Download design, synthesis and anticancer activity of some novel 1,2,4

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 5 pp. 1147ñ1153, 2016
ISSN 0001-6837
Polish Pharmaceutical Society
DRUG SYNTHESIS
DESIGN, SYNTHESIS AND ANTICANCER ACTIVITY OF SOME NOVEL
1,2,4-TRIAZOLES CARRYING BIOLOGICALLY ACTIVE
SULFONAMIDE MOIETIES
MOSTAFA M. GHORAB1,2*, MANSOUR S. ALSAID1 and MOHAMMED S. AL-DOSARI1
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia
2
Department of Drug Radiation Research, National Center for Radiation Research and Technology,
Nasr City, Cairo 113701, Egypt
1
Abstract: Thirteen novel 1, 2, 4-triazoles incorporating a biologically active sulfonamide moieties 1-13 were
designed and synthesized. The structures of the prepared compounds were elucidated on the basis of elemental
analyses, IR, 1H-NMR, 13C-NMR and mass spectral data. All the newly synthesized compounds were evaluated
for their in vitro anticancer activity against various cancer cell lines. The corresponding triazole carrying a biologically active free sulfonamide with unsubstituted phenyl ring 1 and triazole bearing sulfonamide with
dimethylpyrimidine 11 were the most potent in this study which showed higher activity than the reference drug
2í,7í-dichlorofluorescein (DCF). Cytotoxic screening of the tested compounds could offer an encouraging
framework in the field that may lead to the discovery of potent anticancer activity.
Keywords: Synthesis, triazoles, benzenesulfonamides, anticancer activity
From the literature survey it was found that
1,2,4-triazoles and their derivatives have great
importance in medicinal chemistry and can be used
for the synthesis of numerous heterocyclic compounds with different biological activities such as
antiviral, antibacterial, antifungal, antituberculosis,
anticonvulsant, antidepressant, anti-inflammatory
and anticancer activities (1). They have been reported to be inhibitors of glycogen synthase kinase-3
(2), antagonists of GABA receptors (3, 4), agonists
of muscarine receptors (5), be neuroleptic (6), and
these compounds also show anti-HIV-1 (7), cytotoxic (8), antihistaminic (9), and antiproliferative
(10) activities. The advent of high-throughput
screening systems has allowed us to evaluate a large
number of small molecules in parallel and automated fashions. In response to this screening innovation, one of the greatest concerns in recent drug discovery programs has been directed toward how to
design and prepare compound libraries for getting
ìhitsî in various biological assays (11). In this
regard, historical reviews of drug discovery often
give us practical lessons. One highly informative
example is represented by the sequential development of sulfonamide therapeutics such as antibiotic
sulfa drugs, insulin-releasing hypoglycemic agents,
carbonic anhydrase inhibitory diuretics, high-ceiling
diuretics, and antihypertensive drugs (12-14). These
diverse pharmacological effects were serendipitously found through the serial derivatization of a single
chemical structure of sulfanilamide, indicating that
the sulfonamide moiety is a crucial functionality
capable of interacting with multiple cellular targets.
Therefore, we have seriously considered that novel
anticancer chemotherapeutics might be discovered
from the sulfonamide class. E7010 was shown to
reversibly bind to the colchicine site of β-tubulin,
thereby halting mitosis (15-19). The compound
exhibited good in vivo efficacy against rodent
tumors and human tumor xenografts (20). As a p.o.active antimitotic agent, E7010 demonstrated objective responses in 2 of 16 patients in the single-dose
study of phase I trials; spinal cord metastasis was
reduced by 74% in a patient with uterine sarcoma,
and a minor response was observed in a pulmonary
adenocarcinoma patient (21). In contrast to E7010,
* Corresponding author: e-mail: [email protected]; [email protected], phone: +966-53-4292-860; fax: +966-01-4670-560.
1147
1148
MOSTAFA M. GHORAB et al.
E7070 was found to block cell cycle progression of
P388 murine leukemia cells in the G1 phase, accompanied by a decrease in the S-phase fraction (16).
Although its precise mode of action has not yet been
determined, E7070 appears to be considerably different from conventional anticancer drugs in clinical
use with respect to its cell cycle effect and its tumor
type selectivity (18-22). Furthermore, preclinical
animal tests established the promising efficacy of
E7070 against human tumor xenografts (22). Thus,
the compound has progressed to clinical evaluation
in collaboration with the European Organization for
Research and Treatment of Cancer (23). In the phase
I setting, one patient with a uterine adenocarcinoma
experienced a partial response with a > 50% shrinkage of measurable tumors after i.v. administration on
the weekly schedule (24). Another partial response
was reported in a patient with breast cancer on the
daily ◊ 5 schedule (25). Phase II studies of E7070
are currently ongoing in Europe and the United
States. On the basis of the significant observations
described above, together with our interest in the
synthesis of biologically active heterocyclic compounds (26-31) we decided to synthesize several
novel sulfonamide carrying a biologically active
1,2,4-triazole analogs of E7010, E7070, ER-67865,
and ER-68487 (Fig. 1) to evaluate their anticancer
activity.
Germany) were used for thin layer chromatography.
A developing solvent system of chloroform/
methanol (8 : 2, v/v) was used and the spots were
detected by ultraviolet light. IR spectra (KBr disc)
were recorded using an FT-IR spectrophotometer
(Perkin Elmer, USA). 1H-NMR spectra were
scanned on a NMR spectrophotometer (Bruker AXS
Inc., Switzerland), operating at 500 MHz for 1H- and
125.76 MHz for 13C spectra. Chemical shifts are
expressed in ppm values relative to TMS as an internal standard, using DMSO-d6 as a solvent.
Elemental analyses were done on a model 2400
CHNSO analyzer (Perkin Elmer, USA). All the values were within ± 0.4% of the theoretical values. All
reagents used were of AR grade. The starting materials for sulfonamide derivatives were purchased
from Sigma (USA) and were directly used for the
preparation of target compounds.
Synthesis of 1,2,4-triazole-sulfonamide derivatives (1-13).
General procedure
A mixture of benzoylhydrazine (1.22 g, 0.01
mol), dimethylformamide-dimethylacetal (1.91 g,
0.01 mol)) and sulfa-drugs (0.012 mol) in dry acetonitrile (15 mL) containing acetic acid (3 mL) was
refluxed for 9 h., then left to cool. The solid product
formed was collected by filtration and recrystallized
from dioxane to give compounds 1-13, respectively.
EXPERIMENTAL
Chemistry
Melting points (uncorrected) were determined
in open capillary on a Gallenkamp melting point
apparatus (Sanyo Gallenkamp, UK). Precoated silica gel plates (Kieselgel 60 F254, 0.25 mm, Merck,
4-(3-Phenyl-4H-1,2,4-triazol-4-yl) benzenesulfonamide (1)
Yield 66%; m.p. 191.9OC. IR (KBr, cm-1):
3202, 3114 (SO2NH2), 3074 (CH arom.), 1615
(C=N), 1367, 1161 (SO2). 1H-NMR (DMSO-d6):
7.4-7.9 (m, 11H, Ar-H + SO2NH2), 9.7 (s, 1H, CH
Figure 1. Drug discovery flow chart of a series of antitumor sulfonamides
Design, synthesis and anticancer activity of some novel 1,2,4-triazoles...
triazole). 13C-NMR (DMSO-d6): 127.4 (2), 127.9
(2), 128.7 (2), 128.9 (2), 131.5 (2), 133.7 (2), 158.1,
166.3. MS m/z (%): 300 (M+) (10.08), 74 (100).
Analysis: calcd. for C14H12N4O2S (300): C, 55.99; H,
4.03; N, 18.65%; found: C, 55.68; H, 4.32; N,
18.34%.
N-[4-(3-phenyl-4H-1,2,4-triazol-4-yl) phenylsulfonyl]acetamide (2)
Yield 81%; m.p. 233.8OC. IR (KBr, cm-1): 3254
(NH), 3067 (CH arom.), 2913, 2836 (CH aliph.),
1703 (C=O), 1378, 1183 (SO2). 1H-NMR (DMSOd6): 2.8 (s, 3H, COCH3), 7.3-8.0 (m, 9H, Ar-H), 9.3
(s, 2H, SO2NH + CH triazole). 13C-NMR (DMSOd6): 19.0, 127.7 (2), 128.2 (2), 129.4 (2), 129.9,
132.9 (2), 133.1, 134.9, 137.3, 144.1, 154.2, 191.8.
MS m/z (%): 342 (M+) (8.34), 121 (100). Analysis:
calcd. for C16H14N4O3S (342): C, 56.13; H, 4.12; N,
16.36%; found: C, 56.41; H, 4.37; N, 16.11%.
N-carbamimidoyl-4-(3-phenyl-4H-1,2,4-triazol-4yl) benzenesulfonamide (3)
Yield 77%; m.p. 225.3OC. IR (KBr, cm-1):
3343, 3222, 3132 (NH, NH2), 3054 (CH arom.),
1373, 1152 (SO2). 1H-NMR (DMSO-d6): 7.5 (s,
3H, NH2 + NH imino, exchangeable with D2O),
7.6-7.9 (m, 9H, Ar-H), 10.5 (s, 2H, SO2NH + CH
triazole), 13C-NMR (DMSO-d6):126.7 (2), 127.9
(2), 128.9 (3), 129.8 (2), 132.3 (2), 133.0, 142.8,
162.3, 166.3. MS m/z (%): 342 (M+) (3.94), 119
(100). Analysis: calcd. for C15H14N6O2S (342): C,
52.62; H, 4.12; N, 24.55%; found: C, 52.29; H,
4.46; N, 24.84%.
N-(3-methylisoxazol-5-yl)-4-(3-phenyl-4H-1,2,4triazol-4-yl) benzenesulfonamide (4)
Yield 69%; m.p. 133.8OC. IR (KBr, cm-1): 3254
(NH), 3071 (CH arom.), 2943, 2854 (CH aliph.),
1602 (C=N), 1366, 1145 (SO2). 1H-NMR (DMSOd6): 2.3 (s, 3H, CH3), 6.2 (s, 1H, CH isoxazole), 6.48.0 (m, 9H, Ar-H), 10.5 [s, 2H, SO2NH + CH triazole). 13C-NMR (DMSO-d6): 12.6, 97.5, 127.1 (2),
127.9 (2), 128.7 (2), 129.6, 129.9 (2), 132.2, 133.5,
137.0 (2), 154.4, 161.0, 170.9. MS m/z (%): 381
(M+) (7.97), 81 (100). Analysis: calcd. for
C18H15N5O3S (381): C, 56.68; H, 3.96; N, 18.36%;
found: C, 56.34; H, 3.59; N, 18.09%.
N-(3,4-dimethylisoxazol-5-yl)-4-(3-phenyl-4H1,2,4-triazol-4-yl) benzenesulfonamide (5)
Yield 71%; m.p. 254.2OC. IR (KBr, cm-1): 3332
(NH), 3088 (CH arom.), 2932, 2822 (CH aliph.),
1589 (C=N), 1367, 1166 (SO2). 1 H-NMR (DMSOd6): 2.1, 2.4 (2s, 6H, 2CH3), 6.7-8.3 (m, 9H, Ar-H),
1149
10.0 (s, 2H, SO2NH + CH triazole). 13C-NMR
(DMSO-d6): 6.7, 10.3, 113.0, 127.9 (2), 128.1 (2),
128.9 (2), 129.0, 129.1 (2), 132.3 (2), 132.7 (2),
153.6, 160.4, 161.5. MS m/z (%): 395 (M+) (9.41),
174 (100). Analysis: calcd. for C19H17N5O3S (395):
C, 57.71; H, 4.33; N, 17.71%; found: C, 57.42; H,
4.69; N, 17.98%.
N-(1-phenyl-1H-pyrazol-5-yl)- 4-(3-phenyl-4H1,2,4-triazol-4-yl) benzenesulfonamide (6)
Yield 76%; m.p. 317.6OC. IR (KBr, cm-1): 3197
(NH), 3049 (CH arom.), 1584 (C=N), 1372, 1165
(SO2). 1H-NMR (DMSO-d6): 6.8-8.7 (m, 16H, ArH), 9.2 (s, 2H, SO2NH + CH triazole). 13C-NMR
(DMSO-d6): 110.3, 121.6 (2), 124.8, 125.9 (2),
126.2 (2), 127.4 (2), 128.7 (2), 128.9, 130.4 (2),
133.6, 135.5, 135.8, 142.7, 143.9 (2), 147.6, 155.8.
MS m/z (%): 442 (M+) (7.53), 92 (100). Analysis:
calcd. for C23H18N6O2S (442): C, 62.43; H, 4.10; N,
18.99%; found: C, 62.10; H, 4.35; N, 18.64%.
4-(3-Phenyl-4H-1,2,4-triazol-4-yl)-N-(thiazol-2yl) benzenesulfonamide (7)
Yield 83%; m.p. 243.0OC. IR (KBr, cm-1): 3231
(NH), 3100 (CH arom.), 1601 (C=N), 1365, 1149
(SO2). 1H-NMR (DMSO-d6): 7.5-7.9 (m, 11H, ArH), 10.5 (s, 2H, SO2NH + CH triazole), 13C-NMR
(DMSO-d6): 122.3, 127.9 (2), 128.7 (3), 128.9 (2),
132.3 (3), 133.0 (2), 166.3 (2). MS m/z (%): 383
(M+) (19.48), 76 (100). Analysis: calcd. for C17H13
N5O2S2 (383): C, 53.25; H, 3.42; N, 18.26%; found:
C, 53.56; H, 3.11; N, 17.93%.
4-(3-Phenyl-4H-1,2,4-triazol-4-yl)-N-(pyridin-2yl) benzenesulfonamide (8)
Yield 88%; m.p. 197.2OC. IR (KBr, cm-1): 3363
(NH), 3082 (CH arom.), 1620 (C=N), 1393, 1159
(SO2). 1H-NMR (DMSO-d6): 6.6-8.1 (m, 13H, ArH), 11.0 (s, 2H, SO2NH + CH triazole). 13C-NMR
(DMSO-d6): 112.6, 117.5, 126.1 (2), 126.2 (3),
129.2 (3), 129.3 (2), 139.2 (2), 139.4 (2), 146.7,
152.8, 153.2. MS m/z (%): 377 (M+) (4.32), 77
(100). Analysis: calcd. for C19H15N5O2S (377): C,
60.46; H, 4.01; N, 18.56%; found: C, 60.78; H, 3.83;
N, 18.19%.
4-(3-Phenyl-4H-1,2,4-triazol-4-yl)-N-(pyrimidin2-yl) benzenesulfonamide (9)
Yield 73%; m.p. 268.8OC. IR (KBr, cm-1): 3194
(NH), 3077 (CH arom.), 1598 (C=N), 1375, 1191
(SO2). 1H-NMR (DMSO-d6): 6.0-8.4 (m, 12H, ArH), 11.2 (s, 2H, SO2NH + CH triazole),13C-NMR
(DMSO-d6): 112.6, 125.2 (2), 125.3 (2), 129.0 (2),
129.1 (3), 130.1 (2), 130.3 (2), 153.5, 157.7 (2),
1150
MOSTAFA M. GHORAB et al.
158.7. MS m/z (%):378 (M+) (6.74), 58 (100).
Analysis: calcd. for C18H14N6O2S (378): C, 57.13; H,
3.73; N, 22.21%; found: C, 57.48; H, 3.47; N,
21.88%.
N-(4-methylpyrimidin-2-yl)-4-(3-phenyl-4H1,2,4-triazol-4-yl) benzenesulfonamide (10)
Yield, 75%; m.p. 239.1OC. IR (KBr, cm-1):
3280 (NH), 3039 (CH arom.), 2941, 2855 (CH
aliph.), 1618 (C=N), 1359, 1164 (SO2). 1H-NMR
(DMSO-d6): 2.0 (s, 3H, CH3), 6.6-8.3 (m, 11H, ArH), 11.1 (s, 2H, SO2NH + CH triazole).13C-NMR
(DMSO-d6): 23.8, 112.5, 125.5 (4), 130.5 (5), 136.7
(4), 153.4, 157.4, 158.0, 168.4. MS m/z (%): 392
(M+) (13.62), 92 (100). Analysis: calcd. for
C19H16N6O2S (392): C, 58.15; H, 4.11; N, 21.42%;
found: C, 57.82; H, 4.43; N, 21.11%.
N-(4,6-dimethylpyrimidin-2-yl)-4-(3-phenyl-4H1,2,4-triazol-4-yl) benzenesulfonamide (11)
Yield 78%; m.p. 248.3OC. IR (KBr, cm-1): 3312
(NH), 3063 (CH arom.), 2967, 2863 (CH aliph.),
1613 (C=N), 1356, 1181 (SO2). 1H-NMR (DMSOd6): 2.2 (s, 6H, 2CH3), 6.0 (s, 1H, CH pyrimidine),
7.5-7.9 (m, 9H, Ar-H), 10.9 (s, 2H, SO2NH + CH triazole). 13C-NMR (DMSO-d6): 23.8 (2), 112.6, 127.1
(4), 127.9 (3), 128.9 (2), 132.3 (2), 133.0 (2), 157.2,
166.3 (3). MS m/z (%): 406 (M+) (23.24), 79 (100).
Analysis: calcd. for C20H18N6O2S (406): C, 59.10; H,
4.46; N, 20.68%; found: C, 58.84; H, 4.15; N,
20.32%.
N-(2,6-dimethoxypyrimidin-4-yl)-4-(3-phenyl4H-1,2,4-triazol-4-yl) benzenesulfonamide (12)
Yield 68%; m.p. 153.6OC. IR (KBr, cm-1): 3228
(NH), 3059 (CH arom.), 2933, 2862 (CH aliph.),
1622 (C=N), 1368, 1181 (SO2), 1H-NMR (DMSOd6): 3.80, 3.89 (2s, 6H, 2OCH3), 6.2 (s, 1H, CH
pyrimidine), 6.4-7.5 (m, 9H, Ar-H), 7.9 (s, 2H,
SO2NH + CH triazole). 13C-NMR (DMSO-d6): 54.3,
54.8, 88.4, 113.1 (3), 122.6 (3), 124.9 (4), 129.6 (3),
154.2, 161.6, 164.3, 172.2. MS m/z (%): 438 (M+)
(19.38), 142 (100). Analysis: calcd. for C20H18N6O4S
(438): C, 54.79; H, 4. 14; N, 19.17%; found: C,
54.46; H, 4.43; N, 19.50%.
N-(5,6-dimethoxypyrimidin-4-yl)-4-(3-phenyl4H-1,2,4-triazol-4-yl) benzenesulfonamide (13).
Yield 72%; m.p. 198.1OC. IR (KBr, cm-1): 3310
(NH), 3073 (CH arom.), 2974, 2832 (CH aliph.),
1611 (C=N), 1366, 1154 (SO2). 1H-NMR (DMSOd6): 3.6, 3.8 (2s, 6H, 2OCH3), 6.0-8.1 (m, 10H, ArH), 10.6 (s, 2H, SO2NH + CH triazole).13C-NMR
(DMSO-d6): 54.3, 60.6, 112.6 (2), 125.6 (3), 127.2
(3), 130.2 (4), 151.0 (3), 151.2, 153.9, 161.5. MS
m/z (%): 438 (M+) (2.27), 152 (100). Analysis:
calcd. for C20H18N6O4S (438): C, 54.79; H, 4.14; N,
19.17%; found: C, 54.40; H, 4.45; N, 19.45%.
In vitro anticancer evaluation
Cell culture
Human cancer cell lines HeLa (cervical), A549
(lungs) and Lovo (colorectal) were grown in DMEM
Table 1. In vitro anticancer screening of the synthesized compounds against four cell lines.
Compd. No.
A549 (lungs)
HeLa (cervical)
Lovo (colorectal)
MDA-231 (breast)
IC50(µg/mL)a
1
37.01
68.96
NA
67.24
2
NA
NA
NA
NA
3
NA
NA
NA
NA
4
NA
NA
NA
NA
6
NA
NA
NA
NA
7
NA
NA
NA
NA
8
NA
NA
NA
NA
9
NA
NA
NA
NA
10
NA
NA
NA
NA
11
NA
55.71
NA
73.77
12
NA
NA
NA
NA
13
NA
NA
NA
NA
DCF
124.87
54.07
114.12
113.94
All experiments were performed in triplicate, and the mean is used to calculate the IC50. NA = No activity, DCF = 2',7'-dichlorofluorescein.
a
Design, synthesis and anticancer activity of some novel 1,2,4-triazoles...
1151
Scheme 1. Synthetic pathways for compounds 1-13
+ GlutaMax (Invitrogen), and MDA MB321 (breast)
were grown in DMEM-F12 + GlutaMax) medium
(Invitrogen), supplemented with 10% heat-inactivated bovine serum (Gibco) and 1◊ penicillin-streptomycin (Gibco) at 37OC in a humified chamber with
5% CO2 supply. The source of the used cancer cell
lines is ATCC, Virginia, USA, and all experiments
were performed in triplicate, and the mean is used to
calculate the IC50.
Cytotoxicity assay
The in vitro anticancer screening was done at
Pharmacognosy Department, College of Pharmacy,
King Saud University, Riyadh, Saudi Arabia. Cells
were seeded (105 cells/well) in 96-well flat-bottom
plates (Becton-Dickinson Labware) a day before
treatment and grown overnight. Compounds were
dissolved in dimethyl sulfoxide (DMSO; Sigma)
and finally prepared as 1.0 mg/mL stocks, respectively, in the culture media. The final concentration
of DMSO never exceeded 0.1% in the treatment
doses. Four different doses of compounds (50, 25,
12.5 and 6.25 µg/mL) were further prepared by
diluting the stocks in culture media, and cells were
treated (in triplicate/dose). 2í,7í-dichlorofluorescein
(DCF) was included as standard reference drug
(positive control) and untreated culture was considered as negative control. The treated cultures were
further incubated for 48 h. At 48 h post-treatment,
cell viability test was performed using TACS MTT
Cell Proliferation and Viability Assay Kit (TACS)
acc. to manufacturerís instructions. The optical density (OD) was recorded at 570 nm in a microplate
reader (BioTek, ELx800) and cell survival fraction
was determined. The cell survival fraction was calculated as [(A-B)/A], where A and B are the optical
densities (OD) of untreated and of treated cells,
respectively. The IC50 values of the tested compound
were estimated using the best fit regression curve
method in Excel.
Microscopy
A direct visual investigation was made under
an inverted microscope (Optica, 40◊ and 100◊) to
1152
MOSTAFA M. GHORAB et al.
observe any morphological changes in the cells
cultured with different treatment doses at 24 and
48 h.
Chemistry
The aim of this work was to design and synthesize a new series of 1,2,4-triazoles having a biologically active benzenesulfonamide moieties to
evaluate their anticancer activity. There are many
reported methods to synthesize substituted-1,2,4-triazole derivatives. An efficient one-pot, three components synthesis of substituted-1,2,4-triazoles has
been developed by Michael (32), utilizing a wide
range of substituted primary amines, acyl
hydrazines,
and
dimethoxy-N,N-dimethylmethanamine. In this paper, the corresponding
1,2,4-triazole-sulfonamides 1-13 were synthesized
by the Michael method: dimethoxy-N,N-dimethylmethanamine and benzoylhydrazine were reacted in
acetonitrile containing acetic acid as catalyst for 9 h,
and then sulfonamide derivatives were added to the
mixture to obtain the corresponding 1,2,4-triazolesulfonamides 1-13, respectively (Scheme 1). The
structures of the obtained products were established
on the basis of microanalysis, IR, 1H-NMR, 13CNMR and mass spectral data.
In vitro anticancer evaluation
The synthesized compounds were evaluated
for their in vitro anticancer activity against human
lung cancer cell line (AS49-Raw), cervical (Hela)
cancer cell line, colorectal cell line (Lovo) and
breast cancer cell line (MDA-MB231) using
2í,7ídichlorofluorescein (DCF) as reference drug in
this study. The relationship between surviving fraction and drug concentration was plotted to obtain the
survival curve of cancer cell lines. From the results
(Table 1) it was found that 1,2,4-triazole 1 having
free sulfonamide SO2NH2 with unsubstituted phenyl
ring exhibited higher activity against lung and breast
cancer cell lines with IC50 values (37.01, 67.24
µg/mL) than the positive control DCF with IC50 values (124.87 and 113.94 µg/mL). Also, it was found
that compound 1 exhibited a remarkable activity
against Hela cell line with IC50 value (68.96 µg/mL).
In addition, compound 1 revealed no activity against
Lovo (colorectal) cell line. On the other hand, 1,2,4triazole 11 containing sulfonamide with dimethylpyrimidine showed higher activity with IC50 value
(73.77 µg/mL) against breast cancer cell line compared with DCF with IC50 value (113.94 µg/mL).
Compound 11 with IC50 value (55.71 µg/mL) is
nearly as active as DCF with IC50 value (54.07
µg/mL) as positive control against HeLa cell line.
CONCLUSION
In this work, a novel 1,2,4-triazoles-sulfonamides hybrids were synthesized and their in vitro
anticancer activity was evaluated on four human
tumor cancer cell lines. Among the tested compounds, two candidates 1 and 11 were the most
potent in this study, which showed higher activity
than the reference drug 2í,7í-dichlorofluorescein
(DCF). The active compounds could be considered
as useful templates for further development to
obtain more potent anticancer agent(s).
Acknowledgment
The authors would like to extend their sincere
appreciation to the Deanship of Scientific Research
at King Saud University for its funding of this
research through the Research Group Project No.
RGP- 302.
REFERENCES
1. Xiang L., Xue-Qiang L., He-Mei L., XueZhang Z., Zhi-Hui S.: Org. Med. Chem. Lett. 2,
26 (2012).
2. Olesen P.H., Sorensen A.R., Urso B., Kurtzhals
P., Bowler A.N. et al.: J Med. Chem. 46, 3333
(2003).
3. Bascal Z., Holden-Dye L., Willis R.J., Smith
S.W.G., Walker R.J.: Parasitology 112, 253
(1996).
4. Biagi G., Giorgi I., Livi O, Lucacchini A.,
Martini C., Scartoni V.: J. Pharm. Sci. 82, 893
(1993).
5. Moltzen E.K., Pedersen H., Bogeso K.P., Meier
E., Frederiksen K. et al.: J. Med. Chem. 37,
4085 (1994).
6. Chakrabarti J.K., Hotten T.M., Pullar I.A.,
Steggles D.J.: J. Med. Chem. 32, 2375 (1989).
7. Alvarez R., Velazquez S., San-Felix A., Aquaro
S., De Clercq E.et al.: J. Med. Chem. 37, 4185
(1994).
8. Sanghvi Y.S., Bhattacharya B.K., Kini G.D.,
Matsumoto S.S., Larson S.B. et al.: J. Med.
Chem. 33, 336 (1990).
9. Buckle D.R., Rockell C.J.M., Smith H., Spicer
B.A.: J. Med. Chem. 29, 2262 (1986).
10. Hupe D.J., Boltz R., Cohen C.J., Felix J., Ham
E. et al.: J. Biol. Chem. 266, 10136 (1991).
11. Schreiber S.L.: Science 287, 1969 (1964).
12. Drews J.: Science 287, 1964 (1960).
13. Maren T.H.: Ann. Rev. Pharmacol. Toxicol. 16,
309 (1976).
Design, synthesis and anticancer activity of some novel 1,2,4-triazoles...
14. Supuran C.T, Scozzafava A.: Exp. Opin. Ther.
Patents 10, 575 (2000).
15. Yoshino H., Ueda N., Niijima J., Sugumi H.,
Kotake Y. et al.: J. Med. Chem. 35, 2496
(1992).
16. Owa T., Yoshino H., Okauchi T., Yoshimatsu
K., Ozawa Y. et al.: J. Med. Chem. 42, 3789
(1999).
17. Owa T., Okauchi T., Yoshimatsu K., Sugi N.H.,
Ozawa Y. et al.: Bioorg. Med. Chem. Lett. 10,
1223 (2000).
18. Owa T., Nagasu T.: Exp. Opin. Ther. Patents
10, 1725 (2000).
19. Yoshimatsu K., Yamaguchi A., Yoshino H.,
Koyanagi N., Kitoh K.: Cancer Res. 57, 3208
(1997).
20. Koyanagi N., Nagasu T., Fujita F., Watanabe
T., Tsukahara K. et al.: Cancer Res. 54, 1702
(1994).
21. Yamamoto K., Noda K., Yoshimura A.,
Fukuoka M., Furuse K., Niitani H.: Cancer
Chemother. Pharmacol. 42, 127 (1998).
22. Ozawa Y., Sugi N.H., Nagasu T., Owa T.,
Watanabe T. et al.: Eur. J. Cancer 37, 2275
(2001).
1153
23. Punt C.J., Fumoleau .P, van de Walle B., Faber
M.N., Ravic M., Campone M.: Ann. Oncol. 12,
1289 (2001).
24. Punt C.J.A., Fumoleau P., Walle B.V.D.,
Deporte-Fety R., Bourcier C. et al.: Proc. Am.
Assoc. Cancer Res. 41, 609 (2000).
25. Raymond E., ten Bokkel-Huinink W.W., Taieb
J., Beijnen J.H., Mekhaldi S. et al.: Proc. Am.
Assoc. Cancer Res. 41, 611 (2000).
26. Ghorab M.M., Alsaisd M.S., Nissan Y.M.: Acta
Pol. Pharm. Drug Res. 72, 65 (2015).
27. Ghorab M.M., Alsaid M.S., Nissan Y.M.: Acta
Pol Pharm. Drug Res. 71, 603 (2014).
28. Ghorab M.M., Ragab F.A., Heiba H.I., Bayomi
A.A.: Arzneimittelforschung 61, 719 (2011).
29. Ghorab M.M., Ragab F.A., Heiba H.I., Youssef
H.A., El-Gazzar M.G.: Bioorg. Med. Chem.
Lett. 20, 6316 (2010).
30. Ghorab M.M., Ragab F.A., Hamed M.M.:
Arzneimittelforschung 60,141 (2010).
31. Shaaban M.A., Ghorab M.M., Heiba H.I.,
Kamel M.M., Zaher N.H., Mostafa M.I.: Arch.
Pharm. (Weinheim) 343, 404 (2010).
32. Stocks M.J., Cheshire D.R., Reynolds R.: Org.
Lett. 6, 2969(2004).
Received: 4. 07. 2015