Design, Synthesis, and In Vitro Antileishmanial and Antitumor Activities of New Tetrahydroquinolines

Article abstract of DOI:10.1002/jhet.3046

A novel series of tetrahydroquinolines containing acetohydrazide, oxopyrazole, oxothioxodihydropyrazole, and thioxotriazole have been synthesized. Antileishmanial, antitumor, and cytotoxicity activities of synthesized compounds were evaluated in vitro. Antileishmanial activity of the most synthesized compounds showed tremendous activity towards Leishmania major. Most of the test compounds exhibited significant level of tumor inhibition. The tetrahydropyrano[2,3-b]quinolin-2-one 6 and 4-oxo-4H-pyrazol-3-yloxytetrahydroquinoline-3-carbonitrile derivatives 18 showed 100% tumor inhibition comparable with standard drug vincristine (100% tumor inhibition). Tetrahydroquinolines under investigation showed cytotoxicity with LD₅₀ values in the range 0.56–3.01?μg/mL compared with standard drug MS-222 with LD₅₀ value of 4.30?μg/mL. The presence of a pyrazole ring markedly improved the activity profiles of tetrahydroquinoline. All newly synthesized compounds were characterized by IR, ¹H NMR, and MS.

Full text of DOI:10.1002/jhet.3046

Month 2017
Design, Synthesis, and In Vitro Antileishmanial and Antitumor Activities
of New Tetrahydroquinolines
a
a
a
*
Hassan Mohamed Fawzy Madkour, Maher Abd El-Aziz Mahmoud El-Hashash, Marwa Sayed Salem,
Al-Shimaa Omar Ali Mahmoud,a and Yasser M. A. S. Al-Qahramanb
aSynthetic Organic Chemistry Laboratory, Chemistry Department, Faculty of Science, Ain Shams University, Abbasiya,
Cairo 11566, Egypt
bDepartment of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan
*
E-mail: marwa_k@sci.asu.edu.eg
Received July 25, 2017
DOI 10.1002/jhet.3046
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Ar
O
CN
O
N
N
N
Ph
PhCOCl
Ar
N
Ar
Ar
N
CN
O
CN
O
CN
O
O
O
S
AcOH
CS2, KOH, EtOH
NH2
H
NH
NH
N
N
N
N
O
H3C
A
novel
series
of
tetrahydroquinolines
containing
acetohydrazide,
oxopyrazole,
oxothioxodihydropyrazole, and thioxotriazole have been synthesized. Antileishmanial, antitumor, and
cytotoxicity activities of synthesized compounds were evaluated in vitro. Antileishmanial activity of the
most synthesized compounds showed tremendous activity towards Leishmania major. Most of the test
compounds exhibited significant level of tumor inhibition. The tetrahydropyrano[2,3-b]quinolin-2-one 6
and 4-oxo-4H-pyrazol-3-yloxytetrahydroquinoline-3-carbonitrile derivatives 18 showed 100% tumor
inhibition comparable with standard drug vincristine (100% tumor inhibition). Tetrahydroquinolines under
investigation showed cytotoxicity with LD50 values in the range 0.56–3.01 μg/mL compared with standard
drug MS-222 with LD50 value of 4.30 μg/mL. The presence of a pyrazole ring markedly improved the
1
activity profiles of tetrahydroquinoline. All newly synthesized compounds were characterized by IR, H
NMR, and MS.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
biological and pharmaceutical activities [8,9], including
anti-HIV [10,11], anticancer [12,13], antimalarial [14],
cholesteryl ester transfer protein inhibitors [15], and
antidiabetic [16]. Among various tetrahydroquinolines,
biological profile of 1,2,3,4-tetrahydroquinolines and
5,6,7,8-tetrahydro-quinolines is extensively studied.
Recently, the 5,6,7,8-tetrahydroquinolines have drawn
considerable attention due to their interesting
pharmacological applications as Rearranged during
Transfection (RET) tyrosine kinase inhibitors [17],
antifungal [18], anticancer [19], anti-HIV [20,21], and C5
a receptor antagonists agents [22].
Pyrazole derivatives are an important class of
heterocyclic systems because of their highly appreciable
biological and pharmacological activities. Several
pyrazole compounds have been reported to be potential
therapeutic agents for the treatment of inflammation
[23,24], antitumor properties [25], and AIDS [26]. Hence,
Quinoline is a heterocyclic system of remarkable
importance to mankind. Several quinolones that have
been isolated from natural resources or synthetically
prepared are significant for the sake with respect to
medicinal chemistry and biomedical use. Compounds
containing quinoline moiety are most widely used as
antimalarials [1–3], antibacterials [4], antifungals [5],
anticancer [6], and antileismanial agents [7]. Moreover,
quinoline derivatives are utilized in the design and
construction of fungicides, virucides, biocides, alkaloids,
rubber chemicals, and flavoring agents [5]. Because of
their importance as substructures in a broad range of
natural and designed products, significant efforts continue
to be directed into the development of new quinoline-
based structures.
Tetrahydroquinolines, as quinoline derivatives, represent
an important structural subunit of natural products, and
many tetrahydroquinoline derivatives show interesting
with
a view of further estimate and rating the
pharmacological profile of this class of heterocycles, the
© 2017 Wiley Periodicals, Inc.

H. M. F. Madkour, M. A. E.-A. M. El-Hashash, M. S. Salem,
A.-S. O. A. Mahmoud, and Y. M. A. S. Al-Qahraman
Vol 000
authors were prompted to synthesize some new
heterocycles by incorporating the tetrahydroquinolines
and pyrazole moieties in a single molecular framework.
present). 1H NMR revealed the disappearance of NH
signal and appearance of OH and CH signals of
OH–C = CH–Cl at 12.28 and 3.54 ppm, respectively. The
formation of products 2 and 3 could be explained via the
polarity of the solvent used. In the presence of the less
polar acetone, compound 1 reacts with the electrophilic
haloester in more electrophilic center via SN2 mechanism
with elimination of HCl to give O-alkylated product 2. In
the presence of more polar DMF, 2-pyridone 1 reacts
with the electrophilic haloester in less electrophilic
carbonyl carbon of ester group by tetrahedral mechanism
to lose off ethanol molecule to afford the 2-chloroacetate 3.
The structure of O-alkylated product 2 and 2-
chloroacetate 3 was chemically verified via hydrazinolysis
with hydrazine hydrate in boiling ethanol to give the
RESULTS AND DISCUSSION
Chemistry.
In continuation of our previous works
[27–32], the present work aimed at utilization of the
reactivity of 4-(4-methoxyphenyl)-2-oxo-1,2,3,4,5,6,7,8-
octahydroquinoline-3-carbonitrile
1 towards different
electrophilic and nucleophilic reagents to obtain new fused
and nonfused heterocyclic systems and evaluate them for
antileishmanial, antitumor, and antimicrobial activities.
The starting material 2-pyridone 1 was prepared via
reaction of cyclohexanone, 4-methoxybenzaldehyde,
ethyl cyanoacetate, and ammonium acetate in ethanol
[33]. An example that illustrates the effect of changing
reaction conditions on the nature of the reaction product
in preparative organic chemistry was obtained when
2-pyridone 1 reacted with ethyl chloroacetate in dry
acetone containing anhydrous potassium carbonate to
afford O-alkylated product 2 (cf. Scheme 1). On the
other hand, when 2-pyridone 1 was allowed to react
with ethyl chloroacetate in dimethyl formamide (DMF)
3-cyano-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinolin-
2-yl 2-chloroacetate 3 was isolated. The structure of
compound 3 was confirmed from spectroscopic data and
qualitative and quantitative elemental analyses (Cl is
corresponding acetohydrazide derivative
4
and 2-
hydrazinylacetate derivative 5, respectively. The structural
features of 2-chloroacetate 3 have been chemically proven
via cyclization under the effect of alcoholic potassium
hydroxide solution (10%) to afford tetrahydropyrano[2,3-
b]quinolin-2-one 6. The IR spectrum of 6 displayed
absorption bands at 3420, 3350 cmꢀ1 because of
asymmetric and symmetric stretching of NH2 group and
1
νC=O lactone at 1738. H NMR showed the appearance of
NH2 signal at 4.31 ppm that is exchangeable with D2O.
Thiation of 2-pyridone 1 by phosphorous pentasulfide in
dry toluene gave thione derivative 7. The structure of
thiated product 7 has been confirmed by spectral data. IR
spectrum showed the disappearance of νC=O and
Scheme 1. Reactions of 2-pyridone 1 with different electrophiles.
Ar
Ar
CN
O
CN
O
(i)
(iii)
Cl
OEt
NHNH2
N
2
N
4
O
O
COOEt
Ar
CN
(iii)
O
Ar
CN
N
O
CH2NHNH2
(ii)
O
5
Cl
Ar NH2
N
O
Cl
O
3
(iv)
Ar
N
Ar
N
Ar
N
O
CN
S
CN
O
CN
S
(v)
6
(vi)
OEt
N
8
H
7
Ar
H
1
O
(vii)
CN
Ar =
OCH3
N
H
OCOR
9, R = CH3
10, R = Ph
(i) K2CO3,acetone, reflux for 30h; (ii) K2CO3, DMF, reflux for 9h; (iii) N2H4.H2O, EtOH reflux for 11h; (iv) 10% alc.
KOH reflux for 6h; (v) P2S5 ,toluene reflux for 4h; (vi) ClCH2COOEt, CH3COONa, EtOH, reflux for 4 h; (vii)
Ac2O,and / or PhCOCl, pyridine, reflux for 5h
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Design, Synthesis, and In Vitro Antileishmanial and Antitumor Activities of New
Tetrahydroquinolines
Scheme 2. Synthesis of O-methylated product 11.
appearance of νNH, νC°N, and νC=S at 3164, 2221, and
1258 cmꢀ1, respectively. 1H NMR showed SH signal
at 5.57 ppm exchangeable with D2O. Further,
EI-fragmentation pattern showed the molecular ion peak
at m/z: 296 as the base peak. Treatment of thione
derivative 7 with ethyl chloroacetate in the presence of
anhydrous sodium acetate furnished ethyl 2-(3-cyano-4-
(4-methoxyphenyl)-3,4,5,6,7,8-hexahydroquinolin-2-ylthio)
acetate 8. Acetylation and/or benzoylation of 2-pyridone 1
with acetic anhydride and/or benzoyl chloride did
not afford the expected 1-aroyl/acetyl-2-oxo-1,2-
dihydropyridine derivative [34]. Surprisingly, the
reaction afforded hexahydroquinoline-2-ylacetate 9 and
Ar
Ar
CN
OH
CN
N
H
N
H
O
1
Ar
(ii)
CN
(i)
(iv)
N
OCH3
(iii)
H
Ar =
OCH3
11
hexahydroquinolin-2-yl
benzoate
10
derivatives,
respectively. The ester derivatives 9 and 10 were inferred
from their IR spectra that displayed the carbonyl band
expected for ester group, NH group, and disappearance of
the carbonyl group of 2-pyridone. H NMR showed NH
and benzylic-H signals.
ethoxyacrylate, and carbon disulfide, to afford pyrazole
derivatives 14–16, respectively.
1
The present work has been extended to study the effect
of aliphatic acids, namely, formic and/or acetic acid on
acetohydrazide derivative 4 to afford 4-oxo-4H-pyrazol-
3-yloxytetrahydro-quinoline-3-carbonitrile derivatives 17
and 18, respectively. When acetohydrazide derivative 4
was allowed to react with phenyl isothiocyanate in
pyridine at its boiling point, and/or α-D-glucose
pentaacetate in refluxing ethanol, 5-thioxo-4,5-dihydro-
1H-1,2,4-triazol-3-yltetrahydroquinoline derivative 19,
and N0-glucopyranosyl acetohydrazide derivative 20 were
obtained, respectively (cf. Scheme 3).
As a point of interest, 2-methoxy-4-(4-methoxyphenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 11 has been
obtained via reaction of 2-pyridone 1 with three different
reagents, namely, ethyl chloroacetate, chloroacetic acid,
or/and chloroacetyl chloride under the same reaction
conditions in absolute ethanol containing anhydrous
sodium acetate. According to our speculation,
O-methylation is preferred than N-methylation as
O-methylated product is more thermodynamically stable
than N-methylated product because of the conjugation
of the formed C=C with the cyano functionality. In all
cases, the reaction takes place via the nucleophilic
attack of enolic hydroxyl group on the electronically
deficient carbon of the methylene group of the reagent
followed by hydrolysis to acid in case of ethyl
Biological activity. Antileishmanial activity.
In the
present study on the synthesized heterocyclic compounds
against Leishmania major, it is evidenced from Table 1 and
Figure 1 that a series of heterocyclic compounds showed
tremendous activity. Acetohydrazide derivative 4,
hydrazinylacetate derivative 5, tetrahydropyrano[2,3-b]
quinolin-2-one 6, and oxopyrazol derivatives 12, 14, and
16–18 have shown significant activity against L. major
chloroacetate
and
chloroacetyl
chloride
then
decarboxylated to give O-methylated product 11. The
structure of 11 was chemically confirmed by comparison
with an authentic sample (mp, mixed mp, and TLC)
prepared from O-methylation of 2-pyridone 1 using
methyl iodide in refluxing acetone and anhydrous
K2CO3 (cf. Scheme 2).
with IC50 value of 0.59
0.07 and 0.58
0.08,
respectively compared with amphotericin B (standard drug)
IC50 value (0.56 0.20). The presence of a pyrazole ring
markedly
improved
the
activity
profiles
of
tetrahydroquinoline. On the other hand, further
tetrahydroquinoline derivatives 2, 3, 11, and
hexahydroquinoline 7–10 showed a good activity against
L. major with IC50 value of 0.60 0.09 and 0.62 0.09,
respectively.
Pyrazole derivatives have attracted continued interest
because of their use as an important core structure in
many drug substances, having
a wide range of
pharmacological applications [35–38]. The authors were
promoted to utilize the amino functionality of
acetohydrazide derivative 4 in the design and synthesis of
new heterocyclic systems incorporating pyrazole nucleus.
Thus, acetohydrazide derivative 4 has been allowed to
react with benzoyl chloride and/or benzoic acid in the
presence of phosphorous oxychloride to afford pyrazole
12 and dihydropyrazole 13 derivatives, respectively. On
the other hand, acetohydrazide derivative 4 has been
allowed to react with acetyl acetone, ethyl 2-cyano-3-
Antitumor activity.
The crown gall is a neoplastic
disease of plants that is initiated by the Gram-positive
bacteria Agrobacterium tumefaciens. Because the
mechanism of tumor induction resembles to that in
animals, this test has been used previously to prescreen
antitumor activity of natural and synthetic compounds.
According to the data shown in Table 2 and Figure 2, most
test compounds of this series showed significant level of
tumor inhibition. The tetrahydropyrano[2,3-b]quinolin-2-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. M. F. Madkour, M. A. E.-A. M. El-Hashash, M. S. Salem,
A.-S. O. A. Mahmoud, and Y. M. A. S. Al-Qahraman
Vol 000
Scheme 3. Reactions of acetohydrazide derivative 4 with different electrophile reagents.
O
N
(i)
R
N
Ph
12
Ph
NH
(ii)
R
NH
O
CH
13
N
N
(iii)
R
CH
O
14
Ar
N
CN
O
COOEt
N
(iv)
H
R
N
N
NH
NH
O
4
O
15
O
N
OCH
Ar =
(v)
R
N
S
16
N
(vi)
N
R
O
17
O
R
NH
NH
(vii)
H C
18
N
R
NH
N
(viii)
Ph
S
19
AcO
AcO
OAc
AcO
Ar
N
O
H
N
N
H
(ix)
CN
O
R
R =
O
20
one 6 and 4-oxo-4H-pyrazol-3-yloxytetrahydroquinoline-
3-carbonitrile derivatives 18 showed 100% tumor
inhibition that is comparable with standard drug
vincristine (100% tumor inhibition).
Brine shrimp lethality assay. The cytotoxic activities of
synthetic compounds are shown in Table 3 and Figure 3.
The LD50 data showed that most of the compounds are
cytotoxic with LD50 values in the range 0.56–3.01 μg/mL
compared with standard drug MS-222 with LD50 value of
4.30 μg/mL. From Table 3, it is showed that compounds
5, 6, 12, 14, and oxopyrazol derivatives 16–18 are most
cytotoxic to brine shrimps with LD50 values in the range
0.56–3.01 μg/mL comparatively with standard drug
MS-222 with LD50 value of 4.30 μg/mL. On other hand,
from Table 3, it is evidence that tetrahydroquinolines
2–4, 11 and hexahydroquinolines 7–10 showed good
LD50 values of 3.01–0.85 μg/mL compared with standard
drug MS-222 with LD50 value of 4.30 μg/mL.
EXPERIMENTAL
All melting points were measured on a Gallenkamp
melting point apparatus and are uncorrected. The infrared
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Design, Synthesis, and In Vitro Antileishmanial and Antitumor Activities of New
Tetrahydroquinolines
Table 1
Percent inhibition of synthetic compounds against Leishmania major
Table 2
Antitumor activity of synthetic compounds
Compound no.
L. major
Average number of
tumorsa SE
Percent inhibition
,
Compound no.
of tumorsb c
2
3
4
5
6
7
8
9
10
11
12
14
16
17
18
0.60 0.09
0.60 0.09
0.59 0.09
0.59 0.09
0.59 0.09
0.59 0.09
0.60 0.09
0.62 0.09
0.61 0.09
0.68 0.09
0.58 0.09
0.58 0.09
0.59 0.09
0.58 0.09
0.58 0.09
0.56 0.20
2
3
4
5
6
7
8
9
10
11
12
14
16
17
18
2.8 0.89
1.8 0.679
1.2 0.727
1.0 0.36
0.0 0.0
4.8 1.13
4.2 1.04
3.9 1.02
3.9 1.02
4.1 0.948
1.0 0.36
0.9 0.456
0.9 0.456
0.8 0.388
0.0 0.0
62.66
76.31
85.54
86.66
100
36.31
44.59
48.67
48.32
50.60
86.66
88.16
88.16
89.12
100
Standard drug IC50 (μg/mL SD) amphotericin B
Vincristine
Vehicle control:
DMSO
0.0 0.0
8.3 0.931
100
Percent inhibition activity: 0.99 0.00 = nonsignificant; 0.95–0.80 = low;
0.79–0.70 = moderate; 0.69–0.60 = good; <0.59–0.56 = significant.
aPotato disc antitumor assay, concentration: 1000 μg/mL in DMSO.
bMore than 20% tumor inhibition is significant.
spectra were recorded using potassium bromide disks on a
PyeUnicam SP-3-300 infrared spectrophotometer. 1H
NMR experiments were run at 300 and 400 MHz on a
Varian Mercury VX-300 and a Varian Mercury VX-400
NMR spectrometer using TMS as internal standard in
CDCl3 or DMSO-d6. Chemical shifts are quoted as δ.
The mass spectra were recorded on Shimadzu GCMS-
QP-1000EX mass spectrometers at 70 eV. All spectral
measurements were carried out at Central laboratory of
Ain-Shams University and Main Defense Chemical
Laboratory, Egypt. All the newly synthesized compounds
gave satisfactory elemental analyses. The purity of the syn-
thesized compounds was checked by TLC.
cData represent mean value of 15 replicates.
water bath for 30 h, left to cool, and poured into ice-cold
water. The crude solid product that deposited was
collected, washed with water, and recrystallized
from ethanol to give tetrahydroquinolinyloxyacetate
derivative 2 as yellow crystals, mp 145–147°C, yield
82%. FT-IR (KBr, cmꢀ1): 3126 νCH aromatic, 2938
νCH aliphatic, 2223 νC°N,1736 νC=O ester, 1631 νC=N
.
1H NMR (400 MHz, DMSO-d6): 7.25–6.97 (m, 4H,
Ar–H), 4.88 (s, 2H, OCH2), 4.29 (q, 2H, CH2CH3,
J = Hz), 3.84 (s, 3H, OCH3), 2.63–1.60 (m, 8H,
cyclohexene ring protons), 1.3 (t, 3H, CH2CH3,
Synthesis. Ethyl 2-(3-cyano-4-(4-methoxyphenyl)-5,6,7,8-
tetrahydroquinolin-2-yloxy)acetate (2).
A mixture of 2-
pyridone 1 (5 mmol, 1.41 g), anhydrous K2CO3 (5 mmol,
0.69 g), and ethyl chloroacetate (5 mmol, 0.6 mL) in dry
acetone (30 mL) was heated at reflux temperature on
J = Hz). MS m/z (%): 366 (M
C21H22N2O4 (366.41): C, 68.84; H, 6.05; N, 7.65.
Found: C, 68.67; H, 6.01; N, 7.54.
̇
Figure 1. Percent inhibition of synthetic compounds against Leishmania major. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. M. F. Madkour, M. A. E.-A. M. El-Hashash, M. S. Salem,
A.-S. O. A. Mahmoud, and Y. M. A. S. Al-Qahraman
Vol 000
Figure 3. Brine shrimps lethality assay1 of synthetic compounds.
Figure 2. Antitumor activities of compounds 2–18 compared with vin-
cristine. [Color figure can be viewed at wileyonlinelibrary.com]
exchangeable), 7.25–7.02 (m, 4H, Ar–H), 3.79 (s, 3H,
OCH3), 3.54 (s, 1H, OH–C=CH–Cl), 2.59–1.51 (m, 8H,
cyclohexene ring protons). MS m/z (%): 356 (M
Anal. Calcd for C19H17ClN2O3 (356.8): C, 63.96; H,
̇
Table 3
4.80; Cl, 9.94; N, 7.85. Found: C, 63.78; H, 4.59; Cl,
9.77; N, 7.69.
Brine shrimps lethality assaya of synthetic compounds
Reaction of tetrahydroquinolinyloxyacetate derivative
Numbers of shrimps killed out of 30
Compound no.
2
and/or
tetrahydroquinolin-2-yl
hydrate.
2-chloroacetate
3
with
hydrazine
To
a
solution of
Serial dilutions
of compounds
1000 μg/
100 μg/
10 μg/
LD50
mL
mL
mL
(μg/mL)
tetrahydroquinolinyloxyacetate derivative
2
and/or
tetrahydroquinolin-2-yl 2-chloroacetate 3 (5 mmol) in
ethanol (30 mL), hydrazine hydrate was added (5 mmol,
0.25 mL), and the reaction mixture was heated at reflux
for 11 h and left to cool, and the solid product was
collected, dried, and recrystallized from dioxane to give
acetohydrazide 4 and 2-hydrazinylacetate derivatives 5,
2
3
4
5
6
7
8
9
10
11
12
14
16
17
18
28
30
28
30
30
30
28
25
30
29
30
30
30
30
30
00
25
26
25
27
27
26
25
22
26
24
27
27
27
27
27
00
20
22
21
24
24
23
20
17
22
20
24
24
24
24
24
00
0.92
1.23
0.85
0.56
0.56
0.95
0.92
3.01
1.63
0.94
0.56
0.56
0.56
0.56
0.56
respectively.
2-(3-Cyano-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinolin-
2-yloxy)acetohydrazide (4).
Yellow crystals, mp 175–
177°C, yield 84%. FT-IR (KBr, cmꢀ1): 3431, 3299 νNH2
3193 νNH, 3029 νCH aromatic, 2933 νCH aliphatic, 2219
C°N, 1646 νC=O, 1609 νC=N
1H NMR (400 MHz,
,
ν
.
DMSO-d6): 11.72 (s, 1H, NH, D2O exchangeable),
7.25–7.06 (m, 4H, Ar–H), 4.03 (s, 2H, OCH2CO), 3.81
(s, 3H, OCH3), 3.36 (s, 2H, NH2, D2O exchangeable),
2.88–1.63 (m, 8H, cyclohexene ring protons). MS m/z
Control negative
DMSO
aThe data are based on mean value of three replicates each of 10, 100, and
1000 μg/mL compared with the standard drug MS-222 (LD50 = 4.30 μg/
mL).
(%): 352 (M
̇
(352.39): C, 64.76; H, 5.72; N, 15.90. Found: C, 64.68;
H, 5.81; N, 15.85.
3-Cyano-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinolin-2-
3-Cyano-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinolin-2-
yl 2-chloroacetate (3). A mixture of 2-pyridone 1 (5 mmol,
yl-2-hydrazinylacetate (5).
Pale red crystals, mp over
300°C, yield 70%. FT-IR (KBr, cmꢀ1): 3431, 3299 νNH2
3193 νNH, 3026 νCH aromatic, 2932 νCH aliphatic, 2209
C°N, 1649 νC=O, 1608 νC=N
1H NMR (400 MHz,
1.41 g), anhydrous K2CO3(5 mmol, 0.69 g), and ethyl
chloroacetate (5 mmol, 0.6 mL) in DMF (25 mL)
was heated at reflux 9 h, left to cool, and poured into ice-
cold water. The crude solid product was collected,
washed with water, and recrystallized from petroleum
ether (80–100°C) to give tetrahydroquinolin-2-yl-2-
chloroacetate 3 as a pale brown crystal, mp 280–280°C,
yield 62%. FT-IR (KBr, cmꢀ1): 3012 νCH aromatic, 2938
,
ν
.
DMSO-d6): 11.72 (s, 1H, NH, D2O exchangeable),
7.25–7.06 (m, 4H, Ar–H), 4.03 (s, 2H, NH2, D2O
exchangeable), 3.81 (s, 3H, OCH3), 3.41 (s, 2H,
COCH2NHꢀ), 2.88–1.64 (m, 8H, cyclohexene ring
protons). MS m/z (%): 352 (M
þ , 65). Anal. Calcd for
1
νCH aliphatic, 2222 νC°N,1759 νC=O ester, 1649 νC=N. H
C19H20N4O3 (352.39): C, 64.76; H, 5.72; N, 15.90.
Found: C, 64.82; H, 5.65; N, 15.75.
NMR (400 MHz, DMSO-d6): 12.28 (s, 1H, OH, D2O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Design, Synthesis, and In Vitro Antileishmanial and Antitumor Activities of New
Tetrahydroquinolines
4-Amino-3-chloro-5-(4-methoxyphenyl)-6,7,8,9-
1.41 g) in acetic anhydride (10 mL) was heated at reflux
for 5 h, then left to cool and poured into ice-cold water
with stirring. The crude solid product that deposited was
collected by filtration, washed with water, dried, and
recrystallized from benzene to givehexahydroquinoline-2-
ylacetate 9 as pale brown crystals, mp 125–127°C, yield
75%. FT-IR (KBr, cmꢀ1): 3298 νNH, 3015 νCH aromatic,
tetrahydropyrano[2,3-b]quinolin-2-one (6).
A solution of
tetrahydroquinolin-2-yl 2-chloroacetate 3 (2.5 mmol,
0.89 g) in alcoholic sodium hydroxide 10% (10 mL) was
heated at reflux temperature for 6 h, left to cool, and
neutralized by dilute hydrochloric acid. The crude solid
product that deposited was collected, washed with water,
dried, and recrystallized from ethanol to give
2936 νCH aliphatic, 2224 νC°N,1783 νC=O ester, 1648
1
tetrahydropyrano[2,3-b]quinolin-2-one
6
as brown
ν
C=N. H NMR (300 MHz, DMSO-d6): 12.30 (s, 1H, NH,
crystals, mp 230–232°C, yield 62%. FT-IR (KBr, cmꢀ1):
3420, 3350 νNH2, 3071 νCH aromatic, 2935 νCH aliphatic,
D2O exchangeable), 7.27–6.92 (m, 4H, Ar–H), 3.82 (s,
3H, OCH3, benzylic-H), 3.75 (s, 3H, OCOCH3),
2.62–1.55 (m, 8H, cyclohexene ring protons). MS m/z
1738 νC=O lactone, 1659 νC=N.
1H NMR (400 MHz,
DMSO-d6): 7.34–6.95 (m, 4H, Ar–H), 4.31 (s, 2H, NH2,
D2O exchangeable), 3.81 (s, 3H, OCH3), 2.65–1.01 (m,
(%): 322 (M-2)
(324.37): C, 70.35; H, 6.21; N, 8.64. Found: C, 70.21; H,
̇
8H, cyclohexene ring protons). MS m/z (%): 356 (M
65). Anal. Calcd for C19H17ClN2O3 (356.8): C, 63.96; H,
4.80; Cl, 9.94; N, 7.85. Found: C, 63.87; H, 4.74; Cl,
̇
6.32; N, 8.57.
3-Cyano-4-(4-methoxyphenyl)-1,4,5,6,7,8-
hexahydroquinolin-2-yl benzoate (10).
A mixture of
2-pyridone 1 (5 mmol, 1.41 g) and benzoyl chloride
(5 mmol, 0.6 mL) in dry pyridine (20 mL) was heated on
water bath 5 h, then left to cool and neutralized by
diluted hydrochloric acid for complete precipitation. The
separated material was collected by filtration, washed
with water, dried, and recrystallized from ethanol to
afford hexahydroquinolin-2-yl benzoate 10 as pale yellow
crystals, mp 159–161°C, yield 63%. FT-IR (KBr, cmꢀ1):
9.86; N, 7.68.
4-(4-Methoxyphenyl)-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-
3-carbonitrile (7).
1.41 g) and phosphorous pentasulfide (5 mmol,
1.11 mL) in dry toluene (25 mL) was refluxed for
A mixture of 2-pyridone 1 (5 mmol,
4
h, then collect the solid on hot, dried, and
recrystallized from ethanol to give hexahydroquinoline 7
as pale orange crystals, mp 182–183°C, yield 43%.
FT-IR (KBr, cmꢀ1): 3164 νNH, 3068 νCH aromatic,
2938 νCH aliphatic, 2221 νC°N, disappearance of νC=O
1636 νC=N, 1258 νC=S
3340 νNH, 3011 νCH aromatic, 2938 νCH aliphatic, 2227
1
,
ν
C°N, 1738 νC=O ester, 1647 νC=N. H NMR (300 MHz,
.
1H NMR (300 MHz, CDCl3):
DMSO-d6): 12.31 (s, 1H, NH, D2O exchangeable),
7.27–7.04 (m, 9H, Ar–H), 3.81 (s, 3H, OCH3, benzylic-
H), 2.62–1.55 (m, 8H, cyclohexene ring protons). MS m/z
7.36–7.01 (m, 4H, Ar–H), 5.57 (s, 1H, SH, D2O
exchangeable),3.87 (s, 3H, OCH3), 3.04–1.73 (m, 8H,
cyclohexene ring protons). MS m/z (%): 296 (M
̇
(%): 384 (M-2)
(386.44): C, 74.59; H, 5.74; N, 7.25. Found: C, 74.42; H,
̇
100). Anal. Calcd for C17H16N2OS (296.39): C, 68.89;
H, 5.44; N, 9.45; S, 10.82. Found: C, 68.74; H, 5.32;
N, 9.39; S, 10.75.
5.66; N, 7.34.
2-Methoxy-4-(4-methoxyphenyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (11). Method A. To a
solution of 2-pyridone 1 (5 mmol, 1.41 g), ethyl
chloroacetate,
Ethyl
2-(3-cyano-4-(4-methoxyphenyl)-3,4,5,6,7,8-
hexahydroquinolin-2-ylthio)acetate (8).
To a mixture of
hexahydroquinoline 7 (5 mmol, 1.48 g) and ethyl
chloroacetate (5 mmol, 0.6 mL) in absolute ethanol
(20 mL) fused sodium acetate (10 mmol, 0.82 g) was
added, heated at reflux temperature for 4 h, and left to
cool; the solid product was collected by filtration, dried,
and recrystallized from petroleum ether 80–100°C to
give acetate derivative 8 as yellow crystals, mp 150–
152°C, yield 58%. FT-IR (KBr, cmꢀ1): 3070 νCH
aromatic, 2973 νCH aliphatic, 2218 νC°N, 1738 νC=O
chloroacetic acid (5 mmol), in absolute ethanol
(25 mL), anhydrous sodium acetate (5 mmol, 0.82 g)
was added, then the reaction mixture was refluxed for
8–13 h. The reaction mixture was left to cool and
neutralized by diluted hydrochloric acid for complete
precipitation. The separated product was collected by
filtration, washed with water, dried, and recrystallized
from ethanol to give hexahydroquinoline 11 as yellow
crystals, mp 295–296°C, yield 52%, 61%, and 49%,
respectively. FT-IR (KBr, cmꢀ1): 3290 νNH, 3125 νCH
ester,1651 νC=N.
1H NMR (300 MHz, CDCl3): 7.27–
6.99 (m, 4H, Ar–H), 4.23 (q, 2H, CH2CH3,
J = 6.9 Hz), 4.01 (s, 2H, ꢀS–CH2), 3.86 (s, 3H,
OCH3), 2.45–1.34 (m, 8H, cyclohexene ring protons),
1.32 (t, 3H, CH2CH3, J = 6.9 Hz). MS m/z (%): 384
aromatic, 2933 νCH aliphatic, 2218 νC°N,1646 νC=N
1H NMR (300 MHz, DMSO-d6): 12.27 (s, 1H, NH,
D2O exchangeable), 7.27–7.04 (m, 4H, Ar–H), 3.82
(s, 6H, 2OCH3), 3.57 (s, 1H, benzylic-H), 2.62–1.55
(m, 8H, cyclohexene ring protons). MS m/z (%): 294
(M + 2)
̇
C, 65.95; H, 5.80; N, 7.32; S, 8.38. Found: C, 65.78;
(M-2)
̇
H, 5.68; N, 7.41; S, 8.22.
3-Cyano-4-(methoxyphenyl)1,4,5,6,7,8-hexahydroquinoline-
72.95; H, 6.80; N, 9.45. Found: C, 72.81; H, 6.69;
N, 9.38.
2-ylacetate (9).
A solution of 2-pyridone 1 (5 mmol,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. M. F. Madkour, M. A. E.-A. M. El-Hashash, M. S. Salem,
A.-S. O. A. Mahmoud, and Y. M. A. S. Al-Qahraman
Vol 000
Method B. To a solution of 2-pyridone 1 (5 mmol,
1.41 g), methyl iodide (5 mmol, 0.71 g), and anhydrous
K2CO3 (5 mmol, 0.69 g), in dry acetone (30 mL) was
heated at reflux temperature on water bath for 20 h. The
reaction mixture was left to cool and poured into the
water. The separated product was collected by filtration,
washed with water, dried well, and recrystallized from
ethanol to givehexahydroquinoline11 as yellow crystals,
CDCl3): 7.42–6.99 (m, 5H, Ar–H), 4.77 (s, 2H,
OCH2CO), 3.87 (s, 3H, OCH3), 2.77–1.67 (m, 8H,
cyclohexene ring protons), 1.25 (s, 6H, 2CH3). MS m/z
(%): 416 (M
̇
(416.47): C, 69.21; H, 5.81; N, 13.45. Found: C, 69.12;
H, 5.74; N, 13.38.
Ethyl 5-amino-1-(2-(3-cyano-4-(4-methoxyphenyl)-5,6,7,8-
tetrahydroquinolin-2-yloxy)acetyl)-1H–pyrazole-4-carboxylate
(15). A mixture of acetohydrazide derivative 4 (5 mmol,
mp 295–296°C, yield 66%.
1.76 g) and ethyl 2-cyano-3-ethoxyacrylate (5 mmol,
0.62 g) in ethanol (15 mL) was heated at reflux for 19 h
and left to cool, and the solid product was collected by
filtration, dried, and recrystallized from methanol to give
enaminoester 15 as yellow crystals, mp 114–116°C,
yield 58%. FT-IR (KBr, cmꢀ1): 3375, 3291 νNH2, 3136
νCH aromatic, 2979 νCH aliphatic, 2212 νC°N, 1688 νC=O
4-(4-Methoxyphenyl)-2-(3-oxo-5-phenyl-3H-pyrazol-4-
yloxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (12).
A
mixture of acetohydrazide derivative 4 (1.3 mmol,
0.46 g) and benzoyl chloride (7.2 mmol, 10 mL) in
pyridine (5 mL) was heated on water bath for 12 h,
left to cool, and neutralized by cooled dilute
hydrochloric acid. The solid product that formed
was collected by filtration, washed with water,
dried, and recrystallized from methanol to give
pyrazoltetrahydroquinoline 12 as yellow crystals, mp
95–97°C, yield 77%. FT-IR (KBr, cmꢀ1): 3070 νCH
ester, 1617 νC=N.
1H NMR (400 MHz, DMSO-d6):
13.22 (s, 2H, NH2, D2O exchangeable), 8.78–7.05 (m,
5H, Ar–H), 4.34 (s, 2H, OCH2CO), 4.06 (q, 2H,
CH2CH3), 3.82 (s, 3H, OCH3), 2.97–1.67 (m, 8H,
cyclohexene ring protons), 1.20 (t, 3H, CH2CH3). MS
1
aromatic, 2885 νCH aliphatic, 2213 νC°N, 1686 νC=O. H
NMR (400 MHz, CDCl3): 8.13–7.46 (m, 9H, Ar–H),
3.77 (s, 3H, OCH3), 2.55–1.63 (m, 8H, cyclohexene
m/z (%): 475 (M
(475.5): C, 63.15; H, 5.30; N, 14.73. Found: C, 63.04;
̇
H, 5.15; N, 14.67.
4-(4-Methoxyphenyl)-2-(3-oxo-5-thioxo-4,5-dihydro-3H-
pyrazol-4-yloxy)-5,6,7,8-tetrahydro-quinoline-3-carbonitrile
ring protons). MS m/z (%): 436 (M
for C26H20N4O3 (436.46): C, 71.55; H, 4.62; N, 12.84.
Found: C, 71.41; H, 4.45; N, 12.78.
4-(4-Methoxyphenyl)-2-(3-oxo-5-phenyl-2,3-dihydro-1H-
pyrazol-4-yloxy)-5,6,7,8-tetrahydro-quinoline-3-carbonitrile
̇
(16).
To a solution of acetohydrazide derivative 4
(1.3 mmol, 0.46 g) and carbon disulfide (6.6 mmol,
mL) in ethanol (20 mL), alcoholic potassium
5
(13).
A mixture of acetohydrazide derivative 4
hydroxide 10% was added. The reaction mixture was
heated at reflux on water bath for 10 h, left to cool,
and neutralized by dilute hydrochloric acid. The solid
product that formed was collected, washed with water,
dried, and recrystallized from ethanol to give pyrazol
derivative 16 as pale red crystals, mp 205–207°C,
yield 70%. FT-IR (KBr, cmꢀ1): 3067 νCH aromatic,
(1.3 mmol, 0.46 g) and benzoic acid (1.3 mmol, 0.18 g)
in phosphorous oxychloride (15 mL) was heated on
water bath for 10 h, then left to cool, and the solid
product was collected, dried, and recrystallized from
ethanol to give dihydropyrazole-tetrahydroquinoline 13
as pale brown crystals, mp 222–224°C, yield 69%.
FT-IR (KBr, cmꢀ1): 3410 νNH, 3064 νCH aromatic, 2941
νCH aliphatic, 2241 νC°N
, 1643 νC=O.
1H NMR
2933 νCH aliphatic, 2222 νC°N, 1642 νC=O, 1607 νC=N
,
1
1249 νC=S. H NMR (400 MHz, DMSO-d6): 7.37–7.09
(m, 4H, Ar–H), 3.83 (s, 3H, OCH3), 3.00 (s, 1H,
COCHCS), 1.85–1.04 (m, 8H, cyclohexene ring
(400 MHz, DMSO-d6): 9.98 and 9.76 (2 s, 2H, 2NH,
D2O exchangeable), 8.13–7.11 (m, 9H, Ar–H), 3.77 (s,
3H, OCH3), 2.55–1.63 (m, 8H, cyclohexene ring
protons). MS m/z (%): 392 (M
̇
protons). MS m/z (%): 438 (M
C26H22N4O3 (438.48): C, 71.22; H, 5.06; N, 12.78.
Found: C, 71.34; H, 5.00; N, 12.67.
2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethoxy)-4-(4-
methoxyphenyl)-5,6,7,8-tetrahydro-quinoline-3-carbonitrile
̇
for C20H16N4O3S (392.43): C, 61.21; H, 4.11; N,
14.28; S, 8.17. Found: C, 61.34; H, 4.25; N, 14.12; S,
8.28.
Reaction
of
2-(3-cyano-4-(4-methoxyphenyl)-5,6,7,8-
(14).
To a solution of acetohydrazide derivative 4
tetrahydroquinolin-2-yloxy)acetohydrazide with formic acid
(2.5 mmol, 0.88 g) in absolute ethanol (20 mL),
acetylacetone (2.5 mmol, 0.25 mL) was added, and the
reaction mixture was heated at reflux for 17 h, then left to
cool at room temperature. The crude solid product that
obtained was collected, dried, and recrystallized from
ethanol to give pyrazoltetrahydroquinoline 14 as pale
brown crystals, mp 187–189°C, yield 63%. FT-IR (KBr,
cmꢀ1): 3145 νCH aromatic, 2934 νCH aliphatic, 2206
and/or glacial acetic acid. A mixture of acetohydrazide
derivative 4 (5 mmol, 1.76 g) in formic acid and/or
glacial acetic acid (20 mL) was heated at reflux for
12 h, then the mixture was left to cool at room
temperature and poured into ice-cold water, and the
separated material was collected by filtration, washed
with water, dried well, and recrystallized to afford
pyrazolyloxytetrahydroquinoline derivatives 17 and 18,
respectively.
ν
C°N, 1648 νC=O, 1619 νC=N.
1H NMR (400 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Design, Synthesis, and In Vitro Antileishmanial and Antitumor Activities of New
Tetrahydroquinolines
4-(4-Methoxyphenyl)-2-(3-oxo-3H-pyrazol-4-yloxy)-5,6,7,8-
exchangeable), 7.22–6.98 (m, 4H, Ar–H), 6.33 (d, 1H,
ꢀNH–CH–Oꢀ), 5.46–5.07 (m, 6H, 3CHOCO, O–CH–
CH2–OCOCH3), 4.27 (s, 2H, ꢀOCH2COꢀ), 3.89 (s, 3H,
OCH3), 2.17–1.69 (m, 8H, cyclohexene ring protons),
1.85 (s, 1H, NHCH, D2O exchangeable), 1.29 (s, 12H,
tetrahydroquinoline-3-carbonitrile
(17).
Pyrazolyloxytetrahydroquinoline
derivative
17
recrystallized from methanol to afford pale brown
crystals, mp 130–132°C, yield 58%. FT-IR (KBr, cmꢀ1):
3070 νCH aromatic, 2935 νCH aliphatic, 2219 νC°N, 1685
4COCH3). MS m/z (%): 682 (M
C33H38N4O12 (682.67): C, 58.06; H, 5.61; N, 8.21.
Found: C, 58.14; H, 5.50; N, 8.32.
̇
ν
C=O, 1648 νC=N
6.88 (m, 5H, Ar–H), 3.74 (s, 3H, OCH3), 2.61–1.76 (m,
8H, cyclohexene ring protons). MS m/z (%): 360 (M
.
1H NMR (400 MHz, CDCl3): 7.83–
þ ,
Biological activity. Antileishmanial activity.
All the
50). Anal. Calcd for C20H16N4O3 (360.37): C, 66.66; H,
synthesized heterocyclic compounds were initially
screened for their antileishmanial activity in contrast to
culture of L. major [31,39].
4.48; N, 15.55. Found: C, 66.45; H, 4.34; N, 15.62.
4-(4-Methoxyphenyl)-2-(3-methyl-5-oxo-2,5-dihydro-1H-
pyrazol-4-yloxy)-5,6,7,8-tetrahydro-quinoline-3-carbonitrile
One milligram of every compound was dissolved using
solvent DMSO (1 mL), and 1 mg of amphotericin B was
also solubilized in 1 mL of DMSO; 180 μL of medium
was poured in various wells of 96-well plates; and 20 μL
of the tetrahydroquinoline derivatives solution was then
added in medium and diluted serially. Parasites at log
phase for 3 min were centrifuged at 3000 rpm. Fresh
culture medium was used for diluting the parasites to a
final density of 2 × 106 cells/mL. In all wells, 100 μL of
parasite culture was added. Negative and standard drug
were maintained having DMSO and amphotericin B. For
positive and negative controls, three rows were left
empty. DMSO was diluted serially in medium in case of
negative controls, while in positive control, there were
different concentrations of standard antileishmanial
compound, for example, amphotericin B. Micro titer
plates were incubated for 72 h at 24°C. Every assay was
in duplicate; 15 μL of test culture were then transferred
after 72 h, to enhanced Neubauer counting chamber, and
live promastigotes were counted using light microscope.
Crown gall tumor inhibition (potato disc) assay.
(18).
Pyrazolyloxytetrahydroquinoline derivative 18
recrystallized from ethanol to brown crystals, mp
199–201°C, yield 62%. FT-IR (KBr, cmꢀ1): 3202 νNH
3067 νCH aromatic, 2932 νCH aliphatic, 2221 νC°N, 1665
,
1
ν
C=O, 1607 νC=N. H NMR (400 MHz, DMSO-d6): 13.04,
9.22 (2 s, 2H, 2NH, D2O exchangeable), 7.34–6.95 (m, 4H,
Ar–H), 3.79 (s, 3H, OCH3), 2.97–1.66 (m, 8H,
cyclohexene ring protons), 1.43 (s, 3H, CH3). MS m/z (%):
376 (M
̇
66.29; H, 5.01; N, 15.46. Found: C, 66.14; H, 5.24; N, 15.56.
4-(4-Methoxyphenyl)-2-((4-phenyl-5-thioxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl)methoxy)-5,6,7,8-tetrahydroquinoline-3-
carbonitrile (19). A mixture of acetohydrazide derivative
4
(2.5 mmol, 1.76 g) and phenyl isothiocyanate
(2.5 mmol, 0.34 mL) in pyridine (20 mL) was refluxed
for 9 h, left to cool, and neutralized by cooled dilute
hydrochloric acid. The solid product that formed was
collected, washed with water, dried, and recrystallized
from dioxane to give triazoltetrahydroquinoline 19 as
brown crystals, mp 241–243°C, yield 74%. FT-IR (KBr,
cmꢀ1): 3375 νNH, 3057 νCH aromatic, 2932 νCH aliphatic,
1
Preparation of agar plates and treatment.
These
2222 νC°N, 1650 νC=N, 1249 νC=S. H NMR (400 MHz,
potato discs were then transferred to petri plates each
containing 25 mL of 1.5% agar (1.5 g agar/100 mL
distilled water). Five potato discs were placed on each
plate, and three plates were used for each test sample
along with same number of plates for vehicle control
(DMSO) and reference drug (vincristine). As a stock
solution, 10 mg of each compound was dissolved in
1 mL of DMSO in separate test tubes. Then 0.5 mL of
stock (10 mg/mL) of the test sample was added to
2 mL of a broth culture of A. tumefaciens (At-10, a
48-h culture containing 5 × 109 cells/mL) and 2.5 mL
of autoclaved distilled water to make 1000 μg/mL final
concentration. One drop (10 μL) was drawn from these
test tubes using a sterile pipette, and it was used to
inoculate each potato disc, spreading it over the disc
surface. The process starting from the cutting of the
potatoes to the inoculation was completed in 30 min in
order to avoid contamination. The lids of the petri
plates were taped down with parafilm to minimize
moisture loss.
CDCl3): 7.89 (s, 1H, NH, D2O exchangeable), 7.53–6.99
(m, 9H, Ar–H), 3.90 (s, 2H, OCH2), 3.74 (s, 3H, OCH3),
2.69–1.63 (m, 8H, cyclohexene ring protons). MS m/z
(%): 469 (M
̇
(469.56): C, 66.50; H, 4.94; N, 14.91; S, 6.83. Found: C,
66.41; H, 4.84; N, 14.82; S, 6.75.
(2R,3R,4R,5R,6S)-2-(Acetoxymethyl)-6-(2-(2-((3-cyano-4-(4-
methoxyphenyl)-5,6,7,8-tetrahydro-quinolin-2-yl)oxy)acetyl)
hydrazinyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (20).
A
mixture of acetohydrazide derivative 4 (2.5 mmol,
1.76 g) and α-D-glucose pentaacetate (2.5 mmol, 0.98 g)
in absolute ethanol (20 mL) was heated at reflux for 35 h,
then the mixture was left to cool at room temperature and
the solid product that formed was collected, washed with
water, dried, and recrystallized from ethanol to give 20 as
dark brown crystals, mp over 300°C, yield 55%.FT-IR
(KBr, cmꢀ1): 3306 νNH, 3072 νCH aromatic, 2939 νCH
aliphatic, 2221 νC°N, 1753 νC=O, 1656 νC=O. The 1H
NMR (400 MHz, CDCl3) spectrum exhibited the
following signals(δ/ppm): 8.35 (s, 1H, CONH, D2O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. M. F. Madkour, M. A. E.-A. M. El-Hashash, M. S. Salem,
A.-S. O. A. Mahmoud, and Y. M. A. S. Al-Qahraman
Vol 000
[5] Musiol, R.; Jampilek, J.; Buchta, V.; Silva, L.; Niedbala, H.;
Podeszwa, B.; Palka, A.; Majerz-Maniecka, K.; Oleksyn, B.; Polanski,
J. Bioorg Med Chem 2006, 14, 3592.
[6] Nakamura, T.; Oka, M.; Aizawa, K.; Soda, H.; Fukuda, M.;
Terashi, K.; Ikeda, K.; Mizuta, Y.; Noguchi, Y.; Kimura, Y.; Tsuruo, T.;
Kohno, S. Biochem Bioph Res Co 1999, 255, 618.
[7] Coimbra, E. S.; da Silva, A. D.; Dias, R. M. P.; Corrales, R. C.
N. R.; de Bisp, M. L. F.; Kaiser, C. R.; de Souza, M. V. N. Mediterranean J
Chem 2011, 1, 106.
[8] Dimon, D. B.; Robert, W. JP 2001163859 (2001)
[9] Asolkar, R. N.; Schroder, D.; Heckmann, R.; Lang, S.;
Wagner-Dobler, I.; Laatsch, H. J. Antibiotics 2004, 57, 17.
[10] Su, D. S.; Neville, A. J.; Lim, J. J.; Tinney, E.; Williams, T. M.
PCT Int Appl 2007.
Incubation and analysis.
The petri plates were
incubated at 28°C for 21 days, and the number of tumors
was counted with the aid of dissecting microscope after
staining with Lugol’s solution (5% I2, 10% KI in distilled
water). The numbers of tumors in vehicle control
(DMSO) were used as a reference for activity. The results
were derived from the number of tumors on test discs
versus those on the vehicle control disc. Twenty percent
or more inhibition was considered as significant activity.
Cytotoxicity activity by brine shrimp lethality assay. The
procedure described by Singh et al. was used to perform
the brine shrimp cytotoxicity assay [40]. Artificial sea
water was prepared by dissolving 34 g of sea salt in
1000 mL of distilled water with regular stirring. The
solution was aerified for about 2 h in an open beaker
with vigorous shaking on magnetic stirrer. Shallow
rectangular dish (22 × 32 cm) previously filled with
prepared seawater was used for hatching of Artemiasalina
(brine shrimp eggs) that is composed of two
compartments: One compartment was large, and the other
compartment was small. Both compartments were
separated by a wall consisted of several holes of 2 mm in
diameter. The eggs were spread on the surface of artificial
sea water in the large compartment. The large
compartment was covered with aluminum foil so that
there was darkness in that compartment. The smaller
compartment was lighted up with a lamp. After 24–26 h,
the hatching process started and the newly hatched
nauplii (brine shrimp larvae) traveled towards the smaller
compartment because of presence of light. The nauplii
were collected in a beaker with the help of Pasteur
pipette. Three concentrations of 10, 100, and
1000 μg/mL were used against brine shrimp larvae and
then the rate of death at all concentrations was observed.
To check the number of deaths, each sample quantity
taken was 0.5 mL in 20 mL vial. Furthermore, additional
2 mL artificial sea water was added to evaporate the
solvent. After this, 30 shrimps were transferred to each
vial with final volume adjusted to 5 mL. They were kept
under florescence light at a temperature of 25°C for a
time period of 24 h. Finney computer program was used
to evaluate ED50 after the percentage survival was
calculated.
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