Antitumor activity of novel pyridine, thiophene and thiazole derivatives

Article abstract of DOI:10.1007/s12272-012-0603-z

2-Cyano-N'-[1-(2,5-dimethoxyphenyl)]ethylideneacetohydrazide 1 was obtained via reaction of cyanoacetic acid hydrazide with 2,5-dimethoxyacetophenone. A number of novel pyridines 2aj, 3, 4, thiophenes 5-9 and thiazoles 10-12 were prepared by using the hyd

Full text of DOI:10.1007/s12272-012-0603-z

Arch Pharm Res Vol 35, No 6, 965-973, 2012
DOI 10.1007/s12272-012-0603-z
Antitumor Activity of Novel Pyridine, Thiophene and Thiazole
Derivatives
Mostafa M. Ghorab and Mansour S. Al-Said
Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Riy-
adh 11451, Saudi Arabia
(Received November 3, 2011/Revised December 5, 2011/Accepted December 7, 2011)
2-Cyano-N'-[1-(2,5-dimethoxyphenyl)]ethylideneacetohydrazide
cyanoacetic acid hydrazide with 2,5-dimethoxyacetophenone. A number of novel pyridines 2a-
, thiophenes and thiazoles 10 12 were prepared by using the hydrazide-hydrazone
1 was obtained via reaction of
j
,
3
,
4
5
-
9
-
derivative
1 as a starting material. The structure of the newly synthesized compounds was
characterized by elemental analyses, IR, H-NMR, 13C-NMR and mass spectral data. All the
1
target compounds were subjected to in vitro antitumor activity against Ehrlich Ascites Carci-
noma (EAC) cells. Compounds 2j and
M), 8 when compared with a reference drug IC50 value (68.99
nearly as active as Doxorubicin (CAS 23214-92-8).
6
showed a higher activity with IC50 values (54.54, 61.57
µ
µ
M), while compound is
5
Key words: Dihydropyridine, Thiophene, Thiazole, Antitumor activity
were reported to possess cytotoxicity (Pinney et al.,
1999; Romagnoli et al., 2006; Romagnoli et al., 2010).
INTRODUCTION
A large number of hydrazone and hydrazide-hydra- On the other hand, Tiazofurin (IV) is a high-priority
zone derivatives have been found to exhibit a wide var- candidate for clinical trials with potential importance
iety of pharmacological especially anticancer activity for treatment of the lung and metastases (Robins et
(Krasnaya, 2004; Xia et al., 2008; Liu et al., 2009; al., 1982; Tricot et al., 1989; Weber et al., 2003). Based
Zheng et al., 2009; Pavan et al., 2010). Furthermore, it on the above and as a continuation of our work on the
is well known that the Pirfenidone (PFD) (I), 5-methyl- syntheses of novel anticancer agents (Ghorab et al.,
1-phenyl-2(1H) pyridine is an agent with demonstrated 2009, 2010, 2011; Al-Said et al., 2010; Shaaban et al.,
antifibrotic activity in several organs in experimental 2010), we reported the syntheses of a new series of 2-
animals, including the lung, kidney and uterus. A pyridones, thiophenes, and thiazoles as analogs to the
phase II clinical study showed PFD to be a promising biologically active compounds (I-IV).
agent for treatment of idiopathic pulmonary fibrosis
initiated in mice treated with cyclophosphamide (Kehrer
and Margolin, 1997; Card et al., 2003). Also Milrinone
WIN 47203 (II) and their analogues are cardiotonic
agents for the treatment of heart failure (Pastelin et
MATERIALS AND METHODS
Chemistry
Melting points (oC, uncorrected) were determined in
al., 1983), some 2-pyridones are also reported to possess open capillaries on a Gallenkemp melting point appar-
antitumor activity (French et al., 1974; Srivastava and atus (Sanyo Gallenkemp). Precoated silica gel plates
Robins, 1983; Liu et al., 1992). Additionally, several (silica gel 0.25 mm, 60 G F 254; Merck) were used for
types of benzothiophene (III) and their derivatives thin layer chromatography, and dichloromethane/
methanol (9.5:0.5 mL) mixture was used as a develop-
Correspondence to: Mostafa M. Ghorab, Medicinal, Aromatic
and Poisonous Plants Research Center (MAPPRC), College of
Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Tel: 20-966-534292860, Fax: 20-966-(01)-4670560
ing solvent system and the spots were visualized by
ultraviolet light and/or iodine. Infrared spectra were
recorded in KBr using IR-470 Shimadzu spectrometer
1
(Shimadzu). H-NMR spectra (in DMSO-d6) were re-
E-mail: mmsghorab@yahoo.com
965

966
M. M. Ghorab and M. S. Al-Said
corded on Bruker Ac-300 ultra shield NMR spectro- (C
≡
N), 1710, 1685 (2C=O), 1603 (C=N). 1H-NMR (DMSO-
δ 1.3 [t, 3H, CH3], 2.2 [s, 3H, CH3], 2.4 [s, 3H, CH3
meter (Bruker, ppm at 300 MHz, using TMS as in- d6):
δ
ternal standard). Electron impact Mass Spectra were tolyl], 3.78, 3.80 [2s, 6H, 2OCH3], 4.4 [q, 2H, CH2 ester],
recorded on a Shimadzu Gc-Ms-Qp 5000 instrument 6.7 [s, 2H, NH2 exchangeable with D2O], 7.0-7.4 [m,
(Shimadzu). Elemental analyses were performed on 7H, Ar-H]. 13C-NMR (DMSO-d6): 13.7 (2), 25.3, 54.6 (2),
Carlo Erba 1108 Elemental Analyzer (Heraeus). All 62.7, 92.4, 113.6, 114.1, 115.4, 116.3, 117.9, 119.3, 127.1
compounds were within ± 0.4% of the theoretical (2), 128.0 (2), 129.9, 139.0, 154.6, 155.2, 156.0, 168.5,
values.
168.9, 169.9, 198.6. Anal. Calcd for C26H26N4O5: C, 65.81;
H, 5.52; N, 11.81. Found: C, 65.50; H, 5.20; N, 11.60.
Cyano-N'-[1-(2,5-dimethoxyphenyl)ethylidene]ace-
tohydrazide (1)
Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl)
A mixture of 2-cyanoacetohydrazide (1.0 g, 0.01 mol) ethylideneamino]-6-oxo-4-(2-hydroxyphenyl)-1,6-
and 2,5-dimethoxyacetophenone (1.8 g, 0.01 mol) in dihydropyridine-3-carboxylate (2b)
1,4-dioxane (20 mL) was refluxed for 2 h. The reaction Yield, 72%; m.p. 150-152oC; IR (KBr, cm−1): 3446 (br,
mixture was cooled and the solid product formed upon OH), 3380, 3250 (NH2), 3074 (CH arom.), 2940, 2834
pouring it onto the ice which was crystallized from the (CH aliph.), 2220 (C
ethanol. Yield, 90%; m.p. 71-73oC; IR (KBr, cm−1): 3209 1H NMR (DMSO-d6):
(NH), 3038 (CH arom.), 2961, 2836 (CH aliph.), 2258 3H, CH3], 3.72, 3.79 [2s, 6H, 2OCH3], 4.3 [q, 2H, CH2
(C
N), 1683 (C=O), 1634 (C=N). 1H-NMR (DMSO-d6): ester], 6.9 [s, 2H, NH2 exchangeable with D2O], 7.0-8.0
≡
N), 1743, 1680 (2C=O), 1610 (C=N).
δ
1.2 [t, 3H, CH3 ester], 2.1 [s,
≡
δ
2.2 [s, 3H, CH3], 3.79, 3.80 [2s, 6H, 2OCH3], 4.1 [s, 2H, [m, 7H, Ar-H], 13.9 [s, 1H, OH exchangeable with D2O].
CH2], 6.9-7.9 [m, 3H, Ar-H], 10.9 [s, 1H, NH exchange- 13C-NMR (DMSO-d6): 17.7, 55.4, 66.3, 73.1, 113.9, 114.8,
able with D2O]. 13C-NMR (DMSO-d6): 17.7, 24.8, 55.4 115.6, 116.0, 117.9, 119.4, 121.7, 122.9, 128.5, 129.2,
(2), 113.2, 114.9, 115.6, 116.0, 119.5, 152.8, 154.9, 165.6, 151.2, 151.4, 152.7, 155.5, 162.0, 163.7, 164.6, 198.4.
198.4. MS m/z (%): 261 [M+] (21.3), 163 (100). Anal. Calcd MS m/z (%): 467 [M+] (5.3), 40 (100). Anal. Calcd for
for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C, C25H24N4O6: C, 63.02; H, 5.08; N, 11.76. Found: C,
59.50; H, 5.40; N, 15.70.
62.70; H, 5.30; N, 11.50.
Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl)
ethylideneamino]-6-oxo-4-(4-hydroxyphenyl)-1,6-
dihydropyridine-3-carboxylate (2c)
Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphe-
nyl)ethylideneamino]-6-oxo-4-(substituted aryl)-
1,6-dihydropyridine-3-carboxylate (2a-j)
To a solution of compound
dioxane (30 mL) containing triethylamine (1 mL) and OH), 3210, 3160 (NH2), 3025 (CH arom.), 2940, 2839
ethylbenzalacetate derivatives (0.01 mol) was added. (CH aliph.), 2228 (C N), 1714, 1654 (2C=O), 1588 (C=N).
The reaction mixture was refluxed for 4 h, which was 1H-NMR (DMSO-d6):
1.3 [t, 3H, CH3 ester], 2.2 [s,
then poured onto ice water and the obtained solid was 3H, CH3], 3.71, 3.75 [2s, 6H, 2OCH3], 4.2 [q, 2H, CH2
1
(2.61 g, 0.01 mol), in 1,4- Yield, 68%; m.p. 157-159oC; IR (KBr, cm−1): 3322 (br,
≡
δ
recrystallized from dioxane to give (2a
-j).
ester], 6.9 [s, 2H, NH2 exchangeable with D2O], 7.9-8.1
[m, 7H, Ar-H], 10.8 [s, 1H, OH]. 13C-NMR (DMSO-d6):
Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl) 13.9, 55.9, 61.8, 97.0, 114.5, 115.3, 115.6, 116.3, 116.9,
ethylideneamino]-6-oxo-4-
dine-3-carboxylate (2a)
P
-tolyl-1,6-dihydropyri- 117.2, 123.1, 129.2, 152.1, 152.8, 153.5, 154.5, 161.8,
162.2, 162.5, 162.8. MS m/z (%): 476 [M+] (10.9), 172
Yield, 69%; m.p. 260-262oC; IR (KBr, cm−1): 3447, 3320 (100). Anal. Calcd for C25H24N4O6: C, 63.02; H, 5.08;
(NH2), 3092 (CH arom.), 2939, 2835 (CH aliph.), 2217 N, 11.76. Found: C, 63.30; H, 4.80; N, 12.10.

Novel Pyridines, Thiophenes and Thiazoles as Anticancer Agents
967
Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl) (NH2), 3093 (CH arom.), 2915, 2839 (CH aliph.), 2216
ethylideneamino]-6-oxo-4-(2-methoxyphenyl)-1,6- (C
N), 1724, 1686 (2C=O), 1616 (C=N). 1H-NMR (DMSO-
≡
dihydropyridine-3-carboxylate (2d)
d6): δ 1.3 [t, 3H, CH3 ethyl], 2.2 [s, 3H, CH3], 3.75, 3.81
Yield, 66%; m.p. 126-128oC; IR (KBr, cm−1): 3408, 3320 [2s, 6H, 2OCH3], 4.3 [q, 2H, CH2 ester], 6.1 [s, 2H, O-
(NH2), 3046 (CH arom.), 2935, 2836 (CH aliph.), 2218 CH2-O], 6.9 [s, 2H, NH2 exchangeable with D2O], 7.0-
(C
≡
d6):
N), 1718, 1670 (2C=O), 1603 (C=N). 1H-NMR (DMSO- 8.0 [m, 6H, Ar-H]. 13C-NMR (DMSO-d6): 13.9, 55.5,
δ
1.3 [t, 3H, CH3 ester], 2.3 [s, 3H, CH3], 3.72, 62.1, 98.9, 102.3, 109.0, 113.4, 113.9, 114.3, 115.4, 116.0,
3.77, 3.8 [3s, 9H, 3OCH3], 4.3 [q, 2H, CH2 ester], 6.9 116.6, 116.9, 119.5, 126.2, 148.5, 151.0, 152.8, 153.5,
[s, 2H, NH2 exchangeable with D2O], 7.0-8.0 [m, 7H, 154.3, 154.7, 162.1, 190.8, 198.4. MS m/z (%): 504 [M+]
Ar-H]. 13C-NMR (DMSO-d6): 13.9, 55.7, 56.1, 62.0, (9.6), 47 (100). Anal. Calcd for C26H24N4O7: C, 61.90;
81.9, 114.2, 114.4, 114.7, 114.9, 116.2, 116.7, 117.0, H, 4.80; N, 11.11. Found: C, 61.60; H, 4.40; N, 11.40.
119.5, 123.9, 128.3, 129.5, 151.2, 152.8, 153.5, 154.4,
162.3, 162.6, 162.9, 163.5. MS m/z (%): 490 [M+] (10.8), Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphen-
48 (100). Anal. Calcd for C26H26N4O6: C, 63.66; H, yl)ethylideneamino]-6-oxo-4-(3-nitrophenyl)-1,6-
5.34; N, 11.42. Found: C, 63.30; H, 5.60; N, 11.10.
dihydropyridine-3-carboxylate (2h)
Yield, 65%; m.p. 178-180oC; IR (KBr, cm−1): 3447, 3290
Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl) (NH2), 3086 (CH arom.), 2940, 2836 (CH aliph.), 2207
ethylideneamino]-6-oxo-4-(4-methoxyphenyl)-1,6- (C
≡
N), 1742, 1699 (2C=O), 1636 (C=N). 1H-NMR (DMSO-
dihydropyridine-3-carboxylate (2e)
d6): δ 1.2 [t, 3H, CH3 ester], 2.2 [s, 3H, CH3], 3.71, 3.78
Yield, 76%; m.p. 110-112oC; IR (KBr, cm−1): 3420, 3370 [2s, 6H, 2OCH3], 4.2 [q, 2H, CH2 ester], 6.9 [s, 2H,
(NH2), 3038 (CH arom.), 2935, 2836 (CH aliph.), 2218 NH2 exchangeable with D2O], 7.0-8.1 [m, 7H, Ar-H].
(C
≡
N), 1705, 1684 (2C=O), 1603 (C=N). 1H-NMR (DMSO- 13C-NMR (DMSO-d6): 14.9 (2), 56.4 (2), 63.7, 91.3, 113.6,
d6):
δ
1.3 [t, 3H, CH3 ester], 2.3 [s, 3H, CH3], 3.72, 115.7, 116.5, 116.9, 118.0, 119.4, 121.6, 122.8, 128.1,
3.75, 3.8 [3s, 9H, 3OCH3], 4.3 [q, 2H, CH2 ester], 6.8 134.1, 135.7, 145.9, 154.6, 154.9, 156.4, 164.5, 167.0,
[s, 2H, NH2 exchangeable with D2O], 7.0-8.0 [m, 7H, 168.9, 198.2. MS m/z (%): 505 [M+] (4.4), 40 (100).
Ar-H]. 13C-NMR (DMSO-d6): 13.7, 55.6, 62.9, 81.8, 113.9, Anal. Calcd for C25H23N5O7: C, 59.40; H, 4.59; N,
114.7, 115.2, 116.1, 116.7, 117.0, 119.4, 124.6, 128.0, 13.85. Found: C, 59.70; H, 4.20; N, 13.50.
152.8, 153.5, 154.3, 159.4, 162.3, 162.9, 163.5, 164.1. MS
m/z (%): 490 [M+] (4.9), 148 (100). Anal. Calcd for Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl)
C26H26N4O6: C, 63.66; H, 5.34; N, 11.42. Found: C, 63.40; ethylideneamino]-6-oxo-4-(2,4-dichlorophenyl)-1,6-
H, 5.10; N, 11.70.
dihydropyridine-3-carboxylate (2i)
Yield, 76%; m.p. 95-97oC; IR (KBr, cm−1): 3447, 3320
(NH2), 3091 (CH arom.), 2940, 2835 (CH aliph.), 2218
Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl)
ethylideneamino]-6-oxo-4-styryl-1,6-dihydropyri- (C≡
N), 1745, 1696 (2C=O), 1585 (C=N), 751 (C-Cl). 1H-
dine-3-carboxylate (2f)
NMR (DMSO-d6): δ 1.2 [t, 3H, CH3 ester], 2.2 [s, 3H,
Yield, 63%; m.p. 136-138oC; IR (KBr, cm−1): 3446, 3310 CH3], 3.70, 3.79 [2s, 6H, 2OCH3], 4.2 [q, 2H, CH2
(NH2), 3049 (CH arom.), 2939, 2835 (CH aliph.), 2217 ester], 6.8 [s, 2H, NH2 exchangeable with D2O], 7.0-7.7
(C
d6):
≡
N), 1740, 1699 (2C=O), 1609 (C=N). 1H-NMR (DMSO- [m, 6H, Ar-H]. 13C-NMR (DMSO-d6): 14.3, 55.4, 66.3,
δ
1.3 [t, 3H, CH3 ester], 2.3 [s, 3H, CH3], 3.73, 3.78 93.8, 114.0, 114.6, 115.2, 115.9, 116.1, 119.5, 127.5,
[2s, 6H, 2OCH3], 4.3 [q, 2H, CH2 ester], 6.7 [s, 2H, 130.4, 132.7, 133.4, 134.3, 135.2, 151.9, 152.8, 153.2,
NH2 exchangeable with D2O], 6.8, 6.9 [2d, 2H, CH = 164.2, 165.7, 166.8, 198.4. MS m/z (%): 529 [M+] (3.4),
CH,
J
= 7.1, 7.6 Hz], 7.0-7.9 [m, 8H, Ar-H]. 13C-NMR 47 (100). Anal. Calcd for C25H22Cl2N4O5: C, 56.72; H,
(DMSO-d6): 14.4, 55.8, 62.9, 93.4, 103.2, 114.5, 114.8, 4.19; N, 10.58. Found: C, 56.40; H, 4.50; N, 10.20.
115.1, 116.2, 119.5, 127.1, 127.6, 128.6, 129.1, 134.6,
138.9, 151.1, 152.8, 155.5, 155.8, 158.9, 161.7, 165.6, Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl)
198.4. MS m/z (%): 486 [M+] (5.3), 77 (100). Anal. ethylideneamino]-6-oxo-4-(2,4,5-trimethoxyphen-
Calcd for C27H26N4O5: C, 66.65; H, 5.39; N, 11.52. yl)-1,6-dihydropyridine-3-carboxylate (2j)
Found: C, 66.40; H, 5.70; N, 11.20.
Yield, 81%; m.p. > 300oC; IR (KBr, cm−1): 3481, 3290
(NH2), 3100 (CH arom.), 2941, 2835 (CH aliph.), 2208
Ethyl-2-amino-5-cyano-1-[1-(2,5-dimethoxyphenyl) (C
ethylideneamino]-6-oxo-4-(benzo[d][1,3]dioxol-5- d6):
≡
N), 1701, 1683 (2C=O), 1593 (C=N). 1H-NMR (DMSO-
δ
1.3 [t, 3H, CH3 ester], 2.2 [s, 3H, CH3], 3.72,
3.75, 3.81, 3.86, 3.91 [5s, 15H, 5OCH3], 4.2 [q, 2H, CH2
Yield, 59%; m.p. 170-172oC; IR (KBr, cm−1): 3413, 3310 ester], 6.8 [s, 2H, NH2 exchangeable with D2O], 6.9-7.8
yl)-1,6-dihydropyridine-3-carboxylate (2g)

968
M. M. Ghorab and M. S. Al-Said
[m, 5H, Ar-H]. 13C-NMR (DMSO-d6): 14.0, 55.7, 56.1, nitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g,
56.6, 61.8, 96.1, 107.7, 111.4, 113.0, 113.2, 114.4, 115.5, 0.01 mol) with elemental sulfur (0.32 g, 0.01 mol) were
116.9, 117.4, 117.7, 143.1, 151.3, 153.5, 154.8, 155.6, added. The reaction mixture was refluxed for 2 h, which
156.0, 156.5, 158.3, 162.8, 186.7. MS m/z (%): 550 [M+] was then poured onto ice water and the obtained solid
(3.5), 48 (100). Anal. Calcd for C28H30N4O8: C, 61.08; was recrystallized from dioxane to give
5 and 6,
H, 5.49; N, 10.18. Found: C, 61.40; H, 5.20; N, 9.80.
respectively.
5: Yield, 59%; m.p. 144-146oC; IR (KBr, cm−1): 3390,
4-Amino-6-substituted-1-(1-(2,5-dimethoxyphenyl)
3328, 3220 (2NH2), 3074 (CH arom.), 2932, 2838 (CH
ethylideneamino)-2-oxo-1,2-dihydropyridine-3-car- aliph.), 2211 (C
bonitrile (3,4) (DMSO-d6): 3.6 [s, 3H, CH3], 3.72, 3.76 [2s, 6H, 2OCH3],
A mixture of (2.61 g, 0.01 mol) with either malono- 6.4 [s, 2H, NH2 exchangeable with D2O], 6.8-7.1 [m,
≡
N), 1636 (C=O), 1593 (C=N). 1H-NMR
δ
1
nitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 5H, Ar-H + NH2], 12.0 [s, 1H, NH exchangeable with
0.01 mol) in dioxane (20 mL) containing triethylamine D2O]. 13C-NMR (DMSO-d6): 17.4, 55.7, 85.8, 113.9,
(1 mL) was refluxed for 6 h. The obtained solid was 114.5, 115.8, 119.6, 122.2, 128.0, 150.5, 151.4, 152.6,
then recrystallized from ethanol to give
spectively.
3
and
4
, re- 152.7, 164.5, 198.4. MS m/z (%): 359 [M+] (7.7), 47
(100). Anal. Calcd for C16H17N5O3S: C, 53.47; H, 4.77;
N, 19.49. Found: C, 53.10; H, 4.40; N, 19.20.
4,6-Diamino-1-(1-(2,5-dimethoxyphenyl)ethylidene- 6: Yield, 63%; m.p. 148-150oC; IR (KBr, cm−1): 3411,
amino)-2-oxo-1,2-dihydropyridine-3-carbonitrile
3333, 3245 (2NH2), 3100 (CH arom.), 2925, 2836 (CH
(3)
aliph.), 1734, 1653 (2C=O), 1593 (C=N). 1H-NMR (DMSO-
Yield, 82%; m.p. > 300oC; IR (KBr, cm−1): 3410, 3331 d6):
δ
1.2 [t, 3H, CH3 ester], 3.6 [s, 3H, CH3], 3.70, 3.77
(NH2), 3100 (CH arom.), 2919, 2862 (CH aliph.), 2215 [2s, 6H, 2OCH3], 4.2 [q, 2H, CH2 ester], 5.9 [s, 2H, NH2
(C
N), 1647 (C=O), 1575 (C=N). 1H NMR (DMSO-d6): exchangeable with D2O], 6.9-7.4 [m, 5H, Ar-H + NH2],
2.5 [s, 3H, CH3], 3.5 [s, 6H, 2OCH3], 4.1 [s, 3H, CH 12.4 [s, 1H, NH exchangeable with D2O]. 13C-NMR
≡
δ
+ NH2 exchangeable with D2O], 7.3-7.5 [m, 5H, Ar-H + (DMSO-d6): Anal. Calcd for C18H22N4O5S: C, 53.19; H,
NH2]. 13C-NMR (DMSO-d6): 13.6, 56.8 (2), 72.0, 86.3, 5.46; N, 13.78. Found: C, 52.80; H, 5.10; N, 13.40.
113.6, 114.4, 115.9, 116.2, 119.0, 145.6, 154.8, 155.0,
166.4, 180.6, 198.0. MS m/z (%): 327 [M+] (7.2), 44 3-Amino-N'-[1-(2,5-dimethoxyphenyl)ethylidene)-
(100). Anal. Calcd for C16H17N5O3: C, 58.17; H, 5.23; 5,6-dihydro-4H-cyclopenta-[b]thiophene-2-carbo-
N, 21.39. Found: C, 57.80; H, 5.50; N, 21.70.
hydrazide (7), 3-amino-N'[1-(2,5-dimethoxy-phenyl)
ethylidene]-4,5,6,7-tetrahydrobenzo[b]thiophene-
4-Amino-6-hydroxy-1-(1-(2,5-dimethoxyphenyl)eth- 2-carbohydrazide (8) and 3-amino-N'[1-(2,5-di-
ylideneamino)-2-oxo-1,2-dihydropyridine-3-car- methoxyphenyl)ethylidene)-5,6,7,8-tetrahydro-4H-
bonitrile (4)
cyclohepta[b]thiophene-2-carbohydrazide (9)
To a solution of (2.61 g, 0.01 mol) in ethanol (30 mL)
Yield, 77%; m.p. 119-121oC; IR (KBr, cm−1): 3460 (br,
1
OH), 3216, 3190 (NH2), 3032 (CH arom.), 2965, 2836 containing triethylamine (1 mL) with cyclopentanone
(CH aliph.), 2259 (C
N), 1682 (C=O), 1631 (C=N). 1H- or cyclohexanone, and/or cycloheptanone (0.01 mol)
NMR (DMSO-d6): 2.2 [s, 3H, CH3], 3.73, 3.76 [2s, with elemental sulfur (0.32 g, 0.01 mol) were added.
≡
δ
6H, 2OCH3], 4.1 [s, 2H, NH2 exchangeable with D2O], The reaction mixture was refluxed for 2 h, which was
6.7 [s, 1H, CH], 6.9-7.2 [m, 3H, Ar-H], 10.9 [s, 1H, OH]. then poured onto ice water and the isolated products
13C-NMR (DMSO-d6): 13.7, 55.9, 61.8, 66.3, 114.9, 115.5, were recrystallized from dioxane to give 7-9, respectively.
115.9, 116.1, 119.4, 153.3, 154.9, 164.1, 164.2, 165.6, 7: Yield, 59%; m.p. 126-128oC; IR (KBr, cm−1): 3420,
198.3. MS m/z (%): 328 [M+] (2.6), 47 (100). Anal. 3308, 3210 (NH, NH2), 2938, 2833 (CH aliph.), 1669
Calcd for C16H16N4O4: C, 58.53; H, 4.91; N, 17.06. (C=O), 1576 (C=N). 1H-NMR (DMSO-d6):
Found: C, 58.20; H, 4.60; N, 16.70.
δ
2.0-2.5 [m,
6H, 3CH2 cyclo], 3.0 [s, 3H, CH3], 3.71, 3.76 [2s, 6H,
2OCH3], 5.2 [hump, 2H, NH2 exchangeable with D2O],
3,5-Diamino-4-cyano-N'-[1-(2,5-dimethoxyphenyl) 6.9-7.2 [m, 3H, Ar-H], 10.3 [s, 1H, NH exchangeable
ethylidene)thiophene-2-carbohydrazide (5) and with D2O]. 13C-NMR (DMSO-d6): 14.6, 25.4, 28.3, 34.6,
Ethyl 2,4-diamino-5-[2-(1-(2,5-dimethoxyphenyl)- 56.2 (2), 113.9, 114.6, 116.7, 118.4, 125.8, 140.3, 143.7,
ethylidene)hydrazinecarbony)thiophene-3-car- 145.2, 151.5, 152.9, 164.7, 198.0. MS m/z (%): 359 [M+]
boxylate (6)
(46.8), 43 (100). Anal. Calcd for C18H21N3O3S: C, 60.15;
To a solution of
1
(2.61 g, 0.01 mol) and ethanol (30 H, 5.89; N, 11.69. Found: C, 60.50; H, 5.50; N, 11.30.
mL) containing triethylamine (1 mL), either malono- 8: Yield, 63%; m.p. 72-74oC; IR (KBr, cm−1): 3370,

Novel Pyridines, Thiophenes and Thiazoles as Anticancer Agents
969
3332, 3260 (NH, NH2), 3047 (CH arom.), 2930, 2833 (CH (CH aliph.), 1644 (C=O), 1598 (C=N), 1234 (C=S), 724
1
aliph.), 1653 (C=O), 1576 (C=N). 1H-NMR (DMSO-d6): (C-Cl). H NMR (DMSO-d6):
δ
δ 2.2 [s, 3H, CH3], 3.78,
1.6-2.5 [m, 8H, 4CH2 cyclo], 3.6 [s, 3H, CH3], 3.72, 3.76 3.79 [2s, 6H, 2OCH3], 6.96 [s, 2H, NH2 exchangeable
[2s, 6H, 2OCH3], 6.9 [s, 2H, NH2 exchangeable with with D2O], 6.97-7.6 [m, 7H, Ar-H], 10.6 [s, 1H, NH].
D2O], 7.0-7.6 [m, 3H, Ar-H], 10.9 [s, 1H, NH exchange- 13C-NMR (DMSO-d6): 17.6, 55.4, 80.2, 113.2, 114.2,
able with D2O]. 13C-NMR (DMSO-d6): 14.0, 23.9, 25.5, 115.0, 115.6, 128.6, 131.0, 133.8, 134.7, 148.8, 151.3,
26.8, 55.4, 113.9, 114.9, 119.4, 119.6, 127.1, 143.3, 151.0, 152.8, 153.9, 163.4, 190.2. MS m/z (%): 462 [M+] (13.4),
152.7, 154.3, 157.2, 170.3, 198.4. MS m/z (%): 373 [M+] 66 (100). Anal. Calcd for C20H19ClN4O3S2: C, 51.89; H,
(7.6), 48 (100). Anal. Calcd for C19H23N3O3S: C, 61.10; 4.14; N, 12.10. Found: C, 51.50; H, 4.40; N, 12.40.
H, 6.21; N, 11.25. Found: C, 61.50; H, 6.50; N, 11.60.
9: Yield, 65%; m.p. 101-103oC; IR (KBr, cm−1): 3420, 4-Amino-3-(4-bromophenyl)-N'-[1-(2,5-dimethoxy-
3330, 3210 (NH, NH2), 2929, 2833 (CH aliph.), 1684 phenyl)ethylidene)-2-thioxo-2,3-dihydrothiazole-
(C=O), 1636 (C=N). 1H NMR (DMSO-d6):
δ 1.2-2.5 [m, 5-carbohydrazide (12)
10H, 5CH2 cyclo], 3.6 [s, 3H, CH3], 3.8 [s, 6H, 2OCH3], Yield, 85%; m.p. 190-192oC; IR (KBr, cm−1): 3441, 3285,
6.9 [s, 2H, NH2 exchangeable with D2O], 7.1-7.3 [m, 3162 (NH, NH2), 3094 (CH arom.), 2940, 2839 (CH
3H, Ar-H], 10.9 [s, 1H, NH]. 13C-NMR (DMSO-d6): 17.7, aliph.), 1644 (C=O), 1250 (C=S). 1H-NMR (DMSO-d6):
23.6, 24.8, 29.8, 31.5, 55.4, 114.0, 114.9, 116.2, 119.5,
δ 2.2 [s, 3H, CH3], 3.78, 3.79 [2s, 6H, 2OCH3], 6.96 [s,
128.1, 132.1, 132.9, 149.6, 151.2, 152.8, 164.8, 198.4. 2H, NH2 exchangeable with D2O], 6.98-7.8 [m, 7H, Ar-
MS m/z (%): 387 [M+] (9.2), 63 (100). Anal. Calcd for H], 10.6 [s, 1H, NH exchangeable with D2O]. 13C-NMR
C20H25N3O3S: C, 61.99; H, 6.50; N, 10.84. Found: C, (DMSO-d6): 17.6, 55.4, 80.2, 113.2, 114.2, 115.6, 123.4,
61.60; H, 6.20; N, 10.50.
128.6, 131.3, 133.1, 134.2, 148.8, 151.3, 152.8, 153.8,
163.4, 190.2. MS m/z (%): 507 [M+] (13.8), 64 (100).
4-Amino-N'-[1-(2,5-dimethoxyphenyl)ethylidene)]- Anal. Calcd for C20H19BrN4O3S2: C, 47.34; H, 3.77; N,
3-substitutedphenyl-2-thioxo-2,3-dihydrothiazole- 11.04. Found: C, 47.00; H, 3.40; N, 10.70.
5-carbohydrazide (10-12)
To a solution of compound
ethanol (20 mL) containing triethylamine (1 mL) and
elemental sulfur (0.32 g, 0.01 mol), aryl isothiocyanate
1 (2.61 g, 0.01 mol) in
Antitumor activity (in vitro study)
Reagents
Doxorubicin, the reference drug that was used in this
(0.01 mol) was added. The reaction mixture was study, is one of the most effective antitumor agents used
refluxed for 3 h, and the solid that was obtained upon to produce regressions in acute leukemia's, Hodgkin's
pouring onto ice water was recrystallized from dioxane disease and other lymphomas. The relationship between
to give 10
-
12, respectively.
survival ratio and drug concentration was plotted to
obtain the survival curve of the Ehrlich Ascites Car-
cenoma (EAC) cells. The response which was IC50
4-Amino-N'-[1-(2,5-dimethoxyphenyl)ethylidene)-
3-phenyl-2-thioxo-2,3-dihydrothiazole-5-carbohy- value (Table I) that corresponds to the compound con-
drazide (10)
centration causing (50%) mortality in net cells.
Yield, 87%; m.p. 240-242oC; IR (KBr, cm−1): 3425, 3301,
3160 (NH, NH2), 3091 (CH arom.), 2940, 2829 (CH
aliph.), 1630 (C=O), 1592 (C=N), 1292 (C=S). 1H-NMR
Procedure
The Ehrlich Ascites Carcinoma (EAC) cells were ob-
(DMSO-d6):
δ 2.2 [s, 3H, CH3], 3.78, 3.79 [2s, 6H, tained by needle aspiration of the ascetic from preino-
2OCH3], 6.9 [s, 2H, NH2 exchangeable with D2O], 7.0- culated mice under aseptic conditions (Uma Devi et
7.6 [m, 8H, Ar-H], 10.6 [s, 1H, NH exchangeable with al., 1999). Tumor cells suspension (2.5 × 106 per mL)
D2O]. 13C-NMR (DMSO-d6): 17.6, 55.4, 80.2, 113.2, was prepared in RPMI-1640 media. Tested compounds
113.3, 114.2, 115.6, 128.7, 128.9, 130.0, 134.8, 148.8, were prepared with various dilutions by dissolving:
151.3, 152.8, 153.9, 163.4, 190.3. MS m/z (%): 428 [M+] 100, 50, 25, 10
(5.2), 47 (100). Anal. Calcd for C20H20N4O3S2: C, 56.06; test tubes 0.8 mL RPMI-1640 media containing
µ
g in DMSO (1 mL). In a set of sterile
H, 4.70; N, 13.07. Found: C, 56.30; H, 4.40; N, 13.40.
(glutamine, fetal calf serum as nutrient, streptomycin
and penicillin) 0.1 mL of each of the tested compounds
4-Amino-3-(4-chlorophenyl)-N'-[1-(2,5-dimethoxy- (corresponding to 100, 50, 25, 10
µg) were then 0.1 mL
phenyl)ethylidene)-2-thioxo-2,3-dihydrothiazole- of tumor cell suspension (2.5 × 105) was added. The
5-carbohydrazide (11)
test tubes then incubated at 37oC for 2 h. Trypan blue
Yield, 91%; m.p. 186-188oC; IR (KBr, cm−1): 3440, exclusion test (Takemoto et al., 1982; Raffa et al.,
3285, 3164 (NH, NH2), 3056 (CH arom.), 2940, 2836 2004) was carried out to calculate the percentage of

970
M. M. Ghorab and M. S. Al-Said
non-viable cells after 2 h of incubation (Brusick, 1984).
No. of non-viable cells
------------------------------------------------------------
% of non-viable cells =
×100
Total No. of cells
The results of in vitro cytotoxic activity experiments
are presented in Table I.
Biological testing (Animals, chemicals and facil-
ities)
EAC cell line was maintained in female Swiss albino
mice weighing 25-30 g (the holding company for bio-
logical products and vaccines. VACSERA) were housed
at a constant temperature (24 ± 2oC) with alternating
12 h-light and dark cycles and was fed standard labora-
tory food (Milad Co) along with water ad libitum. All
chemicals and reagents were of the highest grade com-
mercially available. Animal house and biochemical
have been made available by the National Center for
Radiation Research and Technology (NCRRT), Atomic
Energy Authority, Cairo, Egypt. Animal care and handl-
ing was according to the guidelines set by the world
heath organization, Genneva, Switherland and was
approved from the committee for animal care at
NCRRT, AEA.
Scheme 1
spectrum of 2b revealed bands at 3446 cm−1 (OH),
3380, 3250 cm−1 (NH2), 2220 cm−1 (C
N), 1743, 1680
cm−1 (2C=O). IR spectrum of 2c showed bands at 3322
cm−1 (OH), 3210, 3160 cm−1 (NH2), 2228 cm−1 (C
N).
with malononitrile and/or
of the target compounds is illustrated in (Schemes 1- ethyl cyanoacetate furnished the corresponding 1,2-
3). The starting material 2-cyano-N'-[1-(2,5-dimethoxy- dihydropyridine-2-one derivatives and (Scheme 2).
phenyl)ethylideneacetohydrazide was obtained via Analytical and spectral data are consistent with the
the reaction of cyanoacetic acid with 2,5-dimethoxy- proposed structures. IR spectrum of showed bands
acetophenone (Scheme 1). The structure of hydrazide- at 3410, 3331, 3230 cm−1 (NH2), 2215 cm−1 (C
≡
RESULTS AND DISCUSSION
Chemistry
≡
The sequence of reactions followed in the synthesis Interaction of compound
1
3
4
1
3
≡
N), 1647
exhibited signals
1
hydrazone derivative
1
was confirmed by the elemental cm−1 (C=O). H-NMR spectrum of
3
analysis, IR, 1H-NMR and mass spectral data. IR spec- at 4.1, 7.5 ppm for (2NH2) groups. Mass spectrum of
3
trum showed the presence of bands at 3209 cm−1 (NH), showed a molecular ion peak m/z at 327 [M+] (6.9),
3038, 2258 cm−1 (C N), 1683 cm−1 (C=O). 1H-NMR spec- with a base peak at m/z 44 (100). IR spectrum of
trum of
revealed signals at d 2.2 ppm corresponding revealed bands at 3410 cm−1 (OH), 3240, 3216 cm−1
to CH3 group, a singlet at 4.1 ppm for CH2 group, 3.79, (NH2), 2258 cm− (C
3.80 ppm for 2 OCH3 groups. Mass spectrum of showed spectrum of revealed signals at 4.1 ppm for (NH2)
a molecular ion peak m/z 261 (21.3), with a base peak group and 10.9 ppm for (OH) group. Mass spectrum of
≡
4
1
1
1
≡
N), 1682 cm−1 (C=O), H-NMR
1
4
that appeared at m/z 163 (100).
5
showed a molecular ion peak m/z at 328 [M+] (2.5),
was ob- with a base peak m/z at 47 (100).
On the other hand, the reaction of compound
some chemical reactions. Thus, interaction of compound either malononitrile or ethyl cyanoacetate and elem-
with ethyl a-cyanocinnamate derivatives gave the ental sulfur in ethanol containing triethylamine gave
1,6-dihydropyridine derivatives 2a . Structures of 2a the corresponding thiophene derivatives and
were based on analytical and spectral data. Thus, IR respectively (Scheme 2). The reaction goes in parallel
spectrum of 2a showed bands at 3447, 3320 cm−1 to the reported Gewald's thiophene synthesis (Mckibben
(NH2), 2217 cm−1 (C N), 1720, 1685 cm−1 (2C=O). 1H- et al., 1999). IR spectrum of
exhibited bands at 3380,
NMR spectrum of 2a revealed a triplet at 1.3 ppm for 3328, 3210 cm−1 (2NH2), 2211 cm−1 (C N), 1636 cm−1
CH3 ester and a quartet at 4.4 ppm for CH2 ester. IR (C=O). 1H-NMR spectrum of
revealed signals at 6.4,
Evidence for the structure of compound
1
tained through studying its chemical reactivity via
1 with
1
-j
-
5
6,
j
≡
5
≡
5

Novel Pyridines, Thiophenes and Thiazoles as Anticancer Agents
971
Scheme 3
1292 cm−1 (C=S). H-NMR spectrum of 10 revealed
signals at 6.9 ppm corresponding to NH2 group. Mass
spectrum of 10 revealed a molecular ion peak m/z at
428 [M+] (5.2), with a base peak at 47 (100).
1
Scheme 2
7.1 ppm for (2NH2) groups. Mass spectrum of
ed a molecular ion peak m/z at 359 [M+] (7.6), with a
base peak at 47 (100). IR spectrum of showed bands
5 reveal-
Antitumor activity
The relationship between the surviving fraction and
6
at 3411, 3333, 3245 cm−1 (2NH2), 1734, 1653 cm−1 (2C=O). compound concentration was plotted to obtain the
1H-NMR spectrum of
triplet for CH3 ester and 4.2 ppm quartet for CH2 calculated was the IC50 which corresponds to the com-
ester. Mass spectrum of revealed a molecular ion pound concentration causing 50% mortality in net
peak m/z at 374 [M+] (3.5), with a base peak m/z at 62 cells. The results of antitumor activity indicated that
(100). Also, the reaction of with cyclopentanone or 1,6-dihydropyridine 2j having 2,4,5-trimethoxyphenyl
cyclohexanone, and/or cycloheptanone and elemental with cyano group at 4-position and thiophene carry-
sulfur gave the corresponding thiophene derivatives ing o-amino ester with hydrazine carbonyl moiety at
, respectively (Scheme 3). The formation of took 5-position were found to exert the most powerful effect
place according to the similar reported reactions of on EAC cells in vitro IC50 values (54.54 and 61.57 M)
cyclohexanone with methylene reagents and elemental compared with that of the positive control doxorubicin
sulfur (Scrowston, 1981). IR spectrum of showed bands (CAS-23214-92-8) with IC50 value (68.99 M). On the
at 3420, 3308, 3210 cm−1 (NH, NH2), 1669 cm−1 (C=O). other hand, thiophene derivative
containing o-amino
IR spectrum of revealed bands at 3370, 3332, 3260 carbonitrile with hydrazine-carbonyl moiety at 5-posi-
cm−1 (NH, NH2), 1653 cm−1 (C=O). 1H-NMR spectrum of tion (IC50 value = 69.63
m) is nearly as active as
revealed singlet at 6.9 due to NH2 group. Mass spec- doxorubicin as positive control. Compounds 2h 2e
trum of showed a molecular ion peak m/z at 373 10 and 2g showed to have moderate activity.
[M+] (7.7), with a base peak m/z at 48 (100).
In conclusion, the present data showed that 1,6-di-
Finally, the reaction of compound with elemental hydropyridine and thiophene nucleus exhibited promis-
6 showed signals at 1.2 ppm survival curve of EAC cells. The response parameter
6
1
6
7-
9
7-9
µ
7
µ
5
8
µ
7
8,
,
,
8
7,
, 4
1
sulfur and aryl isothiocyanate in ethanol containing ing in vitro cytotoxic activity against EAC cells, espe-
triethylamine yielded the corresponding thiazole cially compounds 2j containing 2,4,5-trimethoxyphenyl
derivatives 10
tion of the later products took place in parallel to the carbonyl at 5-position. Compounds 2j and
reported method (Tormos et al., 1992). Structure of the highest in vitro cytotoxic when compared with the
compounds 10 12 was confirmed based on analytical other tested compounds and doxorubicin as a reference
-12, respectively (Scheme 3). The forma- at 4-position and
6
carrying o-amino with hydrazine
6
exhibited
-
and spectral data. IR spectrum of 10 exhibited bands drug. Also, compound
5 is nearly as active as positive
at 3445, 3380, 3310 cm−1 (NH, NH2), 1684 cm−1 (C=O), control.

972
M. M. Ghorab and M. S. Al-Said
Table I. In vitro cytotoxic activity of the newly synthesized
compounds 1-12
pulmonary injury and ensuing fibrosis in the hamster
model of amiodarone-induced pulmonary toxicity. Toxicol.
Sci., 75, 169-180 (2003).
Non-viable cells (%)a
French, F. A., Blanz, E. J. Jr., Shaddix, S. C., and Brockman,
R. W., Alpha-(N)-formylheteroaromatic thiosemicarbazones.
Inhibition of tumor-derived ribonucleoside diphosphate
reductase and correlation with in vivo antitumor activity.
J. Med. Chem., 17, 172-181 (1974).
Ghorab, M. M., Ragab, F. A., and Hamed, M. M., Design, syn-
thesis and anticancer evaluation of novel tetrahydroquinoline
derivatives containing sulfonamide moiety. Eur. J. Med.
Chem., 44, 4211-4217 (2009).
Ghorab, M. M., Ragab, F. A., Alqasoumi, S. I., Alafeefy, A.
M., and Aboulmagd, S. A., Synthesis of some new pyrazolo
[3,4-d]pyrimidine derivatives of expected anticancer and
radioprotective activity. Eur. J. Med. Chem., 45, 171-178
(2010).
Ghorab, M. M., Al-Said, M. S., and El-Hossary, E. M., Cyto-
toxic evaluation of some new heterocyclic sulfonamide
derivatives. J. Heterocyclic. Chem., 48, 563-571 (2011).
Ghorab, M. M., Ragab, F. A., Heiba, H. I., and El-Hazek, R. M.,
Anticancer and radio-sensitizing evaluation of some new
thiazolopyrane and thiazolopyranopyrimidine derivatives
bearing a sulfonamide moiety. Eur. J. Med. Chem., 46,
5120-5126 (2011).
Compd.
No.
Concentration (
µ
g/mL)
b
IC50
g/mL)
IC50
M)
100 50
25
10
(µ
(µ
Doxorubicin 100
60
50
35
35
40
20
50
10
55
50
30
70
40
40
95
65
55
65
75
70
20
30
39
50
15
10
30
5
20
40
5
5
20
5
37.5
50
>100*
80
68.99
191.57
-
168.06
172.26
-
102.04
-
111.11
99.00
-
54.54
229.35
106.70
69.63
61.57
104.45
83.11
121.44
106.30
-
1
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
3
4
5
6
7
8
9
10
11
12
90
40
60
55
30
60
25
60
70
35
100
60
60
100
70
60
80
85
80
40
50
82
>100*
50
>100*
56
40
15
40
20
20
45
25
35
50
50
45
45
40
35
20
25
20
5
25
5
50
10
30
20
10
40
30
30
40
40
30
5
>100*
30
75
75
25
25
37.5
31
Kehrer, J. P. and Margolin, S. B., Pirfenidone diminishes
cyclophosphamide-induced lung fibrosis in mice. Toxicol.
Lett., 90, 125-132 (1997).
Pinney, K. G., Bounds, A. D., Dingeman, K. M., Mocharla, V. P.,
Pettit, G. R., Bai, R., and Hamel, E., A new anti-tubulin
agent containing the benzo[b]thiophene ring system.
Bioorg. Med. Chem. Lett., 9, 1081-1086 (1999).
47
45.5
>100*
100
10
197.23
aMean of non-viable percentage of three repeated experiments;
bIC50 value: corresponds to the compound concentration
causing 50% mortality in net cells. *Compounds with IC50
> 100 µg/mL are considered to be inactive.
Krasnaya, Z. A., Interaction of 5-acetyl(alkoxycarbonyl)-3-
alkoxycarbonyl-6-methylpyridin-2(1H)-ones with primary
aromatic amines and hydrazine hydrate. Chemistry of
ACKNOWLEDGEMENTS
Heterocyclic Compounds, 40, 1155-1161 (2004).
Liu, M. C., Lin, T. S., and Sartorelli, A. C., Synthesis and anti-
tumor activity of amino derivatives of pyridine-2-carbox-
aldehyde thiosemicarbazone. J. Med. Chem., 35, 3672-
3677 (1992).
Liu, W. Y., Li, H. Y., Zhao, B. X., Shin, D. S., Lian, S., and Miao,
J. Y., Synthesis of novel ribavirin hydrazone derivatives and
anti-proliferative activity against A549 lung cancer cells.
Carbohydr. Res., 344, 1270-1275 (2009).
The authors are grateful to the sponsorship of the
Research Center, College of Pharmacy and the Dean-
ship of Scientific Research, King Saud University,
Riyadh, Saudi Arabia.
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