoma,
ovarian, renal, prostate, and breast cancer cells [29e31]. The data
reported as mean graph of the percent growth of the treated cells

F.A.M. Al-Omary et al. / European Journal of Medicinal Chemistry 47 (2012) 65e72
67
Scheme 2. Synthesis of the target compounds 34e43, 45 and 46.
respectively; while compounds 38, 39, 40, 41, 45 and 46 showed GI
values of 22.3,12.5, 71.4, 68.1, 14.2 and 13.6% against CNS cancer SNB-
75, respectively. Renal cancer cell line A498 proved to be selectively
sensitive to compounds 38, 40, 41 and 45 with GI values of 11.1, 18.4,
53.8, 21.6%, respectively; while compounds 38, 39, 40, 41, 45 and 46
inhibited the growth of the renal cancer cell line UO-31 by 100, 35.5,
40.7, 100, 26.2 and 21.8%, respectively (Table 3).
response parameters, GI50, TGI, and LC50 were calculated for each
cell line, using the known drug 5-Fluorouracil (5-FU) as a positive
control. Compounds 22 and 38 are almost nine fold more active
than the positive control 5-FU, with GI50, TGI, and LC50 values of 2.5,
>100, >100; and 2.4, 9.1, 36.2 mM, respectively; while compounds
40 and 41 are almost seven fold more active than the positive
control 5-FU, with GI50, TGI, and LC50 values of 2.9, 12.4, 46.6 and
Close examination of the data presented in Tables 2 and 3,
revealed that compounds 22, 38, 40, and 41 are the most active
members of this study, showing effectiveness toward numerous
cell lines belong to different tumor subpanels. The same analogy
indicated that compounds 15, 18, 20 and 27 possess moderate
antitumor activity; while compounds 14, 19, 21, 23, 26, 39, 45 and
46 are the least active antitumors in the present investigation.
Compounds 22, 38, 40, and 41 passed the primary anticancer
3.0, 16.3, 54.0 mM, respectively (Table 4).
2.3. Structure-activity correlation
Structure-activity correlation, based on the number of cell lines
proved sensitive toward each of the synthesized individual
compounds, revealed that, 6,7,8,9-tetrahydro-5H-pyrido[4,3-d]
thiazolo[3,2-a]pyrimidines (38e41, 45 and 46) are more active
antitumors than their 6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quina-
zolines (14, 15, 18e23, 26 and 27) counterparts.
assay at an arbitrary concentration of 100 mM. Consequently, those
active compounds were carried over and tested against a panel of
60 different tumor cell lines at a 5-log dose range [29e31]. Three

68
F.A.M. Al-Omary et al. / European Journal of Medicinal Chemistry 47 (2012) 65e72
Table 1
Physicochemical properties of the newly synthesized compounds 14e23, 25e27, 34e43, 44e46.
S
S
R
R
O
N
N
N
N
R1
R2
R1
R2
S
S
S
S
R3
R3
14-23
26, 27
25
S
S
R
R
O
N
N
N
N
N
R1
R2
R1
R2
S
S
S
S
N
N
R3
R3
C2H5
C2H5
C2H5
34-43
45, 46
44
Compound
R
R1
R2
R3
Yield, %
Mp, ꢀC
Molecular
formulaea
14
15
16
17
18
19
20
21
22
23
25
26
27
34
35
36
37
38
39
40
41
42
43
44
45
46
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
e
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
e
H
H
Cl
Cl
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
e
H
H
H
H
H
H
H
H
64
71
77
68
84
70
61
72
60
66
95
55
49
43
51
49
55
57
60
72
64
51
40
89
31
37
105e8
112e3
133e5
137e40
155e7
143e5
132e6
145e7
198e201
188e90
104e6
147e50
138e40
122e5
116e9
129e32
134e8
148e50
161e3
191e3
175e8
142e6
136e9
119e21
155e9
132e6
C23H20N2S
C24H22N2S
C23H18Cl2N2S
C24H20Cl2N2S
C25H24N2O2S
C26H26N2O2S
C27H28N2O4S
C28H30N2O4S
C29H32N2O6S
C30H34N2O6S
C16H14OS2
OCH3
OCH3
e
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
e
e
e
e
C19H16N2S3
C20H18N2S3
C24H23N3S
e
e
e
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
e
H
H
Cl
Cl
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
e
H
H
H
H
H
H
H
H
C25H25N3S
C24H21Cl2N3S
C25H23Cl2N3S
C26H27N3O2S
C27H29N3O2S
C28H31N3O4S
C29H33N3O4S
C30H35N3O6S
C31H37N3O6S
C17H17NOS2
C20H19N3S3
C21H21N3S3
OCH3
OCH3
e
H
CH3
e
e
e
e
e
e
a
Analyzed for C, H, N; results were within ꢁ0.4% of the theoretical values for the formulae given.
Concerning the tested thiazolo[2,3-b]quinazoline heterocycles,
the un-substituted analogues such as (E)-9-benzylidene-5-phenyl-
6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazoline (14) and (E)-5-
(thiophen-2-yl)-9-(thiophen-2-yl-methylene)-6,7,8,9-tetrahydro-
5H-thiazolo[2,3-b]quinazoline (26) proved inactive. The intro-
duction of methyl function to position 3- of 14 and 26 produced
compounds 15 and 27 with moderate antitumor potency. Also the
introduction of 4-methoxy function to the 5-phenyl and the 9-
benzylidene moieties of 14 produced 18 with moderate anti-
tumor activity. Addition of 3-methyl function to 18 converts the
compound into the inactive side as in case of 19. The same was also
noticed upon the addition of 3,4-dimethoxy function to the same
positions of 14 to produce the moderate active 20 and the inactive
compound 21. Upon the addition of 3,4,5-trimethoxy function to
the 5-phenyl and the 9-benzylidene moieties of 14 produced 22
with remarkable antitumor potency. Introduction of methyl group
to position 3- of 22 produced the inactive compound 23, this
emphasize that the methyl function at this particular position does
not favor the activity in most cases. The same analogy is also
applicable, more or less, to the tested pyrido[4,3-d]thiazolo[3,2-a]
pyrimidine heterocycles which netted compounds 38, 40 and 41 as
the remarkably active antitumor agents of this study.
3. Conclusion
Compounds 22, 38, 40 and 41 (Fig. 1); are the most active broad-
spectrum antitumor agents of this study with GI50, TGI, and LC50
values of 2.5, >100, >100; 2.4, 9.1, 36.2; 2.9, 12.4, 46.6 and 3.0, 16.3,
54.0 mM, respectively. The synthesized thiazolo[2,3-b]quinazoline
and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine analogues could be
considered as useful template for future development to obtain
more potent antitumor agent(s).

F.A.M. Al-Omary et al. / European Journal of Medicinal Chemistry 47 (2012) 65e72
69
Table 2
Table 3
Percentage growth inhibition (GI%) of in vitro subpanel tumor cell lines at 10
concentration of compounds 14, 15, 18e23, 26, 27.
m
M
Percentage growth inhibition (GI%) of in vitro subpanel tumor cell lines at 10
concentration of compounds 38e41, 45, 46.
mM
Subpanel tumor 14
cell lines
15
18
19
20
21
22
23
26
27
Subpanel tumor
cell lines
38
39
40
41
45
46
Leukemia
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
94.1
e
e
e
e
e
e
e
e
e
e
e
e
e
97.3
84.0
L
90.4
L
e
e
e
e
e
e
94.0
48.3
95.2
67.9
L
97.8
72.1
96.4
L
L
L
e
e
e
e
e
e
e
e
e
e
e
e
e
e
17.5
e
L
L
L
L
L
11.4
e
13.8
e
e
14.4
21.0 13.5
e
e
e
e
e
e
e
e
e
e
L
L
Non-small cell lung cancer
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
L
L
L
L
L
99.5
L
L
e
e
e
e
e
e
e
e
e
e
e
A549/ATCC
EKVX
HOP-62
66.3
51.9
L
88.0
54.8
29.0
L
e
e
e
e
e
e
e
e
61.1
27.1
84.7
53.2
43.9
19.1
L
93.2
37.5
L
98.2
67.6
63.6
L
e
e
e
e
e
e
e
e
e
12.5
e
e
11.4
e
17.7
e
e
11.3
e
NCI-H226
NCI-H23
NCI-322 M
NCI-H460
NCI-H522
Colon cancer
HCT-116
HCC-2998
HT29
11.2 21.6
e
10.5
e
e
e
e
NCI-H226
NCI-H23
NCI-322 M
NCI-H460
NCI-H522
Colon cancer
HCT-116
HCT-15
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
10.3
e
e
e
52.3
46.1
61.7
e
e
e
e
e
e
e
e
e
17.6
e
e
e
e
e
e
e
e
e
e
L
L
L
L
e
e
e
e
e
e
e
e
e
e
e
e
L
L
L
L
e
e
e
e
L
75.8
L
L
L
L
L
L
e
e
e
e
e
e
e
e
14.9
e
e
HT29
KM12
KM12
e
e
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
Melanoma
LOX IMVI
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian cancer
IGORV1
OVCAR-4
NCI/ADR-RES
Renal cancer
A498
ACHN
CAKI-1
UO-31
Prostate cancer
DU-145
CNS cancer
SF-268
SF-295
SNB-19
SNB-75
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
-
e
e
e
e
e
e
e
95.0
L
91.3
79.0
65.0
L
e
e
e
e
e
e
e
e
85.5
71.8
68.3
22.3
L
e
76.0
82.2
52.9
71.4
90.0
89.4
69.2
61.0
68.1
97.9
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
12.5
e
14.2
e
13.6
e
13.3
e
12.4
e
10.4 16.6
e
U251
e
Melanoma
LOX IMVI
M14
L
97.5
L
e
e
e
e
e
e
e
e
L
94.3
L
11.5
61.3
60.9
63.2
62.4
L
L
L
27.4
96.5
87.2
L
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
16.4
e
e
e
e
e
e
e
e
e
L
L
L
L
e
e
e
e
e
e
e
e
13.0
e
e
e
e
e
e
e
e
e
18.8
15.4
e
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian cancer
OVCAR-3
OVCAR-8
NCI/ADR-RES
Renal cancer
786-0
A498
ACHN
CAKI-1
SN12C
TK-10
UO-31
e
e
e
e
e
10.9
74.4
44.8
49.3
e
e
89.7
e
e
e
L
L
L
e
e
10.5
e
e
L
e
e
L
L
76.9
e
e
e
L
95.9
91.2
L
96.5
L
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
L
79.5
90.5
e
e
e
e
e
e
e
e
e
15.4
e
53.2
11.1
83.0
78.3
96.9
70.0
L
e
e
69.9
53.8
L
e
e
e
e
e
e
e
e
e
36.0
e
e
e
e
e
e
e
e
L
L
L
L
e
e
e
e
e
e
14.3
e
e
18.4
79.5
L
83.1
46.5
40.7
21.6
e
e
e
e
11.4 11.3 12.5
e
e
L
e
e
21.4 28.8 32.0 23.3 27.9
20.0 28.7 24.5
e
93.7
98.8
L
e
e
e
e
e
e
e
e
e
e
e
L
e
e
e
35.5
26.2
21.8
Breast cancer
MCF7
BT-549
Prostate cancer
DU-145
Breast cancer
MCF7
BT-549
T-47D
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
76.0
L
69.0
e
e
e
e
e
e
e
e
e
L
e
L
L
e
e
T-47D
74.3
55.2
24.4
e
e
e
80.5
e
84.5
57.0
26.2
e
e
e
e
e
e, GI >10%; nt, not tested; L, compound proved lethal to the cancer cell line.
e
11.4
e, GI >10%; nt, not tested; L, compound proved lethal to the cancer cell line.
4. Experimental
chromatography separations. All the fine chemicals and reagents
used were purchased from Aldrich Chemicals Co, USA. Compounds
7e11, 29e33 were previously reported [12e14,32].
Melting points (ꢀC) were determined on Mettler FP80 melting
point apparatus and are uncorrected. Microanalyses were per-
formed on a PerkineElmer 240 elemental analyzer at the Central
Research Laboratory, College of Pharmacy, King Saud University. All
of the newcompounds were analyzed for C, H and N and agreed with
the proposed structures within ꢁ0.4% of the theoretical values. 1H
NMR,13C NMR were recorded on a Bruker 500 MHz FTspectrometer;
4.1. Chemistry
4.1.1. 2,6-Bis(thien-2-yl-methylene)cyclohexanone (25) and 1-
ethyl-3,5-bis(thien-2-yl-methyl-ene)-piperidin-4-one (44)
chemical shifts are expressed in d ppm with reference to TMS. Mass
spectral (MS) data were obtained on a Perkin Elmer, Clarus 600 GC/
MS and Joel JMS-AX 500 mass spectrometers. Thin layer chroma-
tography was performed on precoated (0.25 mm) silica gel GF254
plates (E. Merck, Germany), compounds were detected with 254 nm
UV lamp. Silica gel(60e230 mesh)was employed for routine column
A mixture of the appropriate cyclic ketone 1 or 28 (0.01 mol) and
2-thiophene carboxaldehyde (24, 0.02 mol) in alcoholic NaOH (10%,
50 ml) was stirred at room temperature for 30 min. The separated
solid was filtered off, washed with water, dried and recrystallized
from ethanol (Table 1). 25: 1H NMR (DMSO-d6)
d 1.66e1.75 (m, 2H,

70
F.A.M. Al-Omary et al. / European Journal of Medicinal Chemistry 47 (2012) 65e72
Table 4
Compounds 22, 38, 40 and 41 median growth inhibitory (GI50, mM), total growth inhibitory (TGI, mM) and median lethal (LC50, mM) concentrations of in vitro subpanel tumor cell
lines.
Compound
Activity
I
II
III
IV
V
VI
VII
VIII
IX
MG-MIDa
22
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
LC50
GI50
TGI
2.0
2.3
1.6
nt
nt
47.8
nt
nt
nt
3.5
10.9
55.0
3.4
10.1
44.6
2.7
1.9
1.8
2.0
2.2
2.5
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
38
2.7
2.5
1.7
3.4
6.7
2.0
4.3
29.3
2.1
5.6
35.3
4.7
9.4
2.8
2.3
6.0
24.9
3.1
9.8
52.8
2.5
2.8
2.5
8.0
2.4
9.1
81.6
18.3
64.9
3.2
40.1
76.5
3.0
22.5
74.7
3.2
48.9
90.5
3.8
43.9
68.1
3.4
29.8
68.4
2.8
b
68.2
3.3
26.7
82.8
5.7
73.4
19.3
43.9
74.7
5.7
36.2
2.9
12.4
46.6
3.0
40
2.6
30.7
b
41
4.0
81.9
44.2
40.1
10.8
54.4
49.7
8.9
47.1
53.4
79.2
49.5
68.2
16.3
54.0
b
b
b
LC50
GI50
TGI
86.5
b
5-FU
15.1
8.4
72.1
70.6
61.4
45.6
22.7
76.4
22.6
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
b
LC50
I, leukemia; II, non-small cell lung cancer; III, colon cancer; IV, CNS cancer; V, melanoma; VI, ovarian cancer; VII, renal cancer; VIII, prostate cancer; IX, breast cancer.
a
Full panel mean-graph midpoint (
Compounds showed values >100
m
m
M).
b
M. nt, not tested.
cyclohexanone-H), 2.01e2.24 (m, 4H, cyclohexanone-H), 6.89 (s,
2H, C]CH), 6.96e7.56 (m, 6H, thienyl-H). 13C NMR
21.7, 23.3, 28.2,
76.8, 77, 77.3, 77.9, 127.6, 129.7, 129.9, 130.4, 132.9, 133, 135.7, 139.6,
189. MS m/z (%): 286 (12, Mþ). 44: 1H NMR (DMSO-d6)
0.97 (s, 2H,
29e33, 0.01 mol) in glacial acetic acid (20 ml) was heated under
reflux for 20 h. Solvent was evaporated under vacuum; the ob-
tained residue was dissolved in chloroform, washed with water,
and the organic layer was separated, dried and evaporated. The
obtained solid was recrystallized from ethanol to yield compounds
d
d
cyclohexanone-H), 1.24 (t, 3H, J ¼ 7.2 Hz, CH3CH2), 2.63 (s, 2H,
cyclohexanone-H), 3.79e3.81 (q, 2H, CH2CH3), 7.49 (s, 2H, C]CH),
14e23 and 34e43 (Table 1). 14: 1H NMR (DMSO-d6)
d 1.73e1.77 (m,
7.52e7.63 (m, 6H, thienyl-H). 13C NMR
d
29, 39, 39.1, 39.3, 39.5, 39.7,
2H, cyclohexanone-H), 1.88 (t, 4H, J ¼ 5 Hz, cyclohexanone-H), 2.88
39.8, 40, 50.5, 53.7, 128.7, 129.2, 130.4, 133.8, 134.6, 134.7, 186.9. MS
(s, 1H, CH), 6.88 (s, 1H, C]CH), 7.02e7.59 (m, 12H, AreH and
m/z (%): 315 (3.9, Mþ).
thiazole-H). 13C NMR
d 22.4, 23.9, 27.8, 28.2, 34.7, 38.9, 39.1, 39.3,
39.5, 39.7, 39.8, 40, 55.1, 55.3, 113.2, 114.1, 128, 131.5, 132.2, 134.2,
4.1.2. 3-Substituted-9-(substituted benzylidene)-5-(substituted
phenyl)-6,7,8,9-tetrehydro-5H-thiazolo[2,3-b]quinazolines (14e23)
and 1-substituted-7-ethyl-5-(substituted benzyl-idene)-9-
(substituted phenyl)-6,7,8,9-tetrahydro-5H-pyrido[4,3-d]thiazolo
[3,2-a]pyramidines (34e43)
134.8, 135.4, 159.7. MS m/z (%): 356 (9.4, Mþ). 15: 1H NMR (DMSO-
d6)
d 1.72e1.73 (m, 2H, cyclohexanone-H), 1.85e1.86 (m, 4H,
cyclohexanone-H), 2.73 (s, 3H, CH3), 2.91 (s, 1H, CH), 6.74 (s, 1H, C]
CH), 7.29e7.55 (m, 10H, AreH), 7.64 (s, 1H, thiazole-H). MS m/z (%):
370 (5.2, Mþ). 16: 1H NMR (DMSO-d6)
d 1.72e1.74 (m, 2H,
A solution of 2-aminothiazole or 2-amino-4-methylthiazole (12
cyclohexanone-H),1.85e1.86 (m, 4H, cyclohexanone-H), 2.88 (s, 1H,
CH), 6.75 (s, 1H, C]CH), 7.37e7.60 (m, 10H, AreH and thiazole-H).
or 13, 0.01 mol), the appropriate
a,b-unsaturated ketone (7e11,
13C NMR
d
22.2, 27.7, 28, 34.2, 39, 39.2, 39.3, 39.5, 39.7, 39.8, 40,
62.9,127,8,128.6,131,132, 133.4,133.6,134,134.5,135.1,136.8,188.7.
MS m/z (%): 425 (1.39, Mþ). 17: 1H NMR (DMSO-d6)
1.72e1.85 (m,
d
6H, cyclohexanone-H), 2.72 (s, 3H, CH3), 2.87 (s, 1H, CH), 6.75 (s, 1H,
C]CH), 7.19 (s, 1H, thiazole-H), 7.37e7.60 (m, 8H, AreH). MS m/z
(%): 439 (5.2, Mþ). 18: 1H NMR (DMSO-d6)
d 1.73e1.75 (m, 2H,
cyclohexanone-H), 1.92e2.20 (m, 4H, cyclohexanone-H), 2.88 (s,
1H, CH), 3.80 (s, 6H, OCH3), 6.65 (s, 1H, C]CH), 6.89e7.59 (m, 10H,
AreH and thiazole-H). 13C NMR
d 22.4, 24, 27.9, 28.2, 34.7, 39, 39.1,
39.3, 39.5, 39.6, 39.8, 40, 55.1, 113.1, 114.1, 128, 131.5, 132.1, 132.2,
134.2, 134.8, 135.4, 136.1, 136.5, 188.6. MS m/z (%): 416 (2.38, Mþ).
19: 1H NMR (DMSO-d6)
d
1.72e1.91 (m, 6H, cyclohexanone-H), 2.69
(s, 3H, CH3), 2.90 (s, 1H, CH), 3.81 (s, 6H, OCH3), 6.56 (s, 1H, C]CH),
6.88e7.59 (m, 9H, AreH and thiazole-H). 13C NMR
23.9, 27.9, 28.2,
d
34.7, 39, 39.1, 39.4, 39.5, 39.7, 39.8, 40, 55.1, 55.3, 63, 114.1, 128,
128.3, 131.5, 132.1, 134,2, 134.8, 135.4, 136.1, 136.5, 159.7, 188.6. MS
m/z (%): 430 (5.09, Mþ). 20: 1H NMR (DMSO-d6)
d 1.74e1.85 (m, 6H,
cyclohexanone-H), 2.92 (s, 1H, CH), 3.79 (s, 12H, OCH3), 6.65 (s, 1H,
C]CH), 6.90e7.18 (m, 6H, AreH). 7.40 (d, 2H, thiazole-H). MS m/z
(%): 476 (0.07, Mþ). 21: 1H NMR (DMSO-d6)
d 1.74e1.85 (m, 5H, CH3,
cyclohexanone-H), 2.11 (t, 4H, J ¼ 5 Hz, cyclohexanone-H), 2.92 (s,
1H, CH), 3.71e3.81 (m, 12H, OCH3), 6.65 (s, 1H, C]CH), 6.90e7.40
(m, 6H, AreH), 7.60 (s, 1H, thiazole-H). 13C NMR
d 22.5, 27.9, 39,
39.2, 39.3, 39.5, 39.7, 39.8, 40, 55.5, 63, 111.6, 114.1, 123.8, 128.1,
129.3, 131.2, 132, 132.5, 133.9, 134.1, 134.3, 134.7, 135.9, 136.3, 148.5,
149.5, 188.5. MS m/z (%): 490 (0.39, Mþ). 22: 1H NMR (DMSO-d6)
Fig. 1. Structures of the active antitumor agents 22, 38, 40 and 41.
d 1.75e1.89 (m, 6H, cyclohexanone-H), 2.95 (s, 1H, CH), 3.68e3.83

F.A.M. Al-Omary et al. / European Journal of Medicinal Chemistry 47 (2012) 65e72
71
(m, 18H, OCH3), 6.68 (s, 1H, C]CH), 6.81e6.97 (m, 6H, AreH and
thiazole-H). MS m/z (%): 536 (15.7, Mþ). 23: 1H NMR (DMSO-d6)
e-H), 7.86e7.90 (m, 6H, thienyl-H). MS m/z (%): 368 (13.2, Mþ). 27:
1H NMR (DMSO-d6)
d
1.90 (t, 2H, J ¼ 12 Hz, cyclohexanone-H), 2.24
d
1.86e1.90 (m, 6H, cyclohexanone-H), 2.08 (s, 3H, CH3), 2.95 (s, 1H,
(s, 3H, CH3), 2.49e2.50 (m, 2H, cyclohexanone-H), 2.87 (t, 2H,
J ¼ 12 Hz, cyclohexanone-H), 3.38 (s, 1H, CH), 7.23 (s, 1H, C]CH),
7.26 (d, 1H, J ¼ 6 Hz, thiazole-H), 7.88e7.90 (m, 6H, thienyl-H). MS
CH), 3.67e3.83 (m, 18H, OCH3), 6.58 (s, 1H, C]CH), 6.79e6.97 (m,
4H, AreH), 7.36 (s, 1H, thiazole-H). MS m/z (%): 550 (2.7, Mþ). 34: 1H
NMR (DMSO-d6)
H), 3.40 (s, 1H, CH), 4.00e4.01 (q, 2H, CH2CH3), 7.33 (s, 1H, C]CH),
7.40e7.79 (m, 12H, AreH and thiazole-H). 13C NMR
22, 29, 38.9,
d
0.96 (t, 3H, CH2CH3), 1.14 (s, 4H, cyclohexanone-
m/z (%): 382 (5.9, Mþ). 45: 1H NMR (DMSO-d6)
d 1.00 (t, 3H,
CH2CH3), 1.23 (s, 4H, cyclohexanone-H), 3.79e3.81 (q, 2H, CH2CH3),
2.59 (s, 1H, CH), 7.07 (s, 1H, C]CH), 7.11 (d, 2H, J ¼ 8.5 Hz, thiazole-
d
39.1, 39.3, 39.4, 39.6, 39.8, 39.9, 42.7, 43.3, 43.5, 50.4, 53.5, 127.7,
H), 7.59e7.67 (m, 6H, thienyl-H). 13C NMR
d 29, 39, 39.1, 39.3, 39.5,
128.3, 128.8, 129, 130.8, 132.1, 133.5, 133.9, 134.3, 188.4. MS m/z (%):
39.6, 39.8, 40, 50.5, 53.8, 55.5, 111.6, 114.1, 123.7, 127.4, 131.9, 134.8,
385 (10.5, Mþ). 35: 1H NMR (DMSO-d6)
d
1.00 (t, 3H, CH2CH3),
148.5, 149.8, 186.4. MS m/z (%): 397 (1.2, Mþ). 46: 1H NMR (DMSO-
1.24(s, 3H, CH3), 2.59 (s, 4H, cyclohexanone-H), 3.70 (s, 1H, CH),
3.76e3.82 (q, 2H, CH2CH3), 7.04 (s, 1H, C]CH), 7.48e7.57 (m, 11H,
AreH and thiazole-H). MS m/z (%): 399 (4.33, Mþ). 36: 1H NMR
d6) d 1.07 (s, 3H, CH3), 1.14 (t, 3H, CH2CH3), 1.82 (s, 4H,
cyclohexanone-H), 2.78 (s, 1H, CH), 3.76e3.81 (q, 2H, CH2CH3), 6.70
(s, 1H, C]CH), 7.07 (s, 1H, thiazole-H), 7.20e7.28 (m, 6H, thienyl-H).
MS m/z (%): 411 (0.3, Mþ).
(DMSO-d6)
d
0.96 (t, 3H, J ¼ 7.4 Hz, CH2CH3), 1.76 (s, 4H,
cyclohexanone-H), 2.13 (s, 1H, CH), 3.76e3.92 (q, 2H, CH2CH3), 7.17
(d, 4H, J ¼ 5.5 Hz, AreH), 7.44 (d, 4H, J ¼ 5.8 Hz, AreH), 7.54 (s, 1H,
4.2. Antitumor screening
1
C]CH), 7.58 (s, 2H, thiazole-H). MS m/z (%): 454 (6.11, Mþ). 37: H
NMR (DMSO-d6)
d
1.58 (t, 3H, J ¼ 7.1 Hz, CH2CH3), 1.83 (s, 3H, CH3),
Under a sterile condition, cell lines were grown in RPMI 1640
media (Gibco, NY, USA) supplemented with 10% fetal bovine serum
(Biocell, CA, USA), 5 ꢂ 105 cell/ml was used to test the growth
inhibition activity of the synthesized compounds. The concentra-
2.95 (s, 4H, cyclohexanone-H), 3.87e3.91 (m, 3H, CH and CH2CH3),
6.95 (s, 1H, C]CH), 7.28e7.49 (m, 8H, AreH), 7.79 (s,1H, thiazole-
H). 13C NMR
d 23.1, 23.6, 28.6, 34.3, 38.2, 39.3, 39.8, 39.9, 40, 42.4,
43.1, 43.5, 43.7, 50.3, 50.8, 124.4, 126.3, 128.6, 128.7, 129, 132.3,
tions of the compounds ranging from 0.01 to 100 mM were prepared
134.4, 136.5, 159.9, 190.2. MS m/z (%): 468 (1.12, Mþ). 38: 1H NMR
in phosphate buffer saline. Each compound was initially solubilized
in dimethyl sulfoxide (DMSO), however, each final dilution con-
tained less than 1% DMSO. Solutions of different concentrations
(0.2 ml) were pipetted into separate well of a microtiter tray in
duplicate. Cell culture (1.8 ml) containing a cell population of
6 ꢂ 104 cells/ml was pipetted into each well. Controls, containing
only phosphate buffer saline and DMSO at identical dilutions, were
also prepared in the same manner. These cultures were incubated
in a humidified incubator at 37 ꢀC. The incubator was supplied with
5% CO2 atmosphere. After 48 h, cells in each well were diluted 10
times with saline and counted by using a coulter counter. The
counts were corrected for the dilution [29e31].
(DMSO-d6)
d
1.01 (t, 3H, J ¼ 5.5 Hz, CH2CH3), 2.57 (s, 4H,
cyclohexanone-H), 3.36 (s, 1H, CH), 3.75e3.78 (q, 2H, CH2CH3), 3.81
(s, 6H, OCH3), 6.89 (s, 1H, C]CH), 7.03 (d, 4H, J ¼ 9 Hz, AreH), 7.48
(d, 4H, J ¼ 9 Hz, AreH), 7.56 (s, 2H, thiazole-H). MS m/z (%): 445
(6.11, Mþ). 39: 1H NMR (DMSO-d6)
d 1.00 (s, 3H, CH2CH3),1.65 (s, 3H,
CH3), 2.59 (s, 4H, cyclohexanone-H), 3.37 (s, 1H, CH), 3.75e3.78 (q,
2H, CH2CH3), 3.81 (s, 6H, OCH3), 6.92 (s, 1H, C]CH), 7.04 (d, 4H,
J ¼ 9 Hz, AreH), 7.46 (d, 4H, J ¼ 9 Hz, AreH), 7.58 (s, 1H, thiazole-H).
MS m/z (%): 459 (1.37, Mþ). 40: 1H NMR (DMSO-d6)
d 0.99 (s, 3H,
CH2CH3), 2.50 (s, 4H, cyclohexanone-H), 3.38 (s, 1H, CH), 3.79 (s,
12H, OCH3), 3.80e3.82 (q, 2H, CH2CH3), 7.07 (s, 1H, C]CH),
7.07e7.10 (dd, 6H, J ¼ 9 Hz, AreH), 7.58 (s, 2H, thiazole-H). MS m/z
(%): 505 (0.59, Mþ). 41: 1H NMR (DMSO-d6)
d
1.01 (t, 3H, J ¼ 6 Hz,
CH2CH3), 1.9 (s, 3H, CH3), 2.06 (s, 4H, cyclohexanone-H), 3.39 (s, 1H,
CH), 3.44e3.47 (q, 2H, CH2CH3), 3.80 (s, 12H, OCH3), 7.04e7.08 (m,
6H, AreH) 7.10 (s, 1H, C]CH), 7.58 (s, 1H, thiazole-H). MS m/z (%):
Acknowledgements
Thanks are due to the NCI, Bethesda, MD, USA for performing
the antitumor testing of the synthesized compounds. The authors
extend their appreciation to the Deanship of Scientific Research at
King Saud University for funding the work through the research
group project No. RGP-VPP-037.
519 (0.79, Mþ). 42: 1H NMR (DMSO-d6)
d 1.27 (t, 3H, CH2CH3), 1.96
(s, 4H, cyclohexanone-H), 2.98 (s, 1H, CH), 3.89e3.92 (m, 18H,
OCH3), 3.94e4.00 (q, 2H, CH2CH3), 6.62 (s, 1H, C]CH), 6.84e7.15
(m, 4H, AreH), 7.28 (s, 2H, thiazole-H). 13C NMR
d 23.1, 24.3, 28.5,
28.7, 38.1, 38.3, 39.2, 40.5, 56, 56.2, 61, 63.4, 76.8, 77, 77.2, 107.8,
110.4, 110.9, 112.1, 113.7, 123.9, 124, 129, 134.5, 136.9, 137, 148.7,
149.6, 153, 189.5. MS m/z (%): 565 (2.21, Mþ). 43: 1H NMR (DMSO-
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d
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d
1.89 (t, 2H, J ¼ 12 Hz,
piperidinecarboxamide (BMS-387032),
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