Synthesis and antitumor activity studies of some new fused 1,2,4-triazole derivatives carrying 2,4-dichloro-5-fluorophenyl moiety

Article abstract of DOI:10.1016/j.ejmech.2009.09.010

A series of 3-(2,4-dichloro-5-fluorophenyl)-6-(substituted phenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (4) (Fig. 1) have been synthesized by the cyclization of 3-(2,4-dichloro-5-fluorophenyl)-1,2,4-triazol-5-thiol (3) with substituted phenacyl bromid

Full text of DOI:10.1016/j.ejmech.2009.09.010

European Journal of Medicinal Chemistry 44 (2009) 5066–5070
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antitumor activity studies of some new fused 1,2,4-triazole
derivatives carrying 2,4-dichloro-5-fluorophenyl moiety
,
b
c
d
K. Subrahmanya Bhat a, Boja Poojary b , D. Jagadeesh Prasad , Prashantha Naik , B. Shivarama Holla
*
a Department of Chemistry, Manipal Institute of Technology, Manipal University, Manipal-576104, India
b Department of Chemistry, Mangalore University, Mangalagangothri-574199, Karnataka, India
c Department of Bio-Sciences, Mangalore University, Mangalagangothri-574199, India
d S. D. M. Institute of Technology, Ujire, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
series of 3-(2,4-dichloro-5-fluorophenyl)-6-(substituted phenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadia-
Received 28 March 2009
Received in revised form
3 September 2009
Accepted 7 September 2009
Available online 11 September 2009
zines (4) (Fig. 1) have been synthesized by the cyclization of 3-(2,4-dichloro-5-fluorophenyl)-1,2,4-tri-
azol-5-thiol (3) with substituted phenacyl bromides. All the newly synthesized compounds were
confirmed by IR, 1H NMR and mass spectral studies. Among the compounds tested for their antitumor
activity three compounds exhibited in vitro antitumor activity with moderate to excellent growth
inhibition against a panel of sixty cancer cell lines of leukemia, non-small cell lung cancer, melanoma,
ovarian cancer, prostate and breast cancer. The compound 4d showed promising antiproliferative activity
Keywords:
1,2,4-Triazoles
1,3,4-thiadiazines
2,4-dichloro-5-fluorophenyl
Anticancer activity
GI50 values
with GI50 values in the range of 1.06–25.4 mM.
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
1,2,4-triazoles also find applications in the preparation of photo-
graphic plates, polymers and as analytical agents [27]. Tri-
azolothiadiazines are reported to posses wide spectrum of
biological activities [28–32].
The Chemistry of N-bridged heterocycles derived from 1,2,4-
triazole has received considerable attention in recent years due to
their usefulness in different areas of biological activities and as
industrial intermediates. 1,2,4-triazole derivatives are known to
exhibit antimicrobial [1–5], antitubercular [6], anticancer [7,8],
anticonvulsant [9], anti-inflammatory and analgesic properties
[10]. The arrangement of three basic nitrogen atoms in triazole
ring induces the antiviral activities in the compounds containing
triazole ring [11]. 1,2,4-triazole nucleus has been incorporated in
to a wide variety of therapeutically interesting drug candidates
including H1/H2 histamine receptor blockers, cholinesterase
active agents, CNS stimulants, antianxiety and sedatives [12],
antimycotic activity such as Fluconazole, Itraconazole and Vor-
iconazole [13,14]. Also there are some known drugs containing
1,2,4-triazole moiety, eg: Triazolam[15], Alprazalam [16], Etizolam
[17], Furacylin [18], Ribavirin [19], Hexaconazole [20], Triadimefon
[21], Mycobutanil [22], Rizatriptan [23], Propiconazole [24], Fluo-
trimaole [25]. A series of 1,2,4-triazole derivatives have been
extensively employed in agriculture as herbicides [26]. Certain
Recently, we have reported the significant anticancer properties
of 1,2,4-triazolo[3,4-b]thiadiazole and 1,3,4-oxadiazole derivatives
having 4-fluoro-3-phenoxyphenyl and 2,4-dichloro-5-fluorophenyl
moiety [33,34]. Prompted by the biological properties of 1,2,4-tri-
azole derivatives and 1,3,4-thiadiazines and in continuation of our
studies on N-bridged heterocycles derived from 1,2,4-triazoles [35],
it was contemplated to synthesize some new 1,2,4-triazolo[3,4-b]-
thiadiazine derivatives (Scheme 2) having 2,4-dichloro-5-fluo-
rophenyl moiety at position 3 of the triazole ring and to screen
them for their anticancer properties. Results of such studies are
discussed in this paper.
2. Chemistry
Thiocarbohydrazide was prepared from hydrazine hydrate and
carbon disulfide following the literature method [36]. This was
heated with 2,4-dichloro-5-fluorobenzoic acid at its melting point
to get 4-amino-3-(2,4-dichloro-5-fluorophenyl)-1,2,4-triazol-5-
thiol (3) (Scheme 1). The reaction of 3-(2,4-dichloro-5-fluo-
rophenyl)-1,2,4-triazol-5-thiol (3) with various phenacyl bromides
* Corresponding author. Tel.: þ91 824 2287262; fax: þ91 824 2287367.
E-mail address: bojapoojary@yahoo.com (B. Poojary).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.09.010

K.S. Bhat et al. / European Journal of Medicinal Chemistry 44 (2009) 5066–5070
5067
Cl
Cl
F
N
N
Br
N
N
N
N
S
R
SH
N
+
Cl
O
Cl
H2N
CH3CO2Na, EtOH
F
3
80-900C, 6h
N
N
F
R
S
Fig. 1. General structure of 1,2,4-triazolo[3,4-b]thiadiazines (4).
N
Cl
N
Cl
in presence of anhydrous sodium acetate and absolute ethanol
yielded 3-(2,4-dichloro-5-fluorophenyl)-6-aryl-1,2,4-triazolo[3,4-
b]-1,3,4-thiadiazines (4a-g) (Scheme 2). The formation of these
compounds (4) (Fig.1) was confirmed by recording their IR, 1H NMR
and mass spectra.
R
4
Scheme 2. Synthesis of triazolothiadiazine derivatives (4).
3. Pharmacology
3.1. Anticancer screening studies
compounds had been carried out. The concentration at which they
cause 50% growth inhibition, GI50 values were determined and the
results obtained are given in Table 3.
Three of the newly synthesized compounds were screened for
their anticancer activities under NCI screening programme [33,34].
The 3- cell line one dose assay has been done for the compounds
4d, 4f and 4g. The 3- cell lines used in present investigation are
NCI-H 460 (Lung), MCF7 (Breast) and SF 268 (CNS). In this current
protocol, each cell line is preincubated on microtiter plate, the test
agents are then added at a single concentration and the culture
incubated for forty eight hours. End point determinations are made
with Sulphorhodamine B, a protein binding dye. Results for each
test agents are reported as the percent growth of the treated cells
when compared to the untreated control cells. The compounds
which reduce the growth of any one of the lines to 32% or less
(negative numbers indicate the cell kill) are passed on for the
evaluation in the full panel of 60 cell line over a five- log dose range.
Compounds 4d, 4f and 4g are found to be active against NCI-H 460
(Lung), MCF7 (Breast) and SF268 (CNS). Results of this study are
given in Table 2. Further, 60 cell line anticancer assay of these
When these three compounds are passed on for extensive
evaluation in the full panel of 60 cell lines over a five- log dose
range, they showed variable antitumor property against most of
the tested subpanel tumor cell lines at GI50 level. The subpanel
tumor cell lines median growth inhibitory concentration (the
average sensitivity of each subpanel towards each of the test
compounds) and the full panel mean graph midpoint (MG-MID:
the average of all cell lines towards each of the test compounds)
are reported in Table 4. Compounds 4d, 4f and 4g showed good
antiproliferative activity against most of the cell lines with GI50
values well below 100 mM concentrations. It is interesting to note
that compound 4d showed significant antitumor activity against
the entire cancer cell lines screened (cf. Table 3). The cell lines
showing activity with GI50 values at <10 mM are K-562, MOLT-4,
NCI-H522, COLO 205, HCT-116, HCT 15, HT29, KM12, SW620, SNB-
75, LOXIMVI, MALME-3M, M14, SK-MEL-28, UACC-62, IGROVI,
OVCAR-4, 786-0, ACHN, CAKI-1, SN12C, TK-10, UO-31, DU-145,
MCF7, NCI/ADR-RES, MDA-MB-435, BT-549 and T-47D. Compound
4g showed significant activity against T-47D with GI50 value of
F
NH
4.93 mM. However, compound 4f is moderately active as GI50
values are in considerably higher range.
The ratio obtained by dividing the compounds full panel MG-
MID (mM) by its individual subpanel MG-MID (mM) is considered as
H2N
Cl
CO2H
NH
NH2
+
S
a measure of compound selectivity. Ratios between 3 and 6 refer to
moderate selectivity, ratios >6 indicate high selectivity and
compounds not meeting of either of these criteria are considered
nonselective. Compound 4d showed high selectivity against
leukemia with selectivity index of 4.82. All the other active
compounds in the present study prove to be nonselective against
any of nine tumor sub panels tested (cf. Table 4).
Among the tested compounds, only 4d, 4f and 4g have shown
very good antiproliferative activity against most of the cell lines.
These compounds contain chlorine atoms at various positions,
whereas other compounds having other substituents are less
active/inactive indicating that presence of chlorine atom is
responsible for their activity. Highest activity was observed for 4d
having chlorine substituent at position 4 of phenyl ring.
Cl
2
1
Cl
N
N
SH
N
Cl
NH2
F
3
Scheme 1. Synthesis of 3-(2,4-dichloro-5-fluorophenyl)-1,2,4-triazol-5-thiol (3).

5068
K.S. Bhat et al. / European Journal of Medicinal Chemistry 44 (2009) 5066–5070
Table 1
Table 3
Characterization data of 3-(2,4-dichloro-5-fluorophenyl)-6-(substituted phenyl)-
GI50 values for compounds (4d, 4f and 4g).
1,2,4-triazolo[3,4-b]-1,3,4-thiadizine derivatives (4a-g).
Cell line
Compd
Comp No.
R
M.P (ꢁC)
Yield (%)
Mol. formula
16H9Cl2FN4S
C17H11Cl2FN4OS
C17H11Cl2FN4S
C16H8Cl3FN4S
C16H8BrCl2FN4S
C16H7Cl4FN4S
C16H6Cl4F2N4S
4d
4f
4g
4a
4b
4c
4d
4e
4f
H
108–10
126–27
98–100
144–45
166–68
148–50
174–75
68
76
72
78
84
72
74
C
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
4-OMe
4-CH3
4-Cl
4-Br
2,4-Cl2
2,4-Cl2-5-F
–
–
27.6
>100
47.5
75.1
25.3
>100
22.0
80.4
17.8
16.9
6.00
25.4
1.69
1.06
–
4g
–
All the compounds showed satisfactory C, H & N analysis. Solvent of crystallization:
Ethanol þ dioxan (4:1).
Non-small cell lung cancer
A549/ATCC
EKVX
18.3
27.4
20.1
16.4
18.1
13.8
16.2
19.1
1.80
58.0
58.5
44.2
54.2
36.5
82.5
76.4
37.3
50.8
23.7
24.6
–
11.3
14.9
21.8
29.1
17.6
24.2
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
3.2. Toxicity studies
Among the compounds tested for their anticancer activity, 4d
showed very good anticancer activity in terms of growth inhibitory
effect on cancer cell lines. Hence, it could be a potential drug
candidate for cancer treatment. Hence this particular compound
was analyzed for its acute toxicity (lethal dose) which is one of the
basic requirements in fixing the therapeutic dose in drug devel-
opment. Median lethal dose (LD50) in male Swiss albino mice (Mus
musculus) was determined by employing the standard methods
[37,38]. From the experiment, oral LD50 of the test compound was
found to be 227 mg/Kg body weight at 24 h duration.
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
7.09
13.6
2.36
1.86
4.6
32.9
35.0
25.4
38.3
40.5
41.9
36.8
19.0
31.6
–
20.2
20.1
28.5
22.6
8.08
1.91
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
4. Conclusions
13.2
15.7
–
19.5
3.37
10.6
36.6
36.4
39.2
25.4
>100
38.2
18.5
20.3
18.9
22.7
26.2
20.4
This study demonstrates the significant antitumor property of
compound 4d against all the sixty cancer cell lines screened.
Further, for the first time we have reported the new class of
potential antitumor agents, with potential for structure activity
studies and toxicological profiling. Therefore, it was concluded that
1,2,4-triazole derivatives with 2,4-dichloro-5-fluorophenyl moiety
at position 3 is an excellent synthon for further study.
Melanoma
LOX IMVI
MALME-3M
M14
SK-MEL-28
UACC-62
UACC-257
1.69
2.37
4.87
6.41
3.63
15.7
34.3
26.6
37.5
40.2
24.9
86.0
21.6
28.4
–
21.5
13.3
30.2
5. Experimental
Melting points were taken in open capillary tubes and are
uncorrected. The purity of the compounds was confirmed by thin
layer chromatography using Merk silica gel 60 F254 coated alumina
plates. IR spectra were recorded on a SHIMADZU-FTIR Spectrom-
eter in KBr (n max in cmꢀ1). 1H NMR spectra were recorded in DMSO-
d6 on EM-390 (300 MHz) NMR spectrometer operating at 70 eV
using TMS as internal standard. FAB MS spectra were recorded on
a JEOL SX 102/DA-6000 Mass spectrometer using argon/Xenon
(6kv, 10 mA) as the FAB gas.
Ovarian cancer
IGROV1
3.39
15.1
5.35
10.6
14.8
25.4
50.4
22.8
>100
>100
57.3
48.0
29.8
11.5
34.5
56.8
26.0
29.2
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
Renal cancer
786-0
A498
2.08
21.0
4.82
4.21
11.4
3.60
3.11
1.89
47.1
–
–
–
ACHN
66.6
35.9
51.0
56.4
77.3
60.2
26.6
20.6
23.2
18.4
37.4
31.3
CAKI-1
RXF 393
SN12C
TK-10
5.1. 4-Amino-3-(2,4-dichloro-5-fluorophenyl)-5-mercapto-1,2,4-
triazole (3)
UO-31
A mixture of 2,4-dichloro-5-fluorobenzoic acid (1) (0.01 mol)
and thiocarbohydrazide (0.015 mol) contained in
a round-
Prostate cancer
PC-3
18.7
3.41
39.2
49.5
16.9
36.6
DU-145
Table 2
Breast cancer
MCF7
NCI/ADR-RES
MDA-MB-231/ATCC
HS 578T
MDA-MB-435
BT-549
T-47D
Anticancer activity data of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives (4d, 4f
& 4g).
6.24
3.12
10.8
–
4.55
3.27
3.90
31.3
30.8
33.7
33.6
24.4
–
16.8
27.4
13.4
21.9
27.8
–
Compd No.
Growth percentage
(Lung) NCI-H 460
(Breast) MCF7
(CNS) SF 268
Activity
4d
4f
4g
3
32
6
3
69
44
3
76
26
Active
Active
Active
17.7
4.93
Samples are tested at 1.00 x10-04 Molar concentrations. Growth percentages less
than 32 are considered as active.

K.S. Bhat et al. / European Journal of Medicinal Chemistry 44 (2009) 5066–5070
5069
396(M þ 4, 78), 392(M þ 2, 74), (Mþ þ 1, 100), 390((Mþ, 49),
Table 4
Sub panel Tumor cell lines, Median Growth Inhibitory Concentration (GI50) and Full
Panel Mean Graph Mid Point (MG-MID).
155(100), 189(37)).
5.2.5. 4d IR (KBr, cmꢀ1
3048(Ar-H), 2988, 2872(–CH2–), 1578(C]N), 1491(C]C),1155(C–
F), 963(C–Cl); 1H NMR (DMSO-d6,
): 2.3(s, 3H, CH3), 3.89(s, 2H,
)
Subpanel tumor cell line
4d
1.37
16.8
5.64
12.47
5.77
12.44
6.51
11.05
5.31
4f
4g
Leukemia
>100
55.37
35.82
>100
43.25
>100
56.35
44.35
28.58
44.66
28.08
20.90
23.66
21.16
23.0
Lung cancer
Colon cancer
CNS cancer
Melanoma
Ovarian cancer
Renal cancer
Prostate cancer
Breast cancer
MG-MID
d
SCH2), 7.31(d, 2H, J ¼ 8.4 Hz, 4-chlorophenyl),7.55(d, 2H, J ¼ 8.4 Hz,
4-chlorophenyl),7.42(s, 1H, JH-F
rophenyl) 7.78(d, 1H, JH-F
¼ 6.2 Hz, 2,4-dichloro-5-fluo-
ortho
¼ 2.3 Hz, 2,4-dichloro-5-fluo-
31.3
meta
26.25
26.75
18.70
22.38
rophenyl); FAB MS (m/z, %): 416(M þ 4, 78), 414(M þ 2, 74),
413(Mþ þ 1, 100), 412((Mþ, 49), 137(100), 189(37)).
6.60
5.2.6. 4e IR (KBr, cmꢀ1
3067(Ar-H), 2962, 2889(–CH2–), 1666(C]N), 1551(C]C),1181(C–
F), 963(C–Cl), 742 & 721(C–Br); 1H NMR (DMSO-d6,
): 3.97(s, 2H,
SCH2), 7.35(d, 2H, J ¼ 8.2 Hz, 4-chlorophenyl),7.62(d, 2H, J ¼ 8.2 Hz,
4-chlorophenyl),7.49(s, 1H, JH-F
)
d
bottomed flask was heated in a mantle until the contents were
melted. The mixture was maintained at this temperature for
15–20 min (Scheme 1). The product obtained on cooling was
treated with sodium bicarbonate solution to dissolve the unreacted
carboxylic acid if any. The solid mass was then washed with water
and collected by filtration. The product was recrystallized from
a mixture of dioxan and ethanol to afford the compound 3. Yield
60%, m.p. 186–88 ꢁC.
¼ 6.6 Hz, 2,4-dichloro-5-fluo-
ortho
rophenyl) 7.84(d,1H, JH-F meta ¼ 2.1 Hz, 2,4-dichloro-5-fluorophenyl);
FAB MS (m/z, %): 461(M þ 4, 78), 459(M þ 2, 74), 458(Mþ þ 1, 100),
457((Mþ, 49), 155(51), 189(44)).
5.2.7. 4f IR (KBr, cmꢀ1
3078(Ar-H), 2940(-CH2-), 1661(C]N), 1559(C]C),1197(C–F),
873 & 833(C–Cl); 1H NMR (DMSO-d6,
): 3.84(s, 2H, SCH2), 7.26(d,
)
d
5.2. Procedure for the preparation of 3-(2,4-dichloro-5-fluorophenyl)-
6-(substituted phenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadizines 4a-g
1H, J ¼ 7.8 Hz, 2,4-dichlorophenyl),7.44(d, 1H, J ¼ 7.8 Hz, 2,4-
dichlorophenyl), 7.61(s, 1H, 2,4-dichlorophenyl) 7.57(s, 1H, JH-F
¼ 5.2 Hz, 2,4-dichloro-5-fluorophenyl) 7.73(d, 1H, JH-F
ortho
met-
A mixture of 4-amino-3-(2,4-dichloro-5-fluorophenyl)-5-mer-
capto-1,2,4-triazole 3 (10 mmol) and substituted phenacyl bromide
(10 mmol) in ethanol (25 ml) was kept under reflux on a water bath
for about 6 h. The reaction mixture was cooled; precipitated solid
was filtered, washed with water, dried and recrystallized from
suitable solvents. Their characterization data are given in Table 1.
¼ 1.9 Hz, 2,4-dichloro-5-fluorophenyl); FAB MS (m/z, %):
a
450(M þ 4, 83), 448(M þ 2, 74), 447(Mþ þ 1, 91), 446((Mþ, 59),
155(33), 189(26)).
5.2.8. 4g IR (KBr, cmꢀ1
3086(Ar–H), 2976 & 2866(–CH2–),1664(C]N),1593(C]C),1126(C–
F), 896 & 833(C–Cl); 1H NMR (DMSO-d6,
): 3.89(s, 2H, SCH2), 7.26–
)
d
5.2.1. 3. IR (KBr, cmꢀ1
)
7.81(m, 4H, aromatic protons), FAB MS (m/z, %): 468(M þ 4, 71),
3236 and 3153 (NH2 assymmetric and symmetric stretching),
466(M þ 2, 67), 465(Mþ þ 1, 100), 464((Mþ, 76), 155(47), 189(38)).
3054(Ar-H),1625(C]N),1561(C]C), 1188(C–F), 892(C–Cl); 1H NMR
(DMSO-d6,
d
): 4.74(s, 2H, NH2), 7.33(s, 1H, JH-F ortho ¼ 8.3 HZ, 2,4-
Acknowledgment
dichloro-5-fluorophenyl) 7.62(d, 1H,, JH-F
¼ 1.8 HZ, 2,4-
meta
dichloro-5-fluorophenyl), 10.46(s, 1H, NH/SH); FAB MS (m/z, %):
282(M þ 4, 57) 280(M þ 2, 54) 279(Mþ þ 1, 100), 278(Mþ, 64),
137(53), 189(33).
KSB is thankful to CSIR, New Delhi for the award of Senior
Research Fellowship [Sanction No: 9/449(30)/2001-EMR-1]. We are
thankful to Dr. V. L. Narayanan, National Cancer Institute, USA for
arranging the anticancer screening of the compounds reported in
this paper.
5.2.2. 4a: IR (KBr, cmꢀ1
3070(Ar-H), 2930
1101(C–F), 865(C–Cl); 1H NMR (DMSO-d6,
)
&
2876(–CH2–), 1646(C]N), 1576(C]C),
): 3.90(s, 2H, SCH2), 7.0–
d
7.8(m, 7H, aromatic protons); FAB MS (m/z, %):382(M þ 4, 58),
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5.2.3. 4b:IR (KBr, cmꢀ1
3028(Ar-H), 2963 & 2895(-CH2-),1667(C]N),1589(C]C),1156(C–
F), 878(C–Cl); 1H NMR (DMSO-d6,
): 3.84(s, 2H, SCH2), 6.93(d, 2H,
J ¼ 8.8 Hz, 4-Methoxyphenyl), 7.66(d, 2H, J ¼ 8.8 Hz, 4-Methox-
yphenyl), 7.28(s, 1H, JH-F ortho ¼ 8.3 Hz, 2,4-dichloro-5-fluorophenyl),
7.57(d, 1H, JH-F meta ¼ 2.2 Hz, 2,4-dichloro-5-fluorophenyl); FAB MS
(m/z, %): 412(M þ 4, 59),410 (M þ 2, 55), 409 (Mþ þ 1, 100), 143(63),
189(51).
)
d
5.2.4. 4c IR (KBr, cmꢀ1
3033 (Ar–H), 2981, 2962 2879(CH3 & –CH2–), 1633(C]N0),
1542(C]C), 1176(C-F), 914(C–Cl),1H NMR (DMSO-d6,
): 2.3(s, 3H,
)
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a

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