Synthesis and antitumor activity of some novel hydrazide, 1,2-dihydropyridine, chromene, and benzochromene derivatives

Article abstract of DOI:10.1002/jhet.829

2-Cyano-N'-[1-(substitutedphenyl)ethylidene]acetohydrazide 2a-c were obtained via reaction of acetophenone derivatives 1a-c with cyanoacetic acid hydrazide. The hydrazidehydrazone derivative 2a underwent a novel series of heterocyclization reactions via its reaction with aromatic aldehydes and/or arylidenemalononitriles to produce arylidene and dihydropyridine derivatives 3,5a-l, respectively. Structures of the newly synthesized compounds were confirmed by elemental analyses, IR, ¹³C-NMR, ¹H-NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in-vitro antitumor activity against Ehrlich Ascities Carcinoma (EAC) cells. Some of them showed interesting cytotoxic activity compared with Doxorubicin (CAS 23214-92-8) as a reference drug. Copyright

Full text of DOI:10.1002/jhet.829

272
Synthesis and Antitumor Activity of Some Novel Hydrazide,
1,2-Dihydropyridine, Chromene, and Benzochromene Derivatives
Vol 49
Mostafa M. Ghorab* and Mansour S. Al-Said
Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy,
King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia
*E-mail: mmsghorab@yahoo.com
Received October 21, 2010
DOI 10.1002/jhet.829
Published online 11 November 2011 in Wiley Online Library (wileyonlinelibrary.com).
2-Cyano-N0-[1-(substitutedphenyl)ethylidene]acetohydrazide 2a–c were obtained via reaction of
acetophenone derivatives 1a–c with cyanoacetic acid hydrazide. The hydrazidehydrazone derivative
2a underwent a novel series of heterocyclization reactions via its reaction with aromatic aldehydes and/
or arylidenemalononitriles to produce arylidene and dihydropyridine derivatives 3,5a–l, respectively.
Structures of the newly synthesized compounds were confirmed by elemental analyses, IR, 13C-NMR,
1H-NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in-vitro
antitumor activity against Ehrlich Ascities Carcinoma (EAC) cells. Some of them showed interesting
cytotoxic activity compared with Doxorubicin (CAS 23214-92-8) as a reference drug.
J. Heterocyclic Chem., 49, 272 (2012).
INTRODUCTION
levels due to mutations have been analyzed in many
cancers, including leukemia and lymphoma [1–4]. From
the literature survey, it was found that the hydrazide
hydrazone group plays an important role for the anti-
cancer activity [5–9]. On the other hand, a number of
dihydropyridine derivatives claimed to possess interest-
ing anticancer activity [10–13]. Also, the importance of
the pyridine ring in the chemistry of biological system
Cancer is one of the difficult diseases to be cured,
and very few effective drugs are available. The develop-
ment of novel, efficient, and less toxic anticancer agents
remains an important and challenging goal in medicinal
chemistry. Understanding the molecular mechanism
involved in cancers will lead to identification of novel
anticancer agents. Changes in DNA, RNA, and protein
C
V
2011 HeteroCorporation

March 2012
Synthesis and Antitumor Activity of Some Novel Hydrazide, 1,2-Dihydropyridine,
Chromene, and Benzochromene Derivatives
273
has greatly realized because of their presence as sub-
structure in many natural products of therapeutic impor-
tance, involved in oxidation-reduction process. The
potent biological activity of various vitamins and drugs
[14–17] is primarily contributed by the presence of
pyridine ring in their molecular make-up. In addition,
compounds having chromene ring are reported for their
anticancer and antileukemic activities [18–20]. In the
light of these facts, and as a continuation of our efforts
towards synthesizing biologically active heterocyclic
compounds especially antitumor activity [21–29], we
planned to prepare a new derivatives of hydrazide, 1,2-
dihydropyridine, chromene and benzochromene deriva-
tives in the hope that new antitumor agents might be
discovered.
The reactivity of hydrazide-hydrazone derivative 2a
toward arylidene-malononitriles was studied. Thus, the
reaction of compound 2a with arylidene- malononitriles
furnished the corresponding 6-amino-1-[1-(2,5-dime-
thoxy-phenyl)ethylideneamino)-2-oxo-4-substituted-1,2-di-
hydropyridine-3,5-dicarbo-nitriles 5a–l. The formation of
compounds 5a–l was proceed via intermediates 4a–l, fol-
lowed by intramolecular cyclization to give 5a–l. The
structure of compounds 5a–l was proved based on analyt-
ical and spectral data. IR spectra of compounds 5a–l
exhibited bands at 3414–3208 cmꢀ1 due to (NH2) groups,
2219–2188 cmꢀ1 (CBN) groups, 1707–1654 cmꢀ1
(C¼¼O) groups, 1H-NMR spectra of compounds 5a–l
revealed signals at 1.7–2.2 ppm corresponding to protons
of the methyl groups; 3.7 ppm due to protons of methoxy
groups and 6.4–6.9 ppm assigned to protons of (NH2)
groups.
Further confirmation for the structure of 5a–l were
obtained through their synthesis via another reaction
root. Thus, interaction of compounds 3a–l with malono-
nitrile in dioxane containing triethylamine as catalyst
yielded the same dihydropyridine derivatives 5a–l (m.p.,
and mixed m.p.).
RESULTS AND DISCUSSION
Several hydrazide-hydrazones, dihydropyridines, chro-
mene and benzochro-mene were designed with the aim
of exploring their antitumor activity (Schemes 1 and 2).
This work reports the possible utility of cyanoacetic
acid hydrazide in the synthesis of 2-cyano-N0-[1-(2,5-
substitutedphenyl)ethylidene]acetohydrazide 2a–c. The
hydrazide-hydrazone derivatives 2a–c were obtained via
reaction of 2,5-dimethoxyacetophenone 1a, or 2,5-
dichloroacetophenone 1b or 2-bromo-4-chloroacetophe-
none 1c with cyanoacetic acid hydrazide. The structure
of compounds 2a–c was established on the basis of
analytical and spectral data. IR spectrum of 2a showed
bands at 3209 cmꢀ1 (NH), 2258 cmꢀ1 (CBN), 1683
On the other hand, when compound 2a reacted with
salicyldehyde or 2-hydroxy-1-naphthaldehyde the chro-
mene 6 and benzochromene 7 were obtained, respec-
tively in good yield. The reaction goes in analogy with
the reported literature [30,31].
The IR spectrum of compound 6 revealed the absence
of (CBN) band and presence of bands at 3420 cmꢀ1
(NH), 1670, 1647 cmꢀ1 (2 C¼¼O), 1622 (C¼¼N), its
mass spectrum exhibited a molecular ion peak m/z at
366 [Mþ] (5.9), with a base peak m/z at 62 (100). IR
spectrum of compound 7 showed the absence of (CBN)
band and presence of bands at 3273 (NH), 1734 (2
C¼¼O). Mass spectrum of 7 revealed a molecular ion
peak m/z at 416 [Mþ] (0.93), with a base peak m/z at
221 (100).
1
cmꢀ1 (C¼¼O). H-NMR spectrum of 2a in (DMSO-d6)
revealed signals at d 2.2 ppm corresponding to CH3
group, group, 3.7 and 3.8 ppm for the two methoxy
groups, a singlet at 4.1 ppm for CH2 group, a multiplet
at 6.9–7.1 ppm for the aromatic protons and a singlet
at 10.9 ppm for an NH group. Mass spectrum of 2a
showed a molecular ion peak m/z at 261 [Mþ] (21.3),
with a base peak m/z at 163 (100). IR spectrum of 2b
revealed bands at 3210 cmꢀ1 (NH), 2266 cmꢀ1
(CBN), 1694 cmꢀ1 (C¼¼O), 737 cmꢀ1 CACl.
Mass spectrum of 2b exhibited a molecular ion peak
m/z 270 [Mþ] (1.94), with a base peak m/z at
167 (100). IR spectrum of 2c revealed bands at
3377 cmꢀ1 (NH), 2217 cmꢀ1 (CBN), 1695 cmꢀ1
(C¼¼O), 724 cmꢀ1 CACl.
In vitro antitumor activity. Doxorubicin, the refer-
ence drug used in this study, is one of the most effective
antitumor agents used to produce regressions in acute
leukemias, Hodgkin’s desease and other lymphomas.
The relationship between survival ratio and drug con-
centration was plotted to obtain the survival curue of
Ehrlich Ascites Carcinoma (EAC) cells. The response
parameter calculated was IC50 value (Table 1), which
corresponds to the compound concentration causing
50% mortality in net cells.
Further evidence for the structure of compounds
2a–c was obtained through studying their chemical
reactivity via some chemical reactions. Thus, interac-
tion of compound 2a with aromatic aldehydes yielded
the arylidene derivatives 3a–l, respectively. The ana-
lytical and spectral data in agreement with the pro-
posed structures.
Structure activity relationship. The parent target
molecules containing the corresponding hydrazide 3a–l,
1,2-dihydropyridine 5a–l, chromene 6 and benzochro-
mene 7 derivatives were synthesized to study their struc-
ture-activity relationship. From these results in (Table 1)
it was found that substitution with either 4-nitrophenyl
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274
M. M. Ghorab and M. S. Al-Said
Vol 49
Scheme 1
Scheme 2
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Synthesis and Antitumor Activity of Some Novel Hydrazide, 1,2-Dihydropyridine,
Chromene, and Benzochromene Derivatives
275
Table 1
In-vitro cytotoxic activity of the newly synthesized compounds 2a-7.
Nonviable cells (%)a
Concentration lg/mL
b
Compd. no
100
50
25
10
IC50 (lg/mL)
IC50 (lM)
Doxorubicin
100
90
60
50
39
50
40
30
20
25
50
30
10
100
40
100
70
50
20
30
30
40
60
60
20
30
50
5
20
40
40
10
10
10
30
5
10
30
30
90
60
10
5
37.5
50
68.99
191.57
185.18
191.08
286.53
234.15
68.49
131.92
-
2a
2b
2c
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
6
7
80
100
50
50
40
50
60
30
30
70
50
100
85
25
60
90
100
30
50
10
>100c
12.5
33
100
100
100
100
100
60
100
50
100
100
70
100
50
100
50
100
100
100
100
100
100
100
70
32.63
83.75
16.20
16.45
56.94
179.42
116.55
242.13
67.91
23.31
22.57
70.61
111.85
54.58
218.34
54.46
49.70
72.46
50.70
18.57
60.09
100
80
80
40
50
30
100
80
6.4
6.5
25
75
50
10
5
5
100
29
50
50
10
20
30
5
30
30
20
5
10
10
31
50
65
60
50
70
25
20
80
100
25
50
50
30
50
100
50
70
80
100
100
100
25
35
25
70
5
6.8
25
a Mean of nonviable percentage of three repeated experiments.
b IC50 value: corresponds to the compound concentration causing 50% mortality in net cells.
c Compounds with IC50 > 100 lg/mL are considered to be inactive.
3h, 4-hydroxy-3-methoxyphenyl 3i, 2-chlorophenyl 3f,
2,4,5-trimethoxyphenyl 3j, and 4-hydroxyphenyl 3c with
IC50 values (16.20, 16.45, 32.63, 56.94, 68.49 lM)
showed a significant cytotoxic activity which was even
higher than that of reference drug doxorubicin (CAS-
23214–92–8) with IC50 value (68.99 lM) as positive
control. The substitution in para-position was found to
enhance the cytotoxic activity rather than in meta-posi-
tion. These findings were clearly observed as the pres-
ence of 4-nitrophenyl 3h, IC50 value (16.20 lM) is
more active than compound 3g bearing 3-nitrophenyl
IC50 value (83.75 lM).
Also, the presence of 4-hydroxy-3-methoxyphenyl 3i
with IC50 value (16.45 lM) is more active than com-
pound 3c carrying 4-hydroxyphenyl at the same position
IC50 value (68.49 lM).
On the other hand, it was found that 1,2-dihydropyri-
dins 5d having 4-methoxyphenyl, 5c bearing 4-hydroxy-
phenyl, 5j carrying 2,4,5-trimethoxyphenyl, 5l with
2-methoxy-1-naphthalene, 5i with 4-hydroxy-3-methoxy-
phenyl, 5g with 3-nitrophenyl and 5b with 4-tolyl
enhances the cytotoxic activity with IC50 values (22.57,
23.31. 49.70, 50.70, 54.46, 54.58, 67.91 lM) rather than
the reference drug doxorubicin.
It was very interesting to observe that the corre-
sponding hydropyridine derivative 5d carrying 4-
methoxyphenyl at 4-position with IC50 value (22.57
lM) is more potent than the hydrazide derivative 3d
having the same moiety with IC50 value (131.92 lM),
which may give an idea about the presence of
4-methoxyphenyl group in compound 3d resulted in a
drop in cytotoxic activity. On the other hand, the
hydrazide derivative 3h bearing 4-nitrophenyl with
IC50 value (16.20 lM) showed higher activity than that
of dihydropyridine derivative 5h with IC50 value
(218.34 lM) carrying the same moiety, which indicate
that this moiety may be enhance the anticancer activity
in compound 3h.
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M. M. Ghorab and M. S. Al-Said
Vol 49
2a: Yield, 90%; m.p. 71–73ꢁC; IR (KBr, cmꢀ1): 3209 (NH),
3038 (CH arom.), 2961, 2836 (CH aliph.), 2258 (CBN), 1683
(C¼¼O), 1634 (C¼¼N). 1H NMR (DMSO-d6) d: 2.21 [s, 3H,
CH3], 3.79, 3.81 [s, 6H, 2OCH3], 4.12 [s, 2H, CH2], 6.91–7.13
[m, 3H, Ar-H], 10.90 [s, 1H, NH]; 13C-NMR (DMSO-d6):
17.71, 24.82, 55.90 (2C), 113.24, 114.91, 115.91, 116.02,
119.54, 152.80, 154.91, 165.61, 198.41. MS (m/z): 261 [Mþ]
(21.3), 163 (100). Anal. Calcd. for C13H15N3O3: C, 59.76; H,
5.79; N, 16.08. Found: C, 59.50; H, 5.40; N, 15.70.
In addition, chromene derivative 6 with IC50 value
(18.57 lM) is more potent than the corresponding ben-
zochromene 7 with IC50 value (60.09 lM), and they
exhibited higher activity when compared with doxorubi-
cin as positive control.
Finally, compounds 5e and 5k with IC50 values
(70.61, 72.46 lM) are nearly as active as doxorubicin as
positive control, whereas compounds 3g, 5f, and 3l
revealed a moderate activity.
2b: Yield, 89%; m.p. 166–168ꢁC; IR (KBr, cmꢀ1): 3210
(NH), 3085 (CH arom.), 2964, 2924 (CH aliph.), 2226 (CBN),
1
1694 (C¼¼O), 1629 (C¼¼N), 737 (CACl). H NMR (DMSO-d6)
d: 2.21 [s, 3H, CH3], 4.12 [s, 2H, CH2], 7.41–7.62 [m, 3H,
Ar-H], 10.34 [s, 1H, NH]. 13C-NMR (DMSO-d6): 17.90,
24.51, 116.01, 130.81, 131.82, 132.41, 135.82 (2C), 140.03,
164.91, 198.72. MS (m/z): 270 [Mþ] (1.94), 167 (100). Anal.
Calcd for C11H9Cl2N3O: C, 48.91; H, 3.36; N, 15.56. Found:
C, 48.60; H, 3.10; N, 15.20.
CONCLUSIONS
We report here the synthesis of some new hydrazide,
1,2-dihydropyridine, chromene and benzochromene
derivatives containing biologically active dimethoxy-
phenyl moiety, it was clearly observed that hydrazide
with either 4-nitrophenyl 3h or 4-hydroxyphenyl 3i or
2-chlorophenyl 3f, 1,2-dihytropyridine with 4-methoxy-
phenyl 5d, 4-hydroxyphenyl 5c, 2,4-dichlorophenyl 5j,
2-methoxynaphthalin 5l, 4-hydroxy-3-methoxyphenyl 5i,
3-nitrophenyl 5g and chromene 6 exhibited higher anti-
tumor activity than the reference drug Doxorubicin.
Also, compounds 5e and 5k are nearly as active as Dox-
orubicin, whereas compounds 3g, 5f, and 3l exhibited a
moderate activity.
2c: Yield, 81%; m.p. > 300ꢁC; IR (KBr, cmꢀ1): 3377
(NH), 3055 (CH arom.), 2953, 2860 (CH aliph.), 2217 (CBN),
1
1695 (C¼¼O), 1627 (C¼¼N), 724 (CACl). H NMR (DMSO-d6)
d: 2.30 [s, 3H, CH3], 4.71 [s, 2H, CH2], 6.81–7.92 [m, 3H,
Ar-H], 9.50 [s, 1H, NH]. 13C-NMR (DMSO-d6): 16.11, 26.72,
117.21, 124.62, 129.21, 131.20, 133.22, 135.41, 138.04,
163.92, 198.20. Anal. Calcd for C11H9BrClN3O: C, 42.00; H,
2.88; N, 13.36. Found: C, 42.30; H, 2.50; N, 13.70.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-substitu-
tedacrylohydrazide, 3a–l. General procedure. A mixture of
2a (2.61 g, 0.01 mol) and aromatic aldehydes (0.01 mol) in
dioxane (30 mL) containing piperidine (0.5 mL) was refluxed
for 3h. The reaction mixture was left to cool then poured onto
ice water containing few drops of HCl and the obtained solid
was crystallized from dioxane to give 3a–l, respectively.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-phenyla-
crylohydrazide, 3a. Yield, 79%; m.p. > 300ꢁC; IR (KBr,
cmꢀ1): 3364 (NH), 3094 (CH arom.), 2940, 2836 (CH aliph.),
2218 (CBN), 1684 (C¼¼O), 1610 (C¼¼N). 1H NMR (DMSO-
d6) d: 3.58 [s, 3H, CH3], 3.72 [s, 6H, 2OCH3], 6.60–7.91 [m,
8H, Ar-H], 8.22 [s, 1H, CH], 9.90 [s, 1H, NH]. Anal. Calcd
for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03. Found: C,
68.50; H, 5.20; N, 12.30.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-P-tolyla-
crylohydrazide, 3b. Yield, 72%; m.p. 210–212ꢁC; IR (KBr,
cmꢀ1): 3314 (NH), 3036 (CH arom.), 2938, 2860 (CH aliph.),
2205 (CBN), 1702 (C¼¼O), 1597 (C¼¼N). 1H NMR (DMSO-
d6) d: 2.51 [s, 3H, CH3 tolyl], 3.60 [s, 3H, CH3], 3.81 [s, 6H,
2OCH3], 6.71–7.92 [m, 7H, Ar-H], 8.10 [s, 1H, CH], 10.81 [s,
1H, NH]. 13C-NMR (DMSO-d6): 17.31, 24.81, 56.30 (2C),
100.31, 114.02, 115.32, 115.87 (2C), 116.88, 119.52, 126.71,
129.04, 130.51, 133.30, 149.21 (2C), 150.92, 158.51, 159.60,
161.91. MS m/z (%) 363 [Mþ] (5.2), 63 (100). Anal. Calcd for
C21H21N3O3: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.10; H,
5.50; N, 11.20.
EXPERIMENTAL
Chemistry. Melting points (ꢁC, uncorrected) were deter-
mined in open capillaries on a Gallenkemp melting point appa-
ratus (Sanyo Gallenkemp, Southborough, UK). Pre-coated
silica gel plates (silica gel 0.25 mm, 60 G F 254; Merck, Ger-
many) were used for thin layer chromatography, dichlorome-
thane/methanol (9.5:0.5 ml) mixture was used as a developing
solvent system and the spots were visualized by ultraviolet
light and/or iodine. Infrared spectra were recorded in KBr
discs using IR-470 Shimadzu spectrometer (Shimadzu, Tokyo,
Japan). 13C-NMR, 1H-NMR spectra in (DMSO-d6) were
recorded on Bruker Ac-300 ultra shield NMR spectrometer
(Bruker, Flawil, Switzerland, d ppm) at 300 MHz, using TMS
as internal standard. Electron impact Mass Spectra were
recorded on
a
Shimadzu Gc-Ms-Qp 5000 instrument
(Shimadzu, Tokyo, Japan). Elemental analyses were performed
on Carlo Erba 1108 Elemental Analyzer (Heraeus, Hanau,
Germany). All compounds were within 6 0.4% of the theoreti-
cal values.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]acetohydra-
zide, 2a, 2-cyano-N0-[1-(2,5-dichlorophenyl)ethylidene]acetohy-
drazide, 2b and N0-[1-(2-bromo-4-chloro-phenyl)ethylidene]-2-
cyanoacetohydrazide, 2c. A mixture of 2-cyanoacetohydrazide
(1 g, 0.01 mol) and either 2,5-dimethoxyacetophenone 1a or
2,5-dichloroacetophenone 1b or 2-bromo-4-chloroacetophenone
1c (0.01 mol) in dioxane (20 mL) was refluxed for 2h. The
reaction mixture was cooled and poured onto ice water. The
solid obtained was crystallized from ethanol to give 2a–c,
respectively.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-(4-hydroxy-
phenyl)acrylohydra-zide, 3c. Yield 68; m.p. 254–256ꢁC; IR
(KBr, cmꢀ1): 3340 (OH), 3269 (NH), 3065 (CH arom.), 2940,
2860 (CH aliph.), 2213 (CBN), 1661 (C¼¼O), 1602 (C¼¼N).
1H NMR (DMSO-d6) d: 3.62 [s, 3H, CH3], 3.71 [s, 6H,
2OCH3], 6.70–8.01 [m, 7H, Ar-H], 8.31 [s, 1H, CH], 9.70 [s,
1H, OH], 10.61 [s, 1H, NH]. 13C-NMR (DMSO-d6): 16.41,
55.50 (2C), 100.31, 114.70 (2C), 115.91, 116.22 (2C), 117.94,
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119.53, 128.12, 151.87 (2C), 152.92, 153.52, 159.61 (2C),
160.01, 161.86. MS m/z (%) 365 [Mþ] (3.2), 277 (100). Anal.
Calcd for C20H19N3O4: C, 65.74; H, 5.24; N, 11.50. Found: C,
65.40; H, 5.50; N, 11.10.
151.87 (2C), 152.79, 153.10, 167.92, 198.41. MS m/z (%) 394
[Mþ] (4.2), 176 (100). Anal. Calcd for C20H18N4O5: C, 60.91;
H, 4.60; N, 14.21. Found: C, 60.70; H, 4.90; N, 14.00.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-(4-hydroxy-
3-methoxyphenyl) acrylohydrazide, 3i. Yield, 77%; m.p. 144–
146ꢁC; IR (KBr, cmꢀ1): 3381 (NH), 2939, 2861 (CH aliph.),
2206 (CBN), 1669 (C¼¼O), 1589 (C¼¼N). 1H NMR (DMSO-
d6) d: 3.60 [s, 3H, CH3], 3.71, 3.92 [2s, 9H, 3OCH3], 6.61–
8.12 [m, 6H, Ar-H], 8.31 [s, 1H, CH], 9.82 [s, 1H, OH], 11.62
[s, 1H, NH]. 13C-NMR (DMSO-d6): 21.40, 55.91 (2C), 56.22,
103.02, 108.41, 113.42, 114.02, 116.54, 118.31, 119.52,
120.04, 120.61, 123.82, 145.31, 152.84, 153.62, 155.41,
157.54, 166.20, 198.12. MS m/z (%) 395 [Mþ] (33.9), 46
(100). Anal. Calcd for C21H21N3O5: C, 63.79; H, 5.35; N,
10.63. Found: C, 63.50; 5.00; N, 10.40.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-(2,4,5-tri-
methoxyphenyl)-acrylohydrazide, 3j. Yield, 66%; m.p. 137–
139ꢁC; IR (KBr, cmꢀ1): 3196 (NH), 2941, 2839 (CH aliph.),
2207 (CBN), 1670 (C¼¼O), 1592 (C¼¼N). 1H NMR (DMSO-
d6) d: 3.61 [s, 3H, CH3], 3.70, 3.80, 3.92 [3s, 15H, 5OCH3],
6.61–8.02 [m, 5H, Ar-H], 8.43 [s, 1H, CH], 11.81 [s, 1H, NH].
MS m/z (%) 439 [Mþ] (19.1), 168 (100). Anal. Calcd for
C23H25N3O6: C, 62.86; H, 5.73; N, 9.56. Found: C, 62.50; H,
5.40; N, 9.20.
2-Cyano-3-(2,4-dichlorophenyl)-N0-[1-(2,5-dimethoxyphenyl)
ethylidene]acrylohyd-razide, 3k. Yield, 78%; m.p. 90–92ꢁC;
IR (KBr, cmꢀ1): 3446 (NH), 2936, 2836 (CH aliph.), 2210
(CBN), 1700 (C¼¼O), 1584 (C¼¼N), 816 (CACl). 1H NMR
(DMSO-d6) d: 3.61 [s, 3H, CH3], 3.72 [s, 6H, 2OCH3], 6.90–
7.81 [m, 6H, Ar-H], 8.04 [s, 1H, CH], 10.41 [s, 1H, NH]. 13C-
NMR (DMSO-d6): 22.40, 55.91, 109.71, 113.92, 114.04,
115.71, 119.10, 119.52, 127.83, 129.81, 131.04, 133.82,
134.81 (2C), 135.87, 152.71, 153.02, 153.21, 172.89, 198.41.
MS m/z (%) 418 [Mþ] (3.9), 177 (100). Anal. Calcd for
C20H17Cl2N3O3: C, 57.43; H, 4.10; N, 10.05. Found: C, 57.10;
H, 3.80; N, 9.70.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-(2-methox-
ynaphthalen-1-yl]-acrylohydrazide, 3l. Yield, 65%; m.p. 199–
201ꢁC; IR (KBr, cmꢀ1): 3300 (NH), 3100 (CH arom.), 2939,
2840 (CH aliph.), 2217 (CBN), 1670 (C¼¼O), 1622 (C¼¼N).
1H NMR (DMSO-d6) d: 3.61 [s, 3H, CH3], 3.70, 3.81 [2s, 9H,
3OCH3], 6.91–8.02 [m, 9H, Ar-H], 8.72 [s, 1H, CH], 12.21 [s,
1H, NH]. 13C-NMR (DMSO-d6): 22.11, 55.42 (2C), 56.61,
106.90, 107.11, 113.42, 113.91, 114.40 (2C), 115.34, 119.54,
123.61, 125.80 (2C), 127.72, 128.71, 130.70, 133.12, 152.73,
152.78, 155.31, 157.89, 158.10, 198.44. MS m/z (%) 429 [Mþ]
(0.9), 169 (100). Anal. Calcd for C25H23N3O4: C, 69.92; H,
5.40; N, 9.78. Found: C, 69.60; H, 5.10; N, 10.10.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-(4-methox-
yphenyl)acrylohydra-zide, 3d. Yield, 72%; m.p. 186–188ꢁC; IR
(KBr, cmꢀ1): 3272 (NH), 3041 (CH arom.), 2934, 2837 (CH
aliph.), 2208 (CBN), 1678 (C¼¼O), 1603 (C¼¼N). 1H NMR
(DMSO-d6) d: 3.61 [s, 3H, CH3], 3.70, 3.81 [2s, 9H, 3OCH3],
6.91–8.02 [m, 7H, Ar-H], 8.40 [s, 1H, CH], 11.91 [s, 1H, NH].
13C-NMR (DMSO-d6): 17.91, 56.12 (2C), 101.71, 113.02,
114.34, 114.80 (2C), 116.61, 117.12, 118.85 (2C), 126.52,
128.81, 150.70 (2C), 152.81, 153.10, 160.72, 161.01, 162.72.
MS m/z (%) 379 [Mþ] (0.7), 161 (100). Anal. Calcd for
C21H21N3O4: C, 66.48; H, 5.58; N, 11.08. Found: C, 66.10; H,
5.20; N, 10.80.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-5-phenyl-
penta-2,4-dienehydrazide, 3e. Yield, 64%; m.p. 102–104ꢁC;
IR (KBr, cmꢀ1): 3327 (NH), 3026 (CH arom.), 2937, 2834
(CH aliph.), 2210 (CBN), 1684 (C¼¼O), 1599 (C¼¼N). 1H
NMR (DMSO-d6) d: 3.61 [s, 3H, CH3], 3.82 [s, 6H, 2OCH3],
6.60 [d, 1H, CH Ph, J ¼ 7.1 Hz], 6.81 [m, 1H, CH], 7.01–
7.64 [m, 8H, Ar-H], 7.92 [d, 1H, C¼¼CH, J ¼ 7.4 Hz], 10.21
[s, 1H, NH]. 13C-NMR (DMSO-d6): 14.61, 55.40, 96.32 (2C),
113.41, 113.94, 114.03, 119.51, 127.20 (2C), 128.02, 128.12,
128.44 (2C), 128.81, 130.04, 132.81, 152.72 (2C), 152.81,
168.10, 198.42. MS m/z (%) 375 [Mþ] (3.6), 43 (100). Anal.
Calcd for C22H21N3O3: C, 70.38; H, 5.64; N, 11.19. Found: C,
70.00; H, 5.40; N, 11.50.
3-(2-Chlorophenyl)-2-cyano-N0-[1-(2,5-dimethoxyphenyl)e-
thylidene]acrylohydr-azide, 3f. Yield, 59%; m.p. 146–148ꢁC;
IR (KBr, cmꢀ1): 3329 (NH), 3056 (CH arom.), 2937, 2836
(CH aliph.), 2215 (CBN), 1705 (C¼¼O), 1589 (C¼¼N), 751
(CACl). 1H NMR (DMSO-d6) d: 3.60 [s, 3H, CH3], 3.71 [s,
6H, 2OCH3], 6.80–7.94 [m, 7H, Ar-H], 8.41 [s, 1H, CH],
12.41 [s, 1H, NH]. 13C-NMR (DMSO-d6): 22.11, 55.41 (2C),
110.30, 114.02, 114.61, 115.14, 117.31, 119.52, 127.01,
127.62, 128.21, 129.72, 131.81, 134.03, 152.81, 153.02,
153.41, 164.10, 198.41. MS m/z (%) 383 [Mþ] (4.2), 205
(100). Anal. Calcd for C20H18ClN3O3: C, 62.58; H, 4.73; N,
10.95. Found: C, 62.20; H, 4.40; N, 10.70.
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-(3-nitro-
phenyl)acrylohydrazide, 3g. Yield, 76%; m.p. 132–134ꢁC; IR
(KBr, cmꢀ1): 3446 (NH), 3082 (CH arom.), 2934, 2834 (CH
aliph.), 2190 (CBN), 1653 (C¼¼O), 1616 (C¼¼N). 1H NMR
(DMSO-d6) d: 3.61 [s, 3H, CH3], 3.70 [s, 6H, 2OCH3],
6.91–8.12 [m, 7H, Ar-H], 8.51 [s, 1H, CH], 10.20 [s, 1H, NH].
13C-NMR (DMSO-d6): 23.82, 55.91 (2C), 108.40, 113.70,
113.91, 116.31, 118.92, 119.34, 121.73, 124.42 (2C), 130.31,
135.02, 139.81, 148.21, 152.12, 152.94, 153.01, 163.62. MS
m/z (%) 394 [Mþ] (5.7), 50 (100). Anal. Calcd for
C20H18N4O5: C, 60.91; H, 4.60; N, 14.21. Found: C, 60.60; H,
4.30; N, 14.50.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-2-
oxo-4-substituted-1,2-dih-ydropyridine-3,5-dicarbonitriles,
5a–l. Method (A): A mixture of 2a (2.61 g, 0.01 mol) and
arylidene malononitriles (0.01 mol) in dioxane (30 mL) con-
taining triethylamine (1 mL) was refluxed for 4 h. The reaction
mixture was poured onto ice water and the solid obtained was
crystallized from dioxane to give 5a–l, respectively.
Method (B): A mixture of compounds 3a–l (0.01 mol) and
malononitrile (0.66 g, 0.01 mol) in dioxane (30 mL) contain-
ing triethylamine (0.5 mL) was refluxed for 5 h. The reaction
mixture was cooled and poured onto ice water and the
obtained solid was crystallized from dioxane to give 5a–l (m.p
and mixed m.p).
2-Cyano-N0-[1-(2,5-dimethoxyphenyl)ethylidene]-3-(4-nitro-
phenyl)acrylohydrazide, 3h. Yield, 81%; m.p. 136–138ꢁC; IR
(KBr, cmꢀ1): 3446 (NH), 2937, 2835 (CH aliph.), 2186
(CBN), 1700 (C¼¼O), 1598 (C¼¼N). 1H NMR (DMSO-d6) d:
3.61 [s, 3H, CH3], 3.72 [s, 6H, 2OCH3], 6.80–8.12 [m, 7H,
Ar-H], 8.70 [s, 1H, CH], 11.62 [s, 1H, NH]. 13C-NMR
(DMSO-d6): 22.13, 55.40, 104.81 (2C), 113.42, 114.43,
115.42, 119.50, 122.31, 123.70, 127.62 (2C), 143.14, 147.51,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

278
M. M. Ghorab and M. S. Al-Said
Vol 49
(2C), 152.71, 153.02, 160.44, 165.10, 178.61, 198.40. MS m/
z (%) 439 [Mþ] (5.2), 46 (100). Anal. Calcd for C25H21N5O3:
C, 68.33; H, 4.82; N, 15.94. Found: C, 68.60; H, 4.50;
N, 15.70.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-2-oxo-
4-phenyl-1,2-dihy-dropyridine-3,5-dicarbonitrile, 5a. Yield, 68%;
m.p. 85–87ꢁC; IR (KBr, cmꢀ1): 3385, 3342 (NH2), 3100 (CH
arom.), 2959, 2853 (CH aliph.), 2217 (CBN), 1654 (C¼¼O),
1
6-Amino-4-(2-chlorophenyl)-1-[1-(2,5-dimethoxyphenyl)ethy-
lideneamino)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile, 5f.
Yield, 59%; m.p. 100–102ꢁC; IR (KBr, cmꢀ1): 3334, 3260
(NH2), 3067 (CH arom.), 2956, 2835 (CH aliph.), 2193
(CBN), 1699 (C¼¼O), 1646 (C¼¼N), 755 (CACl). 1H NMR
(DMSO-d6) d: 2.10 [s, 3H, CH3], 3.72 [s, 6H, 2OCH3], 6.90
[s, 2H, NH2 exchangeable with D2O], 7.01–7.64 [m, 7H, Ar-
H]. 13C-NMR (DMSO-d6): 21.12, 55.51 (2C), 72.43, 112.70,
113.41 (2C), 113.71, 114.01, 115.014, 119.50, 127.54, 128.14,
128.43, 129.70, 133.41, 134.04, 152.71, 152.82, 158.62,
161.83, 166.74, 198.41. MS m/z (%) 447.5 [Mþ] (2.8), 40
(100). Anal. Calcd for C23H18ClN5O3: C, 61.67; H, 4.02; N,
15.64. Found: C, 61.30; H, 4.40; N, 15.90.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-4-(3-
nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile,
5g. Yield, 61%; m.p. 135–137ꢁC; IR (KBr, cmꢀ1): 3380, 3347
(NH2), 3086 (CH arom.), 2935, 2837 (CH aliph.), 2189
(CBN), 1656 (C¼¼O), 1616 (C¼¼N). 1H NMR (DMSO-d6) d:
2.10 [s, 3H, CH3], 3.71 [s, 6H, 2OCH3], 6.80 [s, 2H, NH2
exchangeable with D2O], 7.01–8.02 [m, 7H, Ar-H]. 13C-NMR
(DMSO-d6): 17.70, 55.91 (2C), 66.32, 114.83, 115.54, 116.12,
116.61, 117.40, 119.42, 121.61, 124.23 (2C), 130.14, 134.81,
135.30, 148.22, 151.21, 152.74, 152.90, 167.81, 177.62,
198.43. Anal. Calcd for C23H18N6O5: C, 60.26; H, 3.96; N,
18.33. Found: C, 60.50; H, 3.60; N, 18.00.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-4-
(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile,
5h. Yield, 66%; m.p. 170–172ꢁC; IR (KBr, cmꢀ1): 3372, 3354
(NH2), 3070 (CH arom.), 2942, 2870 (CH aliph.), 2219
(CBN), 1689 (C¼¼O), 1598 (C¼¼N). 1H NMR (DMSO-d6) d:
2.02 [s, 3H, CH3], 3.70 [s, 6H, 2OCH3], 6.81 [s, 2H, NH2
exchangeable with D2O], 6.92–8.31 [m, 7H, Ar-H]. MS m/z
(%) 458 [Mþ] (3.3), 40 (100). Anal. Calcd for C23H18N6O5: C,
60.26; H, 3.96; N, 18.33. Found: C, 60.50; H, 4.20; N, 18.60.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-4-(4-
hydroxy-3-methoxy-phenyl)-2-oxo-1,2-dihydropyridine-3,5-dicar-
bonitriles, 5i. Yield, 56%; m.p. 96–98ꢁC; IR (KBr, cmꢀ1):
3430 (OH), 3336, 3280 (NH2), 3066 (CH arom.), 2940, 2837
(CH aliph.), 2214 (CBN), 1654 (C¼¼O), 1597 (C¼¼N). 1H
NMR (DMSO-d6) d: 2.10 [s, 3H, CH3], 3.71, 3.82 [2s, 9H,
3OCH3], 6.50 [s, 2H, NH2 exchangeable with D2O], 6.81–7.72
[m, 6H, Ar-H], 9.80 [s, 1H, OH]. MS m/z (%) 459 [Mþ] (4.9),
40 (100). Anal. Calcd for C24H21N5O5: C, 62.74; H, 4.61; N,
15.24. Found: C, 62.40; H, 4.90; N, 15.50.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-4-(2,4–
5-trimethoxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile,
5j. Yield, 68%; m.p. 249–251oC; IR (KBr, cmꢀ1): 3384, 3341
(NH2), 3067 (CH arom.), 2942, 2837 (CH aliph.), 2188
(CBN), 1707 (C¼¼O), 1639 (C¼¼N). 1H NMR (DMSO-d6) d:
2.11 [s, 3H, CH3], 3.71, 3.82 [2s, 15H, 5OCH3], 6.40 [s, 2H,
NH2 exchangeable with D2O], 6.81–7.22 [m, 5H, Ar-H]. 13C-
NMR (DMSO-d6): 20.20, 55.64 (2C), 56.31, 56.72, 84.12,
107.31, 113.14, 113.40, 114.01, 115.02, 115.63, 116.13 (2C),
117.84, 119.52, 141.41, 151.50, 152.82, 153.74, 155.91 (2C),
159.63, 165.43, 188.64, 198.42. MS m/z (%) 503 [Mþ] (2.6),
46 (100). Anal. Calcd for C26H25N5O6: C, 62.02; H, 5.00; N,
13.91. Found: C, 62.40; H, 5.30; N, 13.60.
1559 (C¼¼N). H NMR (DMSO-d6) d: 1.71 [s, 3H, CH3], 3.72
[s, 6H, 2OCH3], 6.82 [s, 2H, NH2 exchangeable with D2O],
6.91–7.60 [m, 8H, Ar-H]. 13C-NMR (DMSO-d6): 20.41, 55.62
(2C), 80.71, 114.70, 115.33, 115.82 (2C), 116.11, 117.44,
119.51, 126.20, 127.81, 128.62 (2C), 133.41, 150.71, 152.12,
152.81, 161.20 (2C), 164.62, 198.41. MS m/z (%) 413 [Mþ]
(5.5), 44 (100). Anal. Calcd for C23H19N5O3: C, 66.82; H,
4.63; N, 16.94. Found: C, 66.50, H, 4.40; N, 16.70.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-2-oxo-
4-P-tolyl-1,2-dihy-dropyridine-3,5-dicarbonitrile, 5b. Yield, 71%;
m.p. 96–98ꢁC; IR (KBr, cmꢀ1): 3334, 3212 (NH2), 3094 (CH
arom.), 2957, 2854 (CH aliph.), 2216 (CBN), 1654 (C¼¼O),
1
1599 (C¼¼N). H NMR (DMSO-d6) d: 1.81 [s, 3H, CH3], 2.32
[s, 3H, CH3 tolyl], 3.73 [s, 6H, 2OCH3], 6.82 [s, 2H, NH2
exchangeable with D2O], 6.91–7.52 [m, 7H, Ar-H]. 13C-NMR
(DMSO-d6): 20.41, 24.32, 55.43 (2C), 74.93, 114.84 (2C),
115.32, 115.91, 116.30, 117.41, 119.51, 126.32, 128.02,
129.61, 137.10, 152.22 (2C), 154.52, 159.63, 160.44 (2C),
182.61, 198.42. MS m/z (%) 427 [Mþ] (1.1), 47 (100). Anal.
Calcd for C24H21N5O3: C, 67.44; H, 4.95; N, 16.38. Found: C,
67.10; H, 4.60; N, 16.70.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-4-(4-
hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile,
5c. Yield, 65%; m.p. 128–130ꢁC; IR (KBr, cmꢀ1): 3410 (OH),
3326, 3206 (NH2), 3056 (CH arom.), 2942, 2836 (CH aliph.),
2216 (CBN), 1653 (C¼¼O), 1607 (C¼¼N). 1H NMR (DMSO-
d6) d: 1.81 [s, 3H, CH3], 3.72 [s, 6H, 2OCH3], 6.63 [s, 2H,
NH2 exchangeable with D2O], 6.71–7.92 [m, 7H, Ar-H], 10.71
[s, 1H, OH]. 13C-NMR (DMSO-d6): 20.41, 55.40 (2C), 80.62,
114.11, 115.02, 115.73, 116.21, 117.40, 119.52, 126.31 (2C),
128.12, 152.82 (2C), 153.53, 154.71, 159.44 (2C), 159.81,
160.41, 198.42 (2C). MS m/z (%) 429 [Mþ] (6.8), 47 (100).
Anal. Calcd for C23H19N5O4: C, 64.33; H, 4.46; N, 16.31.
Found: C, 64.70; H, 4.10; N, 16.60.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-4-(4-
methoxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile,
5d. Yield, 76%; m.p. 120–122ꢁC; IR (KBr, cmꢀ1): 3334, 3208
(NH2), 3082 (CH arom.), 2957, 2837 (CH aliph.), 2215
(CBN), 1662 (C¼¼O), 1605 (C¼¼N). 1H NMR (DMSO-d6) d:
1.80 [s, 3H, CH3], 3.72, 3.80 [2s, 9H, 3OCH3], 6.64 [s, 2H,
NH2 exchangeable with D2O], 6.71–7.52 [m, 7H, Ar-H]. 13C-
NMR (DMSO-d6): 20.40, 56.31 (2C), 74.92, 114.00, 114.91,
115.32 (2C), 115.63, 116.14 (2C), 117.44, 119.52, 125.31,
128.10, 152.24, 154.73, 158.91, 159.40 (2C), 160.14, 160.71
(2C), 160.82. MS m/z (%) 443 [Mþ] (5.9), 44 (100). Anal.
Calcd for C24H21N5O4: C, 65.00; H, 4.77; N, 15.79. Found: C,
65.30; H, 4.40; N, 15.50.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-2-oxo-
4-styryl]-1,2-dihydro-pyridine-3,5-dicarbonitrile, 5e. Yield, 69%;
m.p. 130–132ꢁC; IR (KBr, cmꢀ1): 3380, 3348 (NH2), 3067
(CH arom.), 2940, 2860 (CH aliph.), 2218 (CBN), 1680
(C¼¼O), 1636 (C¼¼N). 1H NMR (DMSO-d6) d: 2.11 [s, 3H,
CH3], 3.70 [s, 6H, 2OCH3], 6.51 [s, 2H, NH2 exchangeable
with D2O], 6.61, 6.70 [d, 2H, CH¼CH, J ¼ 7.7, Hz], 6.90–
7.81 [m, 8H, Ar-H]. 13C-NMR (DMSO-d6): 18.50, 55.41
(2C), 66.34, 95.32, 114.03, 115.81 (2C), 116.32, 117.40,
119.52, 126.41, 128.13, 128.64, 129.31 (2C), 137.52, 137.90
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Synthesis and Antitumor Activity of Some Novel Hydrazide, 1,2-Dihydropyridine,
Chromene, and Benzochromene Derivatives
279
have been made available by the National Center for Radiation
Research and Technology (NCRRT), Atomic Energy Authority
(AEA), Cairo, Egypt. Animal care and handling was done
according to the guidelines set by the world heath organiza-
tion, Geneva, Switherland and approved from the committee
for animals care at NCRRT, AEA.
In-vitro antitumor activity. EAC cells were obtained by
needle aspiration of the ascetic fluid from preinoculated mice;
under aseptic conditions [32]. Tumor cells suspension (2.5 ꢂ
106 per mL) was prepared in RPMI-1640 media. Tested com-
pounds were prepared with various dilutions by dissolving:
100, 50, 25, 10 lg of the tested compounds in DMSO (1 mL).
In a set of sterile test tubes 0.8 mL RPMI-1640 media con-
taining (glutamine, fetal calf serum as nutrient, streptomycin
and penicillin), 0.1 mL of each of the tested compounds (cor-
responding to 100, 50, 25, 10 lg) were mixed then 0.1 mL of
tumor cell suspension (2.5 x 105) was added. The test tubes
were incubated at 37ꢁC for 2h. Trypan blue exclusion test was
carried out to calculate the percentage of nonviable cells after
2h of incubation [33,34].
6-Amino-4-(2,4-dichlorophenyl)-1-[1-(2,5-dimethoxyphenyl)
ethylideneamino)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile,
5k. Yield, 71%; m.p. 110–112ꢁC; IR (KBr, cmꢀ1): 3316, 3260
(NH2), 3084 (CH arom.), 2939, 2835 (CH aliph.), 2218
(CBN), 1675 (C¼¼O), 1588 (C¼¼N), 741 (CACl). 1H NMR
(DMSO-d6) d: 2.20 [s, 3H, CH3], 3.71 [s, 6H, 2OCH3], 6.62
[s, 2H, NH2 exchangeable with D2O], 6.91–7.84 [m, 6H,
Ar-H]. 13C-NMR (DMSO-d6): 22.71, 55.62 (2C), 74.84,
114.71, 115.30, 115.92, 116.43, 117.54, 119.41, 126.10,
129.41, 131.14, 133.51, 134.52, 135.54, 151.81 (2C), 152.82,
156.10, 156.42, 158.84, 198.32. MS m/z (%) 482 [Mþ] (1.43),
48 (100). Anal. Calcd for C23H17Cl2N5O3: C, 57.27; H, 3.55;
N, 14.52. Found: C, 57.50; H, 3.20; N, 14.20.
6-Amino-1-[1-(2,5-dimethoxyphenyl)ethylideneamino)-4-(2-
methoxynaphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3,5-dicar-
bonitrile, 5l. Yield, 69%; m.p. 94–96ꢁC; IR (KBr, cmꢀ1): 3414,
3380 (NH2), 3100 (CH arom.), 2940, 2838 (CH aliph.), 2218
(CBN), 1669 (C¼¼O), 1623 (C¼¼N). 1H NMR (DMSO-d6) d:
2.00 [s, 3H, CH3], 3.71 [s, 9H, 3OCH3], 6.92 [s, 2H, NH2
exchangeable with D2O], 6.91–8.32 [m, 9H, Ar-H]. 13C-NMR
(DMSO-d6): 18.31, 55.42 (2C), 56.84, 74.62, 113.43, 114.00,
114.81, 115.12, 115.31, 115.52, 116.41, 119.50, 123.44, 124.51,
126.92, 128.51, 129.70, 130.22, 132.41, 151.41 (2C), 152.90,
155.14, 155.62, 162.93, 163.21, 198.44. MS m/z (%) 493 [Mþ]
(1.32), 46 (100). Anal. Calcd for C28H23N5O4: C, 68.14; H,
4.70; N, 14.19. Found: C, 68.40; H, 4.30; N, 14.50.
No. of non-viable cells
% of non- viable cells ¼
ꢂ 100
Total No. of cells
The results of in-vitro cytotoxic activity experiments are
presented in Table (1). Compounds producing more than
70% of nonviable cells were considered active [35].
N0[1-(2,5-dimethoxyphenyl)ethylidene)-2-oxo-2H-chromene-3-
carbohydrazide, 6 and N0 [1-(2,5-dimethoxyphenyl)ethylidene)-
3-oxo-3H-benzo[f]chromene-2-carbohydrazide, 7. A mixture of
2a (2.61 g, 0.01 mol) and either salicyldehyde or 2-hydroxy-1-
naphthaldehyde (0.01 mol) in dioxane (30 mL) containing
piperidine (0.5 mL) was refluxed for 3 h. The reaction mixture
was poured onto ice water containing few drops of HCl and
the obtained solid was crystallized from dioxane to give 6 and
7, respectively.
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1
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7: Yield, 69%; m.p. 293–295ꢁC; IR (KBr, cmꢀ1): 3273
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