design and synthesis of novel thiophenes bearing biologically active

Transkrypt

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 71 No. 3 pp. 401ñ407, 2014
ISSN 0001-6837
Polish Pharmaceutical Society
DRUG SYNTHESIS
DESIGN AND SYNTHESIS OF NOVEL THIOPHENES BEARING
BIOLOGICALLY ACTIVE ANILINE, AMINOPYRIDINE, BENZYLAMINE,
NICOTINAMIDE, PYRIMIDINE AND TRIAZOLOPYRIMIDINE MOIETIES
SEARCHING FOR CYTOTOXIC AGENTS
MOSTAFA M. GHORAB1,2*, MARWA G. El-GAZZAR2 and MANSOUR S. ALSAID1
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,
Atomic Energy Authority, P.O. Box 29, Nasr City, Cairo, Egypt
1
Abstract: To discover new bioactive lead compounds for medicinal purposes, herein, (E)-3-(substituted
amino)-1-thiophen-2-yl-prop-2-en-1-ones 3ñ8, aminopyridines 9ñ11, benzylamine 12, nicotinamide 13, pyrimidines 14, 15, hexanoic acid 16 and triazolopyrimidine 19 were prepared and tested for cytotoxic activity.
Results showed that the tested compounds exhibited a remarkable activity, especially compounds 3 and 19 with
IC50 values (55.2 and 50.49 µM, respectively) compared to doxorubicin (IC50 = 71.8 µM) as a reference drug.
Keywords: thiophene, aniline, aminopyridine, nicotinamide, pyrimidine, triazolo-pyrimidine, cytotoxic
activity
Carlo Erba 1108 Elemental Analyzer. All these data
were within ±0.4% of the theoretical values. The IR
spectra (KBr) were measured on Shimadzu IR 110
spectrophotometer (Shimadzu, Koyoto, Japan),
1
HNMR and 13CNMR spectra were obtained by a
Bruker proton NMR-Avance 500 instrument (500
MHz) (Bruker, Germany), in dimethyl sulfoxide-d6 as
a solvent, using tetramethylsilane (TMS) as an internal
standard. All reactions were monitored by thin layer
chromatograph using precoated aluminium sheets
(Silica gel Merck 60 F254) and were visualized by UV
lamp (Merck, Germany). All chemicals were commercially supplied from Sigma-Aldrich, USA.
Thiophenes have been reported to possess
interesting biological and pharmacological activities
and several derivatives with this ring are used as
antibacterial (1ñ4), anti-inflammatory (5), anticancer (6ñ12), and antiviral (13) agents. Moreover,
from the literature survey it was found that aniline,
pyridine, nicotinamide, pyrimidine, triazolopyrimidine derivatives showed wide spectrum of biological
activities, especially anticancer activities (14ñ19).
As a part of our ongoing research program directed
towards developing new approaches to a variety of
heterocyclic ring systems for anticancer activity,
especially those containing sulfur compounds
(20ñ27), we report herein the utility of (E)-3(dimethylamino)-1-(thiophen-2-yl)prop-2-en-1-one
2 (28) for the synthesis of target compounds.
EXPERIMENTAL
(E)-3-(dimethylamino)-1-thiophen-2-yl-prop-2en-1-one (2)
Compound 2 was prepared according to previously described method (28).
Chemistry
Melting points are uncorrected and were determined on BUCHI melting point apparatus B-545
(BUCHI Labortechnik AG CH-9230 Flawil, Switzerland). Elemental analyses (C, H, N) were performed on
(E)-3-(3-substituted phenylamino)-1-thiophen-2yl-prop-2-en-1-ones (3ñ8)
General procedure
A mixture of 2 (28) (1.81 g, 0.01 mol) and the
appropriate amine, namely: 3-ethylaniline, 4-
* Corresponding author: e-mail: [email protected]
401
402
MOSTAFA M. GHORAB et al.
ethoxyaniline, 3,4,5-trimethoxyaniline, 2-chloro-5nitroaniline, 2-methyl-4-nitroaniline and 2,4-dibromoaniline (0.01 mol) in ethanol (20 mL) containing
acetic acid (5 mL) was refluxed for 2 h. The precipitated product was collected by filteration, washed
with ethanol and crystallized from dioxane to give
3ñ8, respectively.
(E)-3-(3-ethylphenylamino)-1-thiophen-2-ylprop-2-en-1-one (3)
Yield 88%; m.p. 110.5OC; IR (KBr, cm-1): 3464
(NH), 2960, 2836 (CH aliph.), 1624 (C=O), 1HNMR (DMSO-d6, δ, ppm): 1.19 (t, 3H, CH3), 2.6 (q,
2H, CH2), 6.0, 6.3 (2d, 2H, CH=CH, J = 7.3 Hz),
7.0ñ8.1 (m, 7H, Ar-H), 11.7 (d, 1H, NH, J = 7.1 Hz).
13
C-NMR (DMSO-d6, δ, ppm): 15.4, 28.1, 93.0,
113.1, 114.9, 115.5, 128.4, 129.6, 132.5, 139.9,
140.8, 143.7, 145.4, 146.8, 182.7. Analysis: calcd.
for C15H15NOS (257.35): C 70.01, H 5.87, N 5.44%;
found: C 70.32, H 6.20, N 5.60%.
(E)-3-(4-ethoxyphenylamino)-1-thiophen-2-ylprop-2-en-1-one (4)
(NH), 3070 (CH arom.), 2970, 2866 (CH aliph.),
1632 (C=O). 1H-NMR (DMSO-d6, δ, ppm): 1.3 (t,
3H, CH3), 3.9 (q, 2H, CH2), 5.9, 6.9. (2d, 2H,
CH=CH, J = 7.3, 7.4 Hz), 7.4ñ7.9 (m, 7H, Ar-H),
11.7 (d, 1H, NH, J = 8.1 Hz). 13C-NMR (DMSO-d6,
δ, ppm): 14.8, 63.2, 96.0, 115.3, 115.4, 116.9, 117.6,
129.2, 133.2, 134.0, 144.4, 146.2, 147.1, 154.9,
180.4. Analysis: calcd. for C15H15NO2S (273.35): C
65.91, H 5.53, N 5.12%; found: C 65.68, H 5.22, N
5.40%.
(E) 3-(3,4,5-trimethoxyphenylamino)-1-thiophen2-yl-prop-2-en-1-one (5)
1636 (C=O). 1H-NMR (DMSO-d6, δ, ppm): 3.6, 3.7
(2s, 9H, 3OCH3), 6.3, 6.8 (2d, 2H, CH=CH; J = 8.3
Hz), 7.2ñ7.9 (m, 5H, Ar-H), 10.9 (d, 1H, NH, J = 8.1
Hz). Analysis: calcd. for C16H17NO4S (319.38): C
60.17, H 5.37, N 4.39%; found: C 59.88, H 5.09, N
4.72%.
(E)-3-(2-chloro-5-nitrophenylamino)-1-thiophen2-yl-prop-2-en-1-one (6)
1628 (C=O), 1562, 1346 (NO2), 732 (C-Cl). 1HNMR (DMSO-d6, δ, ppm): 6.2, 6.8 (2d, 2H,
CH=CH, J = 7.0, 7.1 Hz], 7.3ñ8.0 (m, 6H, Ar-H),
10.6 (d, 1H, NH, J = 7.7 Hz). Analysis: calcd. for
C13H9ClN2O3S (308.74): C 50.57, H 2.94, N 9.07%;
found: C 50.20, H 3.30, N 9.38%.
(E)-3-(2-methyl-4-nitrophenylamino)-1-thiophen-2-yl-prop-2-en-1-one (7)
(NH), 3100 (CH arom.) 2970, 2840 (CH aliph.),
1636 (C=O), 1581, 1373 (NO2), 1H-NMR (DMSOd6, δ, ppm): 2.1 (s, 3H, CH3), 6.4, 6.9 (2d, 2H,
CH=CH, J = 7.0, 7.1 Hz), 7.0ñ7.9 (m, 6H, Ar-H),
C14H12N2O3S (288.32): C 58.32, H 4.20, N 9.72%;
found: C 58.08, H 4.12, N 9.41%.
(E)-3-(2,4-dibromophenylamino)-1-thiophen-2yl-prop-2-en-1-one (8)
1628 (C=O), 771 (CñBr). 1H-NMR (DMSO-d6, δ,
ppm): 6.1, 6.8 (2d, 2H, CH=CH, J = 7.4, 7.5 Hz),
7.1ñ7.9 (m, 6H, Ar-H), 12.0 [d, 1H, NH, J = 8.1 Hz].
13
C-NMR (DMSO-d6, δ, ppm): 95.5, 114.8, 116.6,
120.0, 128.6, 132.6, 134.8, 137.5, 138.6, 143.7,
145.5, 146.5, 183.4. Analysis: calcd. for C13H9
Br2NOS (387.09): C 40.34, H 2.34, N 3.62%; found:
C 40.10, H 2.62, N 3.33%.
(E)-3-(substituted amino)-1-thiophen-2-yl-prop2-en-1-ones (9ñ11)
A mixture of 2 (1.81 g, 0.01 mol) and 4aminopyridine or 3-amino-2-chloropyridine and/or
2-amino-4-chloropyridine (0.01 mol) in ethanol (20
mL) containing acetic acid (5 mL) was refluxed for
8 h. The reaction mixture was filtered while hot and
crystallized from dimethylformamide/ethanol to
give 9ñ11, respectively.
(E)-3-(pyridin-4-ylamino)-1-thiophen-2-yl-prop2-en-1-one (9)
Yield 90%, m.p. 213.4OC; IR (KBr, cm-1): 3433
1639 (C=O), 1620 (C=N). 1H-NMR (DMSO-d6, δ,
ppm): 6.4, 6.8 (2d, 2H, CH=CH, J = 7.6 Hz),
7.1ñ8.3 [m, 7H, Ar-H], 10.8 (d, 1H, NH, J = 7.2 Hz).
Analysis: calcd. for C12H10N2OS (230.29): C 62.59,
H 4.38, N 12.16%; found: C 62.24, H 4.56, N
12.39%.
(E)-3-(2-chloropyridin-3-ylamino)-1-thiophen-2yl-prop-2-en-1-one (10)
(NH), 3055 (CH arom.) 2940, 2863 (CH aliph.),
1701 (C=O), 1639 (C=N), 856 (C-Cl). 1H-NMR
(DMSO-d6, δ, ppm): 6.2, 7.2 (2d, 2H, CH=CH, J =
Design and synthesis of novel thiophenes bearing biologically active aniline...
6.8, 6.9 Hz), 7.3ñ8.0 (m, 6H, Ar-H], 12.0 (d, 1H,
NH, J = 7.4 Hz) 13C-NMR (DMSO-d6, δ, ppm): 96.3,
123.6, 124.1, 128.6, 136.0, 138.0, 141.4, 142.4,
143.5, 145.4, 146.3, 183.7. Analysis: calcd. for
C12H9ClN2OS (264.73): C 54.44, H 3.43, N 10.58%.
found: C 54.63, H 3.81, N 10.21%.
(E)-3-(4-chloropyridin-2-ylamino)-1-thiophen-2yl-prop-2-en-1-one (11)
1632 (C=O), 1592 (C=N), 775 (C-Cl). 1H-NMR
7.6, 7.7 Hz), 7.2ñ8.0 (m, 5H, Ar-H), 8.3 (s, 1H,
N=CH), 10.6 (d, 1H, NH, J = 8.2 Hz). 13C-NMR
(DMSO-d6, δ, ppm): 97.3, 115.6, 123.4, 131.3,
133.1, 134.2, 148.8, 151.3, 152.8, 153.8, 163.4,
190.2. Analysis: calcd. for C12H9ClN2OS (264.01):
C 54.44, H 3.43, N 10.58%; found: C 54.71, H 3.72,
N 10.30%.
(E)-3-(4-chlorobenzylamino)-1-thiophen-2-ylprop-2-en-1-one (12), (E)-N-(3-oxo-3-thiophen-2yl-prop-1-en-yl nicotinamide (13) and (E)-3(pyrimidin-2-yl-amino)-1-thiophen-2-yl-prop-2en-1-one (14)
A mixture of 2 (1.81 g, 0.01 mol) and 4chlorobenzylamine or nicotinamide and/or 2aminopyrimidine (0.01 mol) in ethanol (20 mL) and
acetic acid (20 mL) was heated under reflux for 12
h. The obtained solid was crystallized from dioxane
to give 12ñ14, respectively.
12: Yield 67%; m.p. 131.7OC; IR (KBr, cm-1):
3300 (NH), 3076 (CH arom.), 2940, 2834 (CH
aliph.) 1642 (C=O), 831 (CñCl). 1H-NMR (DMSOd6, δ, ppm): 3.8 (s, 2H, CH2), 6.7, 7.4 (2d, 2H,
CH=CH, J = 6.8, 6.9 Hz), 7.3ñ7.9 (m, 7H, Ar-H),
C12H12ClN2OS (277.03): C 60.54, H 4.35, N 5.04%;
found: C 60.83, H 3.95, N 5.28%.
3448 (NH), 3078 (CH arom.), 2970, 2846 (CH
aliph.), 1640, 1635 (2C=O), 1610 (C=N). 1H-NMR
(DMSO-d6, δ, ppm): 7.2, 8.2 (2d, 2H, CH=CH; J =
7.1, 7.6 Hz], 7.3ñ9.1 (m, 7H, Ar-H + NH). 8.4 (s,
1H, N = CH). 13C-NMR (DMSO-d6, δ, ppm): 99.6,
125.6, 128.8, 132.1, 135.1, 136.9, 138.1, 140.2,
142.6, 148.6, 151.8, 166.7, 186.3. Analysis: calcd.
for C13H10N2O2S (258.05): C 60.45, H 3.90, N
10.85%; found: C 60.59, H 3.56, N 10.31%.
3290 (NH), 3074 (CH arom.), 2960, 2836 (CH
aliph.), 1628 (C=O), 1573 (C=N). 1H-NMR
403
6.6; 6.7 Hz), 7.5ñ8.5) (m, 6H, Ar-H), 10.6 (d, 1H,
NH, J = 6.9 Hz). Analysis: calcd. for C11H9N3OS
(231.05): C 57.13, H 3.92, N 18.17%; found: C
57.27, H 3.46, N 18.49).
(E)-5-(3-oxo-3-thiophen-2-yl-prop-1-enylamino)pyrimidin-2,4-(1H,3H)-dione, (15), 6-(E)3-oxo-3-thiophen-2-yl-prop-1-enylamino)hexanoic acid (16) and 7-thiophen-2-yl-[1,2,4]triazolo[1,5-a]pyrimidine (19)
To a solution of 2 (1.81 g, 0.01 mol) in acetic
acid (20 mL) was added appropriate amine, namely:
5-aminouracil or 6-aminocaproic acid and/or 2H1,2,4-triazol-3-amine 17 (0.012 mol). The reaction
mixture was refluxed for 10 h, then cooled. The
solid that deposited after cooling was filtered off and
crystallized from dioxane-ethanol mixture to give
15, 16 and 19, respectively.
3433, 3275, 3232 (3NH), 3089 (CH arom.), 2980,
2816 (CH aliph.), 1720, 1660, 1643 (3C=O), 1HNMR (DMSO-d6, δ, ppm): 6.3, 7.2 (2d, 2H,
CH=CH, J = 7.8 Hz], 7.3ñ8.1 (m, 6H, Ar-H + 2NH
+ CH pyrimidine), 10.6 (d, 1H, NH, J = 7.0, Hz).
Analysis: calcd. for C11H9N3O3S (263.27): C 50.18,
H 3.45, N 15.96; found: C 50.55, H 3.12, N 15.69%.
16: Yield 61%; m.p. 219.8OC; IR (KBr, cmñ1)
3490 (OH), 3160 (NH), 2931, 2858 (CH aliph.),
1683, 1628 (2C=O). 1H-NMR (DMSO-d6, δ, ppm):
1.3- 2.7 (m, 10H, 5CH2], 6.1, 7.2 [2d, 2H, CH=CH,
J = 7.6, 7.7 Hz], 7.6-7.9 [m, 3H, Ar-H], 9.4 (s, 1H,
NH, D2O-exchangeable), 10.9 [s, 1H, OH, D2Oexchangeable]. Analysis: calcd. for C13H17NO3S: C,
58.40; H, 6.41; N, 5.24%; found: C, 58.62; H, 6.72;
N, 5.39%.
3105 (CH arom.), 2924, 2860 (CH aliph.), 1620
(C=N). lH-NMR (DMSO-d6, δ, ppm): 7.0ñ8.0 (m,
4H, Ar-H), 8.3 (s, 1H, CH-pyrazole), 7.5, 7.9 (2d,
2H, 2CH pyrimidine, J = 7.8 Hz). Analysis: calcd.
for C9H6N4S (202.24): C 53.45, H 2.99, N 27.70%;
found: C 53.75, H 3.22, N 27.90%.
In vitro cytotoxic activity
The human tumor breast cancer cell line
(MCF7) was obtained from the National Cancer
Institute, Cairo, Egypt. The cytotoxic activity of
some newly synthesized compounds was measured
by the Sulforhodamine-B stain (SRB) assay as
reported by Skehan et al. (29). Cells were plated in
96-multiwell plate (104 cells per well) for 24 h
before treatment with the compounds to allow
attachment of cell to the wall of the plate. Tested
compounds were dissolved in DMSO and diluted
404
with saline to the appropriate volume. Different concentrations of the compounds under test (5, 12.5, 25
and 40 µmol/L) were added to the cell monolayer.
Triplicate wells were prepared for each individual
dose. Monolayer cells were incubated with the compounds for 48 h at 37OC and in atmosphere of air and
5% CO2. After 48 h, cells were fixed, washed and
(1)
stained for 30 min. with 0.4% (w/v) SRB dissolved
in 1% acetic acid. Unbound dye was removed by
four washes with 1% acetic acid, and attached stain
was recovered with Tris-EDTA buffer. Color intensity was measured in an ELISA reader (Sunostick
Medical Technology, SPR-960B, U.K.). Negative
control was added by using the cell lines with the
(2)
(3)
(4)
(8)
(13)
(3-16)
(5)
(9)
(10)
(14)
(15)
(6)
(7)
(11)
(12)
(16)
Scheme 1. Synthetic pathways for compounds 2ñ16
Table 1. In vitro cytotoxic activity of some newly synthesized compounds against human breast cancer cell line (MCF7).
Compound concentration (µmol/L)
Compd.
no.
a
Control
5
12.5
25
40
Surviving fraction (mean ± SE) a
IC50
µΜ
DOX
1.00
0.721 ± 0.020
0.546 ± 0.020
0.461 ± 0.010
0.494 ± 0.030
71.8
3
1.00
0.614 ± 0.002
0.519 ± 0.009
0.365 ± 0.028
0.279 ± 0.047
55.2
6
1.00
0.810 ± 0.058
0.647 ± 0.026
0.471 ± 0.030
0.311 ± 0.022
72.7
9
1.00
0.887 ± 0.032
0.672 ± 0.024
0.479 ± 0.023
0.393 ± 0.015
100
12
1.00
0.683 ± 0.085
0.680 ± 0.016
0.534 ± 0.022
0.348 ± 0.043
112.1
13
1.00
0.806 ± 0.008
0.631 ± 0.033
0.418 ± 0.032
0.332 ± 0.081
79.06
15
1.00
0.829 ± 0.017
0.636 ± 0.015
0.490 ± 0.003
0.460 ± 0.027
83.3
19
1.00
0.577 ± 0.044
0.421 ± 0.012
0.369 ± 0.014
0.211 ± 0.065
50.49
n = 3. DOX = doxorubicin.
405
(2)
17
19
18
Scheme 2. Synthetic pathway for compound 19
solvent without drug. The relation between surviving fraction and drug concentration was plotted to
get the survival curve of each tumor cell line after
the specified time. The concentration required for
50% inhibition of cell viability (IC50) was calculated
and compared with the reference drug doxorubicin
and the results are given in Table 1.
RESULTS AND DISCUSSION
Chemistry
Schemes 1 and 2 outline the synthetic pathway
used to obtain compounds 3-16, 19. The starting
material (E)-3-(dimethylamino)-1-thiophen-2-ylprop-2-en-1-one 2 was prepared via reaction of
acetylthiophene 1 with dimethylformamidedimethylacetal (DMF-DMA) (28). Treatment of
compound 2 with aniline derivatives gave the corresponding secondary amine derivatives 3ñ8, respectively (Scheme 1). The structure of the later products
were assigned on the basis of their analytical and
spectral data. IR spectra of compounds 3ñ8 exhibited, in each case, NH absorption bands in the region
3408ñ3468 cm-1. Also, the enaminone 2 reacted with
4-aminopyridine or 3-amino-2-chloropyridine
and/or 2-amino-4-chloropyridine in ethanol/acetic
acid to give the corresponding pyridine derivatives
9ñ11, respectively (Scheme 1). When compound 2
was reacted with 4-chlorobenzylamine in refluxing
ethanol/acetic acid, it furnished the corresponding
(E)-3-(4-chlorobenzylamine)-1-thiophene-2-ylprop-2-en-1-one 12. On the other hand, nicotinamide 13, pyrimidine 14 and 15 derivatives were
obtained in good yield via reaction of compound 2
with nicotinamide or 2-aminopyrimidine or
aminouracil. (E)-4-(3-oxo-3-thiophen-2-yl-prop-1enylamino)butanoic acid 16 was obtained via reaction of 2 with 6-aminocapproic acid (Scheme 1).
The reactivity of enaminone 2 towards some heterocyclic amines was also examined. Thus, reaction of
2 with 5-amino-1,2,4-triazole in ethanol/acetic acid
yielded the respective 1,2,4-triazolo[1,5-a]pyrimidine derivative 19 through the formation of intermediate 18. (Scheme 2). To account for the formation
of the product 19 it is suggested that the studied
reaction started with Michael-type addition of the
exocyclic amino group of the amine used to the activated double bond of 2 followed by in-situ tandem
elimination of dimethylamine to give the intermediate 18, then, dehydrative cyclization to give 19
(Scheme 2). The 1H-NMR spectrum of 19 revealed
two doublets signals at 7.5, 7.9 ppm with J = 7.8 Hz
assignable to two vicinal protons of the pyrimidine
ring residue.
In vitro cytotoxic activity
Some newly synthesized compounds were
evaluated for their in vitro cytotoxic activity against
human breast cancer cell line (MCF7). Doxorubicin,
which is one of the most effective anticancer agents,
was used as the reference drug in this study. The
relationship between surviving fraction and drug
concentration was plotted to obtain the survival
curve of breast cancer cell line (MCF7). The
response parameter calculated was the IC50 value,
which corresponds to the concentration required for
50% inhibition of cell viability. Table 1 shows the in
vitro cytotoxic activity of the tested compounds
compared to the reference drug. It was found that, in
the negative control, solvent has no effect on the
406
cells as the surviving fraction is 1.00, the most
potent compounds were the aniline derivative 3 having ethyl group at 3-position (IC50 = 55.2 µM) and
the triazolopyrimidine derivative 19 (IC50 = 50.49
µM), which were found to be more potent than the
reference drug doxorubicin (IC50 = 71.8 µM). Also,
the aniline derivative 6 (IC50 = 72.7 µM) was found
to be nearly as potent as the reference drug. Isosteric
replacement of the benzene ring with pyridine led to
a drop in the activity as in compound 9 (IC50 = 100
µM) and also a drop in the activity was shown by
replacing the aniline ring with benzyl amine moiety
as in compound 12 (IC50 = 112.1 µM), an improvement in the activity was observed upon incorporation of nicotinamide moiety in compound 13 (IC50 =
79.06 µM), while the pyrimidine derivative 15 (IC50
= 83.3 µM) showed less activity.
CONCLUSION
From the above results, we can conclude that
administration of the tested compounds on human
breast (MCF7) cell lines showed promising cytotoxic activity. The most potent compounds are (E)-3(3-ethylphenylamino)-1-thiophen-2-yl-prop-2-enone 3 (IC50 = 55.20 µM) and 7-thiophen-2-yl[1,2,4]triazolo[1,5-a]pyrimidine 19 (IC50 =50.49
µM), which were found to be more potent than doxorubicin (IC50 = 71.8 µM), and aniline 6 carrying
chloro moiety at 2-position, nitro group at 5-position
(IC50 = 72.7 µM), which is as potent as the reference
drug.
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-VPP-302.
REFERENCES
1. Pardeshi S., Bobade V.D.: Bioorg. Med. Chem.
Lett. 21, 6559 (2011).
2. Khera M.K., Cliffe I.A., Prakash O.: Bioorg.
Med. Chem. Lett. 21, 5266 (2011).
3. Bondock S., Fadaly W., Metwally M.A: Eur. J.
Med. Chem. 45, 3692 (2010).
4. Lu X., Wan B., Franzblau S.G., You Q.: Eur. J.
Med. Chem. 46, 3551 (2011).
5. Hu Y., Yang S., Shilliday F.B., Heyde B.R.,
Mandrell K.M., Robins R.H., Xie J. et al.: Drug.
Metab. Dispos. 38, 1522 (2010).
6. Lin H.L., Zhang H., Medower C., Hollenberg
P.F., Johnson W.W.: Drug. Metab. Dispos. 39,
345 (2011).
7. Romagnoli R., Baraldi P.G., Cara C.L., Hamel
E., Basso G., Bortolozzi R., Viola G.: Eur. J.
Med. Chem. 45, 5781 (2010).
8. Romagnoli R., Baraldi P.G., Carrion M.D.,
Cruz-Lopez O., Tolomeo M., Grimaudo S., Di
Cristina A. et al.: Bioorg. Med. Chem. 18, 5114
(2010).
9. Medower C., Wen L., Johnson W.W.: Chem.
Res. Toxicol. 21, 1570 (2008).
10. Dallemagne P., Khanh L.P, Alsaïdi A., Varlet
I., Collot V., Paillet M., Bureau R., Rault S.:
Bioorg. Med. Chem. 11, 1161 (2003).
11. Dallemagne P., Khanh L.P., Alsaïdi A., Renault
O., Varlet I., Collot V., Bureau R., Rault S.:
Bioorg. Med. Chem. 10, 2185 (2002).
12. Simoni D., Romagnoli R., Baruchello R.,
Rondanin R., Rizzi M., Pavani M.G., Alloatti
D. et al.: J. Med. Chem. 49, 3143 (2006).
13. Rashad A.E., Shamroukh A.H., Abdel-Megeid
R.E., Mostafa A., El-Shesheny R., Kandeil A.,
Ali M.A., Banert K.: Eur. J. Med. Chem. 45,
5251 (2010).
14. Fedeles B.I., Zhu A.Y., Young K.S., Hillier
S.M., Proffitt K.D., Essigmann J.M., Croy R.G.:
J. Biol. Chem. 286, 33910 (2011).
15. Abdel-Megeed M.F., Badr B.E., Azaam M.M.,
El-Hiti G.A.: Bioorg. Med. Chem., 20, 2252
(2012).
16. Zhang H., Lu X., Zhang L.R., Liu J.J., Yang
X.H., Wang X.M., Zhu H.L.: Bioorg. Med.
Chem. 20, 1411 (2012).
17. Liu H.Y., Ding L., Yu Y., Chu Y., Zhu H.: J.
Chromatogr. B Analyt. Technol. Biomed. Life
Sci. 893, 49 (2012).
18. Huang L.H., Zheng Y.F., Lu Y.Z., Song C.J.,
Wang Y.G., Yu B., Liu H.M.: Steroids 77, 710
(2012).
19. Zhang N., Ayral-Kaloustian S., Nguyen T.,
Afragola J., Hernandez R., Lucas J., Gibbons J.,
Beyer C.: J. Med. Chem. 50, 319 (2007).
20. Ghorab M.M., Ragab F.A., Heiba H.I., Arafa
R.K., El-Hossary E.M.: Eur. J. Med. Chem.
459, 3677 (2010).
21. Ghorab M.M., Ragab F.A., Hamed M.M.: Eur.
J. Med. Chem. 44, 4211 (2009).
22. Ghorab M.M., Ragab F.A., Alquasoumi S.I.,
Alafeefy A.M., Aboulmagd S.A.: Eur. J. Med.
Chem. 45, 171 (2010).
23. Ghorab M.M., Ragab F.A., Heiba H.I., Youssef
H.A., El-Gazzar M.G.: Bioorg. Med. Chem.
Lett. 20, 6316 (2010).
24. Ghorab M.M., Ragab F.A., Heiba H.I., ElGazzar Marwa G., El-Gazzar Mostafa G: Acta
Pharm. 61, 415 (2011).
25. Ghorab M.M., Ragab F.A., Heiba H., El-Gazzar
Marwa
G.,
El-Gazzar
Mostafa
G.:
Arzneimittelforschung 62, 46 (2012).
26. El-Said M.S., El-Gazzar M.G., Al-Dossari
M.S., Ghorab M.M: Arzneimittelforschung 62,
149 (2012).
407
27. Al-Said M.S., El-Gazzar M.G., Ghorab M.M:
Eur. J. Chem. 3, 228 (2012).
28. Greenhill J.V: Adv. Heterocycl. Chem. 67, 207
(1997).
29. Skehan P., Storeng R., Scudiero D., Monks A.,
McMahon J., Vistica D., Warren J.T. et al.: J.
Natl. Cancer Inst. 82, 1107 (1990).
Received: 10. 09. 2013

design and synthesis of novel thiophenes bearing biologically active

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