Synthesis and in vitro anticancer evaluation of novel pyridine derivatives bearing tetrahydronaphthalene scaffold

Article abstract of DOI:10.24820/ark.5550190.p011.056

A new series of tetralin-pyridine hybrids was synthesized in good yields starting from 2-(pyridin-2-yl)oxy)acetohydrazide as a synthon. The treatment of this acid hydrazide with six different aromatic aldehydes resulted in the formation of the correspondi

Full text of DOI:10.24820/ark.5550190.p011.056

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Synthesis and in vitro anticancer evaluation of novel pyridine derivatives
bearing tetrahydronaphthalene scaffold
Eman Kh. Hamza,a Nehal A. Hamdy,a* Eman S. Zarie,a Issa M. I. Fakhr,a Ahmed H. M. Elwahy,b and
Hanem M. Awada
aNational Research Centre, El-Buhouth St., Dokki, P.O. 12622, Giza, Egypt
bDepartment of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
E-mail: drnehalhamdy63@hotmail.com
Received 09-05-2019
Accepted 02-06-2020
Published on line 02-16-2020
Abstract
A new series of tetralin-pyridine hybrids was synthesized in good yields starting from 2-(pyridin-2-
yl)oxy)acetohydrazide as a synthon. The treatment of this acid hydrazide with six different aromatic
aldehydes resulted in the formation of the corresponding arylidenehydrazides as cis/trans conformers,
which upon treatment with thioglycolic acid afforded 4-thiazolidinone derivatives. The acid hydrazide
synthon also reacted with a variety of activated reagents to give the corresponding tetralin-pyridine
derivatives in good yields. The in vitro cytotoxic activity of the new compounds were tested showing that
these compounds appeared as promising active anti-cancer compounds.
Keywords: Tetralin, pyridine, benzylidenehydrazides, thiazolidinones, anticancer activity
DOI: https://doi.org/10.24820/ark.5550190.p011.056
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Introduction
Cancer diseases are considered as the second common cause of death after heart disease worldwide.1,2
Chemotherapy is still one of the most important roles for cancer treatment. The major issue in the use of
chemotherapeutics is the undesirable side effects. Therefore, search for new agents, not only for the
treatment of cancer but also to overcome cancer resistance to drug treatment as well as to avoid drug
side effects, is a challenge goal.
In this respect, many pyridine derivatives have been synthesized and their biological and
chemotherapeutic activities have been investigated and reported.3-6 The pyridine moiety is found in many
pharmaceutical drugs such as Isoniazid (anti-tuberculosis drug), Omeprazole (antihistaminic drug),
Pioglitazone (anti-diabetic drug), Sorafenib and Regorafenib (anticancer drugs) as well as in many
agrochemicals such as pyridinenitrile (fungicide), Nitapyrin (bactericide) and Picloram (herbicide). The
pyridine motif is also present in a number of biologically active molecules including niacin (vitamin B3),
pyridoxine (vitamin B6) and the toxic alkaloid (nicotine) (Figure 1).7-11
Figure 1. Structures of some pyridine containing pharmaceutical drugs, agrochemicals and a number of
biologically active molecules.
Moreover, tetrahydronaphthalene derivatives have attracted much attention in the medicinal field
because of their broad range of pharmacological properties.12-18 Furthermore, tetrahydronaphthalene
(tetralin) is also an efficient ring, which is found in the structures of some anticancer drugs such as
doxorubicin and epirubicin (Figure 2).19
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Figure 2. Tetralin containing anticancer drugs
Motivated by these findings and in conjunction with our ongoing research work on pyridine
chemistry,20-25 as well as on the development of new anticancer agents with improved efficacy, high
selectivity and minimum toxicities,26-28 we report herein the synthesis of novel derivatives based on
5,6,7,8-tetrahydronaphthalene-pyridine scaffolds as new hybrid molecules. The anticancer activities of
the new compounds have also been evaluated.
Results and Discussion
Chemistry
The starting 2-(pyridin-2-yl)oxy)acetohydrazide 7 was synthesized in a good yield using the synthetic
route outlined in scheme 1. Thus, according to our reported procedure,29 2-oxo-6-(tetrahydronaphthalen-
2-yl)-1,2-dihydropyridine-3-carbonitrile 4 was obtained in a good yield by a four-component reaction of 2-
acetyl-5,6,7,8-tetrahydronaphthalene 130 with 4-fluorobenzaldehyde 2a, ethyl cyanoacetate 3 and excess
ammonium acetate in n-butanol at reflux. Reaction of 4 with ethyl bromoacetate 5 in the presence of
anhydrous K2CO3 in dry acetone afforded ethyl 2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-
tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)acetate 6, which upon treatment with hydrazine hydrate in
absolute ethanol afforded the desired acetohydrazide 7 31 (Scheme 1).
Scheme 1. Synthesis of the acetohydrazide compound 7.
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Hydrazides are useful important intermediates and their condensation products are reported to
possess a wide range of biological activities.32,33 In this work, the acetohydrazide 7 was used as a versatile
precursor for the synthesis of novel interesting pyridine derivatives, via its reactions with a variety of
reagents (Scheme 2-6).
New Schiff base derivatives 8a-f were obtained by condensation of acetohydrazide derivative 7 with a
series of aromatic aldehydes namely, 4-fluorobenzaldehyde 2a, benzaldehyde 2b, 4-bromobenzaldhyde
2c, 4-chlorobenzaldehyde 2d, 4-cyanobenzaldhyde 2e and 4-methoxybenzaldehyde 2f in ethanol and a
catalytic amount of glacial acetic acid at reflux. The IR spectra of 8a-f revealed absorption bands between
3212-3198 and 2224-2220, 1681-1664 cm-1 assignable for NH, CN and C=O groups, respectively, while no
absorption bands for the NH2 group in their spectra were detected. The disappearance of the absorption
1
bands due to NH2 in both IR as well as in the H NMR spectra of 8 confirmed that the hydrazide-NH2
completely reacted with –CHO groups of the used aldehydes leading to the formation of the
1
corresponding Schiff bases (scheme 2). The H and 13C NMR spectra of the hydrazone derivatives 8a-f
displayed additional signals at the aromatic region due to aromatic ring protons derived from the
aldehyde moiety, in addition to the characteristic signals belonging to benzylidene amino group (CH=N).
The 1H NMR spectra of compounds 8a-f exhibited two sets of signals each belonging to the -OCH2, -N=CH
and -NH groups, of the trans and cis conformers, recorded between δ 5.61-5.64 and 5.07-5.12; 8.07-8.16
and 8.26-8.39; 11.64-12.01 and 11.80-12.19 ppm, respectively. In addition, the C4-proton of
tetrahydronaphthalene appeared also as two doublets between 7.01-7.06 and 7.06-7.11 ppm,
corresponding to trans and cis conformers. The ratios of trans/cis conformers in each case were
1
calculated by using H NMR data. The 13C NMR spectra of these compounds revealed also two sets of
signals between 62.77-66.28 and 63.47-66.93 ppm; 139.97-142.98 and 141.99-145.92 ppm characteristic
for the OCH2 and N=CH carbons, respectively. The C4 of tetrahydronaphthalene was also observed as two
sets of signals between δ 127.42-128.86 and 127.58-129.35 ppm. Moreover, the -OCH3 protons of
1
compound 8f appeared as a singlet signal at δ 3.81 ppm in the HNMR spectrum, and its 13C NMR
spectrum revealed the OCH3 carbon at δ 56.07 ppm.
According to the literature,34–39 compounds having arylidene-hyrazide structure may exist as E/Z
geometrical isomers around C=N double bonds and cis/trans amide conformers (Scheme 3). It has been
reported that, compounds containing imine bond exists at higher percentage of the geometrical E isomer
about –C=N double bond in dimethyl-d6 sulfoxide solution.37 While the Z isomer can be stabilized by an
intramolecular hydrogen bond in less polar solvents. In compounds 8a-f, no signal belonging to Z isomer
1
was observed as the H NMR data were obtained in dimethyl-d6 sulfoxide solution. On the other hand,
the dimethyl-d6 sulfoxide solution of compounds 8a-f indicated that among the cis/trans conformers of
the geometrical E isomer, the trans conformer predominates.34–37
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Scheme 2. Synthesis of compounds 8, 11 and 13.
1
The cis/trans conformer ratios of the E isomers can easily be determined by H NMR integration. The
data obtained from chemical shift values of OCH2, N=CH, and NH protons of cis/trans conformers in the
1H NMR and that obtained from chemical shift values of OCH2 and N=CH carbons in the 13C NMR spectra
of compounds 8 proved that the E isomers and trans conformer structures (I) are the dominant forms
among the four possible structures.34–37 In the the trans conformers, the proton signals of N=CH and NH,
are shifted upfield compared to those of the cis conformer. On the other hand, because of the steric
hindrance, the OCH2 proton signal of the trans conformer is shifted downfield compared to the that of
the cis conformer.34
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Scheme 3. E/Z Geometrical isomers and cis/trans amide conformers of compounds 8a-f.
Compounds 8a-f containing imine bond have been synthesized for preparing other derivatives like
thiazolidinones due to their broad spectrum of biological activities.40 Thiazolidinone derivatives belong to
the most frequently studied moieties of medicinal interest which attributed to the presence of
thiazolidine in the structre of penicillin.41
The 4-thiazolidinone derivatives 11a and 11c-f were synthesized by refluxing the imine 8a and 8c-f
with thioglycolic acid 9 in dry benzene according to the reported method (Scheme 2).42 The formation of
thiazolidinone derivatives were assumed to occur by the addition of the SH group of thioglycolic acid to
the CH=N bond of the hydrazine moiety of 8a and 8c-f to yield the corresponding acyclic non-isolable
intermediates 10 which underwent the elimination of water molecule by intramolecular cyclization to
afford the final cyclocondensation products 11.43
1
The structures of the newly synthesized compounds were confirmed by IR, H-NMR and 13C-NMR as
well as elemental analyses. The IR spectra of compounds 11a and 11c-d showed absorption bands at
3435-3441 (NH), 2220-2224 (CN), 1711-1729 (C=O of 4-thiazolidinone ring) and 1675-1685 cm–1 (C=O
1
amide). The H-NMR spectra for 11a and 11c-f showed the two methylene protons of the thiazolidinone
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ring as doublet of doublets signals at δ 3.73-3.77, 3.85-3.93 ppm and the methine protons as singlet
signals at δ 5.68-5.83 ppm. The OCH2 groups appeared as doublet of doublets signals between δ 5.00-
5.06, 5.09-5.15 ppm and the NH groups appeared as singlet signals at δ 10.57-10.82 ppm. 13C NMR
spectral data also supports the formation of compounds 11a and 11c-f. Thus, the two carbonyl groups
were observed between δ 166.55-167.11 and 168.21-168.87 ppm; the SCH2CO and the NCHS carbons
appeared at δ 32.71-35.39 ppm and at δ 59.65-65.38 ppm, respectively.
Moreover, condensation of 7 with isatin 12 in ethanol at reflux in the presence of a catalytic amount
of glacial acetic acid yielded the hydrazone derivative 13. The structure of 13 was confirmed by IR
spectrum which showed absorption bands at 3427 and 3212 cm-1 due to (2NH) and at 2228, 1709 and
1
1657 cm-1 due to CN, C=O of isatin ring and C=O (amide), respectively. Moreover, the H NMR spectrum
of 13 showed a D2O-exchangeable NH signal at δ 11.35 ppm characteristic for the NH proton of the isatin
moiety. On the other hand, the hydrazine function proton (=N–NH–) appeared as two singlet signals at δ
12.78 and 13.40 ppm, respectively, due to trans/cis conformers. Furthermore, the 13C NMR spectrum of
this compound showed two carbonyl groups at δ 167.90 and 168.75 ppm, confirming the structure of 13
(Scheme 2).
Fusion of a mixture of acetic acid hydrazide 7 and acetic anhydride 14 afforded the new acetic-N'-
acetyl-2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-
yl)oxy)acetohydrazonic anhydride 15 (Scheme 4). The IR spectrum of 15 revealed the presence of two
bands at 1742 and 1670 cm-1 due to the acetoxy C=O and the amide C=O, respectively, which is in
1
agreement with that reported in the literature.44 In addition, the H NMR spectrum of 15 showed two
methyl protons at δ 2.34 ppm and at δ 2.35 ppm for NHCO-CH3 and for OCO-CH3, respectively. Likewise,
the 13C NMR spectrum of 15 showed the two methyl carbons of the acetoxy and the acetamide groups at
δ 22.49 and 22.58 ppm, respectively, in addition to the two carbonyl groups at δ 168.63 and 170.56 ppm,
respectively.
Benzoylation of 7 was achieved via its reaction with benzoyl chloride 16 in refluxing pyridine to give
N'-(2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-
yl)oxy)acetyl)benzohydrazide 17 (Scheme 4).
The IR spectrum of compound 17 revealed strong absorption bands at υ 3432, 3230, 1728 and 1716
1
cm-1 attributable to two NH groups and two C=O groups, respectively. The H NMR spectrum of
compound 17 revealed two singlets at δ 10.37 and δ 10.46 ppm assigned to the two NH protons, in
addition to multiplet signals in the region δ 7.45-7.99 ppm characteristic to the aromatic protons. 13C
NMR spectrum of 17 gave a further evidence for its structure as it showed the two carbonyl groups at δ
165.36 and 168.08 ppm, respectively.
Our study was extended to include the synthesis of 2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-
tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N'-formylacetohydrazide 19 in good yields by heating
acetohydrazide 7 with formic acid 18 at reflux (Scheme 4). The IR spectrum of compound 19 displayed an
absorption band at 1724 cm–1 corresponding to the carbonyl C=O of the formyl group, which appeared in
the 13C NMR spectrum at δ 169.7 ppm. Its 1H NMR spectrum revealed a singlet at δ 8.04 ppm assigned to
the formyl proton.
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Scheme 4. Synthesis of compounds 15, 17, 19 and 20.
Methyl (pyridin-2-yl)oxy)acetyl)hydrazine-1-carbodithioate 20 was also synthesized by the reaction
of acetohydrazide 7 with carbon disulfide and methyl iodide in ethanolic solution in the presence of
triethylamine (TEA), according to the reported method.45 The structure of this compound was confirmed
according to its correct analytical and spectroscopic data. The 1HNMR spectrum of 20 showed signals at δ
10.76 and at δ 10.80 assigned for two NH protons and at 2.56 ppm corresponding to -SCH3 group while its
13
carbon appeared at δ 19.56 ppm in the C NMR in addition to the C=S which appeared at δ 205.10 ppm.
Further structural verification was obtained from its mass spectroscopy, which showed the correct
molecular ion peak at m/z 506.30 (M+, 100).
The acetohydrazide derivative 7 is also a very useful intermediate for further cyclocondensation
reactions. Thus, cyclocondensation of 7 with acetylacetone 21 afforded the corresponding
dimethylpyrazole derivative 23 as a single product via initial formation of the intermediate hydrazone
1
2243 (Scheme 5). The structure of compound 23 was confirmed based on the IR, H NMR, 13C NMR and
mass spectral data, which were in agreement with the assigned structure. Thus, the absence of signals
corresponding to NH, NH2 protons in both the IR and 1H NMR spectra confirmed that they were involved
1
in the cyclization. Also, H-NMR spectrum of 23 showed two singlets at δ 2.29 ppm and 2.45 ppm
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characteristic for the two CH3 groups and a singlet at δ 6.35 ppm due to the H-4 of the pyrazole moiety.
The 13C NMR spectral of 23 revealed two characteristic singlets at δ 150.45 and 154.54 ppm for C3 and C5
of the pyrazole nucleus, respectively, in addition to the two methyl groups at δ 13.56 and 13.60 ppm.
Scheme 5. Synthesis of compounds 23 and 26.
Furthermore, cyclocondensation of 7 with ethyl cyanoacetate in ethanol containing KOH at reflux
gave a novel pyrazole derivative 26. The formation of this compound proceeded through nucleophilic
transformation to give the non-isolable acyclic intermediate 24, followed by intramolecular cyclization via
loss of ethanol molecule and tautomerization under the reaction conditions to give 25. Subsequent
acetylation of the amino group of 25 afforded the final product 26 in a good yield (Scheme 5). The
structure of 26 was confirmed based on its correct analytical and spectral data. Its IR spectrum showed
absorption bands at υ 3440 (OH), 3196 (NH), 2218 (CN) and 1606 (C=O) cm-1. Also, the 1H-NMR spectrum
of compound 26 indicated the presence of a singlet signal integrated by three protons at δ 1.87 ppm for
COCH3 protons, and a singlet signal integrated by two protons at δ 5.11 ppm assigned to methylene
protons. In addition, the aromatic protons as well as the pyrazole-H4 appeared at δ 7.42-7.93 ppm, in
addition to signals at δ 9.89 and 10.21 ppm characteristic for NH and OH groups, respectively.
On the other hand, attempted synthesis of pyrazole 29 via the reaction of acetohydrazide 7 with
[bis(methylthio)methylene] malononitrile 27 in ethanol was unsuccessful. The reaction gave instead the
oxadiazole derivative 30. The reaction seems to proceed via initial formation of the expected acyclic
intermediate
2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N'-
(2,2-dicyano-1-(methyl-thio)vinyl)acetohydrazide 28, which upon intramolecular nucleophilic cyclization
by elimination of methylthiol molecule afforded the oxadiazol derivative 30 (Scheme 6).
The absence of sulfur element in the product of this reaction together with the disappearance of the
amino NH2 group in both IR and 1H-NMR as well as the disappearance of C=O in both the IR and 13C-NMR
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spectra confirmed the exclusion of 29. Moreover, H-NMR and 13C-NMR spectra revealed the loss of the
methylthio groups that can be considered as a strong evidence for the formation of the oxadiazol
derivative 30 which in agreement with that related in the literature.43
Scheme 6. Synthesis of compound 30 from acetohydrazide 7.
1. In-vitro cytotoxicity activities
The in vitro cytotoxic activity of twenty compounds of the synthesized compounds were evaluated
against human colorectal carcinoma cell line (HCT116) and human breast cancer cell line (MCF-7) using
MTT assay. The percentages of the viable cells was measured and compared to that obtained by the
positive control Doxorubicin® (Fig.3,4). The cytotoxic activities of the tested compounds were also
expressed as IC50 µM values (the dose that reduces survival to 50%). Regarding the activity of the
evaluated compounds against HCT116 cancer cells, the results in Table 1 showed that the compounds
possessed high cytotoxicity approximately equal to that obtained by doxorubicin (IC50; 7.7-9.0 µM, IC50
doxorubicin; 8.0 µM). Concerning MCF-7 cancer cells, it is evident that there is a wide variation in the
cytotoxic potency of the tested compounds. Interestingly, the N'-formylacetohydrazide derivative 19 was
approximately three times more active than DOX (IC50; 21.0 µM, IC50 doxorubicin; 68.4 µM). On the other
hand, the activity decreased slightly by the acetohydrazonic anhydride derivative 15 to be twice that of
the reference drug (IC50; 33.3 µM). Although linking the thiazolidinone ring to the oxyacetamide side
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chain as compound 11c led to a decrease in the potency, but it is still a promising antitumor agent
comparable to DOX (IC50; 60.3 µM). It could be noted that the starting acetohydrazide compound 7 and
its p-fluorophenyl shiff,s base analogue 8a appeared to be slightly less potent cytotoxic candidates than
DOX of IC50 values; 72.7 and 71.0 µM, respectively. The results also showed that the rest of the tested
derivatives were weaker than DOX of IC50 values ranging from 78.0-110.9 µM. It could be concluded that
tetralin-pyridine backbone is an interesting antitumor pharmacophore against the breast cancer cells
(MCF-7). The above mentioned data reveal that all the evaluated compounds are more active against the
human colon cancer type rather than against the human breast cancer type. Further structural
modifications and optimization are needed to signify and widen the antitumor spectrum of the
derivatives bearing tetralin-pyridine motif.
Figure 3. Dose dependent cytotoxicity percentages curve of the synthesized compounds on HCT-116
human cancer cells according to MTT assay.
Figure 4. Dose dependent cytotoxicity percentages curve of the synthesized compounds on MCF-7 human
cancer cells according to MTT assay.
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Table 1. Anticancer IC50 values of the tested compounds using MTT assay on the human colorectal and
breast cancer cells
Compound
IC50 (µM) ± SD
HCT-116
8.5 ± 2.1
8.6 ± 2.3
8.0 ± 2.5
7.9 ± 1.9
8.1 ± 2.1
8.1 ± 1.8
7.7 ± 1.9
8.2 ± 2.1
9.0 ± 2.4
8.6 ± 2.3
8.3 ± 2.5
8.7 ± 2.8
7.7 ± 1.6
7.6 ± 1.5
8.0 ± 1.9
8.0 ± 2.1
8.2 ± 2.3
7.7 ± 1.9
9.0 ± 2.3
8.4 ± 2.1
8.0 ± 2.1
MCF-7
7
8a
8b
8c
8d
72.7 ± 5.8
71.0 ± 5.1
82.3 ± 6.5
102.3 ± 7.1
83.0 ± 6.1
71.9 ± 4.1
77.3 ± 3.7
87.9 ± 5.9
60.3 ± 5.1
88.8 ± 5.8
86.3 ± 4.7
71.0 ± 4.1
110.9 ± 5.9
33.3 ± 2.1
94.0 ± 4.5
21.0 ± 2.1
79.4 ± 4.1
131.5 ± 5.1
94.5 ± 4.5
78.0 ± 4.1
68.4 ± 4.1
8e
8f
11a
11c
11d
11e
11f
13
15
17
19
20
23
26
30
Doxorubicin
Conclusions
We successfully synthesized a new series of tetralin-pyridine hybrids in good yields by reacting 2-((3-
cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)acetohydrazide with
a
variety of reagents. The structures of the new compounds were confirmed by spectral data as well as
elemental analyses. Study of the cytotoxic activity of the new compounds on HCT116 and MCF-7 human
cancer cells using MTT assay revealed that these compounds are potent cytotoxic on the human colon
cancer type and some of them showed good activities against breast cancer in vitro.
Experimental Section
1. Chemistry
General. All melting points are uncorrected and were taken in open capillary tubes using an Electro-
thermal IA 9100 apparatus (Shimadzu, Japan). Microanalytical data were performed by Vario El-Mentar
apparatus (Shimadzu, Japan), National Research Centre (NRC), Cairo, Egypt. The found values were within
±0.4% of the theoretical values. Infrared spectra (KBr) were recorded on a Perkin-Elmer 1650
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1
spectrophotometer, NRC. H NMR and 13C NMR spectra were determined on a Varian Mercury (run at
1
300 MHz for H NMR and 75 MHz for 13C NMR) spectrometer (Varian, UK) (Faculty of Science, Cairo
University, Egypt) or with a Bruker AVANCE 400 MHz spectrometer (Bruker) (Aalto university school of
chemical engineering, Finland) with a 5 mm BBFO probe using deuterated dimethylsulfoxide DMSO as a
solvent and the chemical shifts were expressed in δ ppm relative to TMS as an internal reference. Mass
spectra were recorded at 70 eV on EI Ms-QP 1000 EX (Shimadzu, Japan), NRC. Follow-up of the reactions
and checking of the purity of the compounds were made by TLC on silica gel precoated aluminum sheets
(Type 60, F 254, Merck, Darmstadt, Germany) and the spots were detected by exposure to a UV lamp at
254 nm for a few seconds. The chemical names for the prepared compounds are given according to the
IUPAC system. Compounds 129, 4, 6 and 7 were prepared as reported in the literature.30, 31
General procedure for synthesis of compounds (8a-f)
A mixture of acetohydrazide (7) (0.4165 g, 1 mmol) and the appropriate aromatic aldehyde namely: 4-
fluorobenzaldehyde (2a), benzaldehyde (2b), 4-bromobenzaldhyde (2c), 4-chlorobenzaldehyde (2d), 4-
cyanobenzaldhyde (2e) and 4-methoxybenzaldehyde (2f) (1 mmol) in absolute ethanol (30 ml), was
treated with acetic acid (0.5 mL). The clear solution was then heated at reflux for 6 h. The solid precipitate
so formed during the course of the reaction on heating was collected by filtration, washed by hot ethanol
and crystallized from acetic acid to give the benzylidene derivatives 8a-f.
(2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N'-(4-fluoro-
benzylidene)acetohydrazide (8a). Yield 64%; colorless crystals; m.p. 248-249 °C, the ratio of trans/cis
conformers: 76/24; IR spectrum (KBr,cm-1): 3198 (NH), 2925 (CH, alicyclic), 2221 (CN), 1674 (hydrazide
C=O), 1600 (C=N), 1236 (C-F); 1HNMR (400MHz, DMSO-d6, δppm): 1.67 (br.s, 4H, 2CH2 of
tetrahydronaphthalene), 2.69 (m, 4H, 2CH2 of tetrahydronaphthalene), 5.62, 5.09 (2s, 2H, OCH2 trans/cis
conformers), 7.06, 7.11 (2d, J 8.0 Hz, 8.0 Hz 1H, C4-proton of tetrahydronaphthalene, trans/cis
conformers), 7.44-7.55 (m, 4H, Ar-H), 7.73-7.86 (m, 7H, Ar-H), 8.11, 8.33 (2s, 1H, N=CH trans/cis
conformers), 11.84, 12.03 (2s, 1H, NH exchangeable with D2O trans/cis conformers); 13C NMR (101 MHz,
DMSO) δ: 22.40 (2CH2), 28.64, 28.77 (2CH2), 66.28, 66.93 (OCH2 trans/cis conformers), 115.77 (CN),
127.94, 128.17 (C-4 of tetrahydronaphthalene, trans/cis conformers), 142.84, 144.48 (N=CH trans/cis
conformers), (91.43, 106.06, 115.77, 115.99, 124.43, 129.35, 131.07, 131.16, 132.17 , 133.46, 137.08,
139.98, 155.24, 157.08, 162.56, 162.25) (22, Ar-C), 168.68 (hydrazide C=O); MS, m/z (%): 522.25 (M+, 7),
520.37 (M+-2, 2), 358.13 (41), 357.16 (100), 357.13 (71), 345.12 (44), 344.11 (100), 343.11 (31); Analysis
calcd. for: C31H24F2N4O2 (522.56): C, 71.25; H, 4.63; F, 7.27; N, 10.72; Found: C, 71.19; H, 4.58; F, 7.25; N,
10.79.
N'-Benzylidene-2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-
acetohydrazide (8b). Yield 52%; light beige crystals; m.p. 260-261 °C; the ratio of trans/cis conformers:
75/25. IR (KBr, cm-1): 3223 (NH), 2927 (CH, alicyclic), 2220 (CN), 1664 (hydrazide C=O), 1593 (C=N), 1239
1
(C-F); HNMR (400MHz, DMSO-d6, δppm): 1.66 (br.s, 4H, 2CH2 of tetrahydronaphthalene), 2.67 (m, 4H,
2CH2 of tetrahydronaphthalene), 5.62, 5.09 (2s, 2H, OCH2 trans and cis conformers), 7.05, 7.10 (2d, J=8.0
Hz, 8.0 Hz 1H, C-4 proton of tetrahydronaphthalene, trans/cis conformers), 7.47 (d, J = 8 Hz, 5H, Ar-H),
7.71-7.88 (m, 7H, Ar-H + pyridine-H5), 8.12, 8.33 (2s, 1H, N=CH trans/cis conformers), 11.77, 11.95 (2s,
1H, NH exchangeable with D2O trans/cis conformers); 13C NMR (101 MHz, DMSO) δ: 22.40, 22.48 (2CH2),
28.64 (2CH2), 63.50, 65.59 (OCH2, trans/cis conformers), 113.49 (CN), 128.84, 129.35 (C-4 of
tetrahydronaphthalene, trans/cis conformers), 139.97, 143.89 (N=CH trans/cis conformers), (91.24,
103.54, 115.75, 115.97, 124.44, 129.73, 131.07, 131.16, 133.45, 133.99, 135.11, 137.08, 155.24, 157.08,
161.08, 161.71, 163.22 ) (23, Ar-C), 168.68 (hydrazide C=O); MS, m/z (%): 504.48 (M+, 11), 503.18 (M+-1,
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8), 77.13 (73), 63.09 (100), 62.13 (42.31). Analysis calcd.for C31H25FN4O2 (504.57) C, 73.79; H, 4.99; F, 3.77;
N, 11.10; Found: C, 73.68; H, 4.87; F, 3.72; N, 11.21.
N'-(4-Bromobenzylidene)-2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-
2-yl)oxy)acetohydrazide (8c). Yield 57%; light beige crystals; m.p. 236-2372 °C, the ratio of trans/cis
conformers: 78/22. IR spectrum (KBr, cm-1): 3212 (NH), 2925 (CH, alicyclic), 2221 (CN), 1677 (hydrazide
C=O), 1600 (C=N), 1240 (C-F); 1HNMR (300MHz, DMSO- d6, δ ppm): 1.66 (br.s, 4H, 2CH2 of
tetrahydronaphthalene), 2.67 (m, 4H, 2CH2 of tetrahydronaphthalene), 5.61, 5.09 (2s, 2H, OCH2 trans/cis
conformers), 7.04, 7.08 (2d, J 8.4 Hz, 8.4 Hz 1H, C-4 proton of tetrahydronaphthalene, trans/cis
conformers), 7.46 (t, J 8.8 Hz, 2H, Ar-H), 7.65-7.84 (m, 9H, Ar-H+ Pyridine-H5), 8.09, 8.31 (2s, 1H, N=CH
trans/cis conformers), 11.78, 11.92 (2s, 1H, NH exchangeable with D2O trans/cis conformers); 13C NMR
(300 MHz, DMSO) δ: 22.31, 22.38 (2CH2), 28.56, 28.69 (2CH2) 63.42, 64.97 (OCH2, trans/cis conformers),
115.06 (CN), 128.59, 128.77 (C-4 of tetrahydronaphthalene, trans/cis conformers), 142.66, 145.92 (N=CH,
trans/cis conformers), (91.42, 113.46 , 115.58, 115.87, 123.06, 124.33, 127.81, 129.21, 130.89, 131.01,
131.70, 133.42, 137.04 , 139.89, 155.15, 157.07, 161.42, 163.15, 164.71) (23, Ar-C), 168.59 (hydrazide
C=O); MS, m/z (%): 584.11 (M++1, 4.4), 583.11 (M+, 6), 582.09 (M+-1, 2), 385.08 (100), 357.12 (41), 344.11
(42).Analysis calcd.for: C31H24BrFN4O2 (583.46): C, 63.82; H, 4.15; Br, 13.69; F, 3.26; N, 9.60; Found C,
63.79; H, 4.05; Br, 13.58; F, 3.23; N, 9.79.
N'-(4-Chlorobenzylidene)-2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-
2-yl)oxy)acetohydrazide (8d). Yield 67%; beige crystals; m.p. 231-232 °C, the ratio of trans/cis
conformers: 72/28; IR spectrum (KBr, cm-1): 3208 (NH), 2929 (CH, alicyclic), 2221 (CN), 1677 (hydrazide
C=O), 1593 (C=N), 1239 (C-F); 1HNMR (400 MHz, DMSO-d6, δ ppm): 1.67 (m, 4H, 2CH2 of
tetrahydronaphthalene), 2.65 (m, 4H, 4CH2 of tetrahydronaphthalene), 5.61, 5.09 (2s, 2H, OCH2 trans/cis
conformers), 7.06, 7.11 (2d, J 8.0 Hz, 8.0 Hz 1H, C-4 proton of tetrahydronaphthalene, trans/cis
conformers),7.31 (t, J 8.8 Hz, 2H, Ar-H), 7.46 (t , J 8.8 Hz, 2H, Ar-H), 7.79- 7.86 (m, 7H, Ar-H + pyridine-H5),
8.11, 8.33 (2s, 1H, N=CH trans/cis conformers), 11.78, 11.96 (2s, 1H, NH exchangeable with D2O trans/cis
conformers); 13C NMR (101 MHz, DMSO) δ: 21.07, 22.40 (2CH2), 25.83 (2CH2), 64.77, 65.81 (OCH2 trans/cis
conformers), 113.70 (CN), 128.49, 128.93 (C-4 of tetrahydronaphthalene, trans/cis conformers), 142.40,
145.18 (N=CH, trans/cis conformers), (91.86, 109.74, 115.98, 122.86, 129.35, 130.25, 131.16, 133.45,
134.77, 135.60, 136.79, 156.87, 158.47, 163.86) (22, Ar-C), 168.55 (hydrazide C=O); MS, m/z (%):541.23
(M++2, 5), 539.13 (M+, 16), 123.13 (23.63), 59.14 (18.54), 10.15 (100), Analysis calcd. for: C31H24ClFN4O2
(539.01): C, 69.08; H, 4.49; Cl, 6.58; F, 3.52; N, 10.39; Found: C, 68.96; H, 4.38; Cl, 6.46; F, 3.48; N, 10.42.
2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N'-(4-
cyanobenzylidene)acetohydrazide (8e). Yield 70%; pale yellow crystals; m.p. 230-231 °C the ratio of
trans/cis conformers: 70/30; IR spectrum (KBr, cm-1): 3182 (NH), 2929 (CH, alicyclic), 2224 (CN), 1675
1
(hydrazide C=O), 1596 (C=N), 1226 (C-F); HNMR (400MHz, DMSO-d6, δ ppm): 1.67 (br. s, 4H, 2CH2 of
tetrahydronaphthalene), 2.67 (m, 4H, 2CH2 of tetrahydronaphthalene), 5.64, 5.12 (2s, 2H, OCH2 trans/cis
conformers), 7.05, 7.10 (2d, J=8.0 Hz, 8.0 Hz 1H, C-4 proton of tetrahydronaphthalene, trans/cis
conformers),7.45 (t, J 8.7Hz, 2H, Ar-H), 7.79-7.97 (m, 9H, Ar-H + pyridine-H5), 8.16, 8.39 (2s, 1H, N=CH
trans/cis conformers), 12.01, 12.19 (2s, 1H, NH exchangeable with D2O trans/cis conformers); 13C NMR
(101 MHz, DMSO) δ: 22.38, 22.46 (2CH2), 28.63, 28.77 (2CH2); 62.77, 63.47 (OCH2 trans/cis conformers),
113.58 (CN), 118.62 (CN), 127.42, 127.58 (C-4 of tetrahydronaphthalene, trans/cis conformers), 139.97,
141.99 (N=CH trans/cis conformers), (91.43, 111.80, 115.95, 118.62, 116.66, 129.34, 131.06, 131.14,
132.13, 132.73, 133.43, 137.05, 138.43, 155.22, 157.07, 162.05, 163.17) (23C, Ar-C), 169.04 (hydrazide
C=O);MS, m/z (%): 531.30 (M++2, 2), 530.36 (M++1, 3), 529.48 (M+, 6), 528.53 (M+-1, 2), 431.20 (30),
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368.43 (58), 358.22 (100) , 357 (70), 327.30 (58); Analysis calcd. for: C32H24FN5O2 (529.58): C, 72.58; H,
4.57; F, 3.59; N, 13.22; Found: C, 72.47; H, 4.49; F, 3.53; N, 13.31.
2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N'-(4-methoxy-
benzylidene)acetohydrazide (8f). Yield 56%; colorless powder; m.p. 222-223 °C, the ratio of trans/cis
conformers: 75/25; IR spectrum (KBr, cm-1): 3204 (NH), 2928 (CH, alicyclic), 2221 (CN), 1681 (hydrazide
C=O), 1603 (C=N), 1250 (C-F); 1HNMR (400MHz, DMSO-d6, δppm): 1.69 (br.s, 4H, 2CH2 of
tetrahydronaphthalene), 2.69 (m, 4H, 2CH2 of tetrahydronaphthalene), 3.81 (s, 3H, OCH3), 5.39, 5.07 (2s,
2H, OCH2 trans/cis conformers), 7.00-7.13 (m, 3H, C-4 proton of tetrahydronaphthalene trans/cis
conformers + Ar-H), 7.013, 7.061, 7.113 (3d, 3H, C4-proton of tetrahydronaphthalene trans/cis conformers
+ Ar-H), 7.42-7.91 (m, 9H, Ar-H + Pyridine-H5), 8.07, 8.26 (2s, 1H, N=CH trans/cis conformers), 11.64,
11.80 (2s, 1H, NH exchangeable with D2O trans/cis conformers); 13C NMR (101 MHz, DMSO) δ: 22.19
(2CH2), 29.50 (2CH2), 56.07 (OCH3), 65.93, 66.91 (OCH2 trans/cis conformers), 114.80 (CN), 128.86, 128.92
(C-4 of tetrahydronaphthalene, trans/cis conformers), 140.09, 142.36 (N=CH trans/cis conformers),
(89.38, 106.08, 114.17, 116.73, 122.38, 126.46, 129.32, 130.34, 133.38, 134.00, 136.63, 156.93, 157.77,
162.75, 163.64, 164.06 ) (23, Ar-C), 168.07 (hydrazide C=O); MS, m/z (%): 536.47 (M++2, 83), 534.41 (M+,
90), 530.29 (28), 503.20 (39), 496.68 (35), 491.29 (44), 464.09 (45), 459.08 (46), 428.97 (37), 416.78 (33),
360.86 (44), 283.00 (55), 265.46 (72), 150.00 (39), 117.89 (29), 91.84 (43), 65.40 (100); Analysis calcd.for
C32H27FN4O3 (534.59): C, 71.90; H, 5.09; F, 3.55; N, 10.48; Found: C, 71.82; H, 5.03; F, 3.49; N, 10.57.
General procedure for synthesis of thiazolidinone 11a and 11c-f. A solution of Schiff bases (8a and 8c-f)
(0.001 mol), and thioglycolic acid (9) (0.165 g; 0.0015 mol), in dry benzene (50) mL was heated at refluxed
for 6 h. Progress of the reaction was checked by TLC using benzene-ether as eluent. After evaporation of
the solvent under reduced pressure, the resulting viscous liquid was treated with saturated sodium
bicarbonate solution to remove unreacted thioglycolic acid. The product separated out was washed with
water, dried and recrystallized from ethanol to afford compounds 11a and 11c-f.
2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N-(2-(4-
fluorophenyl)-4-oxothiazolidin-3-yl)acetamide (11a). Yield 65%; beigh crystals; m.p. 240-242 °C; IR
spectrum (KBr, cm-1): 3439 (NH), 2924 (CH, alicyclic), 2223 (CN), 1724 (C=O of 4-thiazolidinone ring), 1677
(C=O amide), 1600 (C=N), 1228 (C-F); 1H NMR (400MHz, DMSO-d6, δppm): 1.77, 2.79 (2 br.s, 4H, 4H, 4CH2
of tetrahydronaphthalene), 3.73, 3.89 (2d, 2H, thiazolidinone-CH2), 5.03, 5.10 (2d, 2H, 2-methylene-H of
OCH2), 5.74 (s, 1H, thiazolidinone-H-2), 7.02-7.11 (m, 2H, Ar-H), 7.32 -7.48 (m, 4H, Ar-H), 7.70-7.95 (m, 6H,
Ar-H+ pyridine-H5), 10.63 (s, 1H, NH exchangeable with D2O); 13C NMR (101 MHz, DMSO) δ : 22.61 (2CH2),
28.77 (2CH2) , 35.34 (SCH2CO) , 64.28 (NCHS), 65.80 (OCH2), 97.11 (C-CN), 114.37 (CN), 161.93 (C-F),
167.11 (C=O), 168.56 (C=O), (104.46, 115.77, 124.53 , 127.38, 129.40 , 131.02, 132.06, 133.17, 134 ,
135.12 , 136.01, 157.35 , 157.76 , 163.15, 164.89 ) (21, Ar-C); MS, m/z (%): 596.65 (M+, 8), 97.17 (8.),
85.17 (26.84) , 71.15 (82.42), 57.14 (100); Analysis calcd. for: C33H26F2N4O3S (596.65): C, 66.43; H, 4.39; F,
6.37; N, 9.39; S, 5.37; found: C, 66.38; H,4.28; F, 6.17; N, 9.48; S, 5.24.
N-(2-(4-Bromophenyl)-4-oxothiazolidin-3-yl)-2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydro-
naphthalen-2-yl)pyridin-2-yl)oxy)acetamide (11c). Yield 66%; light beigh crystals; m.p. 246-248 °C; IR
spectrum (KBr, cm-1): 3441 (NH), 2925 (CH, alicyclic), 2220 (CN), 1715 (C=O of 4-thiazolidinone ring), 1675
1
(C=O amide), 1598 (C=N), 1230 (C-F); H NMR (400MHz, DMSO-d6, δppm): 1.75 (br. s, 4H, 2CH2 of
tetrahydronaphthalene), 2.79 (br.s, 4H, 2CH2 of tetrahydronaphthalene), 3.73, 3.89 (2d, 2H,
thiazolidinone-CH2), 5.04, 5.11 (2d, 2H, 2-methylene-H of OCH2), 5.72 (s, 1H, thiazolidinone-H-2), 7.08 (d, J
8.0 Hz, 1H, Ar-H), 7.23 (d, J 8.0 Hz, 2H, Ar-H), 7.38-7.48 (m, 4H, Ar-H), 7.74-7.95 (m, 5H, Ar-H + pyridine-
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H5), 10.72 (s, 1H, NH exchangeable with D2O); 13C NMR (101 MHz, DMSO) δ: 22.53 (2CH2), 28.80 (2CH2),
34.65 (CH2), 60.82 (NCHS), 63.59 (OCH2), 115.07 (CN), (91.65, 107.47, 115.77, 120.60, 125.01, 127.92,
129.28, 130.14, 131.01, 131.34, 133.21, 133.33, 134.90, 136.43, 138.28, 155.01, 157.30, 162.61, 164.62)
(22, Ar-C) 166.55 (C=O), 168.87 (C=O); MS, m/z (%): 656.18 (M+, 6), 440.16 (5), 385.14 (5), 357.94 (9),
344.18 (19), 257.94 (9), 184.01 (19), 89.07 (65), 77.09 (87), 76.09 (94.18), 75.09 (100); Analysis calcd. for:
C33H28BrFN4O3S (657.56): C, 60.28; H, 3.99; Br, 12.15; F, 2.89; N, 8.52; S, 4.88; found: C, 60.19; H, 3.89; Br,
12.11; F, 2.78; N, 8.61; S, 4.83.
N-(2-(4-Chlorophenyl)-4-oxothiazolidin-3-yl)-2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-
tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)acetamide (11d). Yield 62%; light beigh crystals; m.p. 240-
242 °C; IR spectrum (KBr, cm-1): 3439 (NH), 2925 (CH, alicyclic), 2220 (CN), 1711 (C=O of 4-thiazolidinone
1
ring), 1677 (C=O amide), 1600 (C=N), 1231 (C-F); H NMR (400 MHz, DMSO-d6, δ ppm): 1.77 (br.s, 4H,
2CH2 of tetrahydronaphthalene), 2.79 (br.s, 4H, 2CH2 of tetrahydronaphthalene), 3.74, 3.89 (2d, 2H,
thiazolidinone-CH2), 5.06, 5.09 (2d, 2H, 2-methylene-H of OCH2), 5.74 (s, 1H, thiazolidinone-H-2), 7.09 (d, J
8.0 Hz, 1H , Ar-H), 7.27-7.30 (m, 3H, Ar-H), 7.46 (t, J 8.0 Hz, 3H, Ar-H), 7.75-7.84 (m, 4H, Ar-H), 7.90 (s, 1H,
pyridine-H5), 10.67 (s, 1H, NH exchangeable with D2O); 13C NMR (101 MHz, DMSO) δ: 22.53 (2CH2), 28.77
(2CH2) , 32.71 (SCH2CO) , 62.00 (NCHS), 69.33 (OCH2), 97.80 (C-CN), 114.33 (CN), 132.97 (C-Cl), 166.62
(C=O), 168.21 (C=O), (106.72 , 116.11 , 121.83, 126.40 , 128.43 , 129.43 , 131.25 , 133.17 , 134.22 , 136.22
, 140.98 , 155.91 , 157.29 , 162.74, 165.02 ) (21, Ar-C); MS, m/z (%): 613.99 (M+, 14), 210.15 (72.02),
123.12 (23),.71.15 (36.49), 69.18 (100); Analysis calcd. for :C33H26ClFN4O3S (613.10): C, 64.65; H, 4.27; Cl,
5.78; F, 3.10; N, 9.14; S, 5.23; found: C, 64.58; H, 4.19; Cl, 5.69; F, 2.99; N, 9.26 S, 5.19.
2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N-(2-(4-
cyanophenyl)-4-oxothiazolidin-3-yl)acetamide (11e). Yield 60%; light green crystals; m.p. 190-192 °C; IR
spectrum (KBr,cm-1): 3435 (NH), 2928 (CH, alicyclic), 2224 (CN), 1729 (C=O of 4-thiazolidinone ring), 1685
1
(C=O amide), 1595 (C=N), 1233 (C-F); H NMR (400MHz, DMSO-d6, δppm): 1.75 (br. s, 4H, 2CH2 of
tetrahydronaphthalene), 2.77 (br. s, 4H, 2CH2 of tetrahydronaphthalene) 3.75, 3.93 (2d, 2H,
thiazolidinone-CH2), 5.05, 5.09 (2d, 2-methylene-H of OCH2), 5.83 (s, 1H, thiazolidinone-H-2), 7.05 (d, J 8.1
Hz, 1H, Ar-H), 7.45 (d, J 8.0 Hz, 4H, Ar-H), 7.62-7.66 (m, 2H, Ar-H), 7.74- 7.94 (m, 5H, Ar-H + pyridine-H5),
10.82 (s, 1H, NH exchangeable with D2O); 13CNMR (101 MHz, DMSO) δ: 22.55 (2CH2), 28.84 (2CH2), 35.39
(CH2) 59.65 (NCHS), 61.45 (OCH2), 97.45 (C-CN), 111.48 (C-CN), 115. 76 (CN), 121.23 (CN), 168.76 (2 C=O),
(101.66, 117.26, 123.91, 127.58, 128.20, 130.62, 132.33, 134.63, 136.42, 137.93, 157.77, 161.70, 164.75,
166.60), (21, Ar-C); MS, m/z (%): 605.69 (M++2, 3), 603.17 (M+, 10), 430.24 (76), 357.21 (100), 102.13 (61),
76.03 (88); Analysis calcd. for: C34H28FN5O3S (603.67) C, 67.65; H, 4.34; F, 3.15; N, 11.60; S, 5.31; found: C,
67.50; H, 4.22; F, 3.05; N, 11.68; S, 5.22.
2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N-(2-(4-
methoxyphenyl)-4-oxothiazolidin-3-yl)acetamide (11f). Yield 73%; light beigh crystals; m.p. 260-262 °C;
IR spectrum (KBr, cm-1): 3437 (NH), 2919 (CH, alicyclic), 2221 (CN), 1712 (C=O of 4-thiazolidinone ring),
1678 (C=O amide), 1608 (C=N), 1231 (C-F); 1H NMR (400MHz, DMSO-d6, δppm): 1.77, 2.79 (2 br.s, 4H, 4H,
4CH2 of tetrahydronaphthalene), 3.69 (s, 3H, OCH3), 3.77, 3.85(2d, 2H, thiazolidinone-CH2), 5.00, 5.15 (2d,
2-methylene-H of OCH2), 5.68 (s, 1H, thiazolidinone-H-2), 6.79 (d, J 8.0 Hz, 1H, Ar-H), 7.12, 7.22 (2d, J 8.0
Hz, J 8.0 Hz, 2H, Ar-H), 7.47 (d, J 8.0 Hz, 3H, Ar-H), 7.69-7.92 (m, 6H, Ar-H + pyridine-H5), 10.57 (s, 1H, NH
13
exchangeable with D2O); C NMR (101 MHz, DMSO) δ: 22 (2CH2), 29.72 (2CH2), 32.77 (SCH2CO), 56.56
(OCH3), 65.38 (NCHS), 68.15 (OCH2), 114.79 (CN), 166.62 (C=O), 168.55 (C=O), (91.09, 110.31, 113.76,
116.72, 119.97, 128.40, 129.52, 130.55, 131.65, 133.80, 134.90, 135.11, 136.63, 156.95, 157.15, 158.00,
162.54, 164.27) (22, Ar-C); MS, m/z (%): 608.69 (M+, 10), 91.15 (2), 85.19 (5), 71.18 (23), 57.15 (100);
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Analysis calcd. for :C34H29FN4O4S (608.69): C, 67.09; H, 4.80; F, 3.12; N, 9.20; S, 5.27;found: C, 66.98; H,
4.75; F, 3.05; N, 9.29; S, 5.23.
2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N'-(2-oxoindolin-
3-ylidene)acetohydrazide (13). A mixture of the hydrazide 7 (0.416g, 1 mmol) and isatin 12 (0.147g, 1
mmol) in absolute ethanol (20 mL) containing glacial acetic acid (0.5 mL) was heated at reflux for 10 h.
The precipitate formed was collected by filtration while hot, washed with hot ethanol, dried and
recrystallized from AcOH to afford compound 13.
Yield: 86%; yellow crystals; m.p. 288‐300 °C; IR spectrum (KBr, cm-1): 3427, 3212 (NH), 2926 (CH, alicyclic), 2228
(CN), 1709 (C=O of isatin ring), 1657 (C=O amide), 1622 (C=N) 1228 (C-F); 1H NMR (DMSO-d6, δ ppm): 1.66 (br.s, 4H,
2CH2 of tetrahydronaphthalene), 2.68 (m, 4H, 2CH2 of tetrahydonaphthalene), 5.30, 5.78 (br. 2s, 2H, OCH2 trans/cis
conformers), 6.97-7.13 (m, 3H, Ar-H), 7.38-7.49 (m, 4H, Ar-H), 7.82-7.87 (m, 5H, Ar-H+Pyridine-H5), 11.35 (s, 1H,
NH of isatin exchangeable with D2O), 12.78, 13.40 (br. 2s, 1H, NH exchangeable with D2O trans/cis conformers); 13C
NMR (101 MHz, DMSO) δ: 22.95 (2CH2), 29.12 (2CH2), 66.39 (OCH2), 114.66 (CN), (93.58, 108.22, 116.26, 116.43,
116.48, 119.47 , 123.20, 123.67, 128.45, 129.80, 131.69, 133.59 , 133.84, 135.17, 136.13, 143.04, 155.90, 156.65,
163.09, 164.77) (24, Ar-C) 167.90, 168.75 (2 C=O); MS, m/z (%): 545.57 (M+, 6), 385.09 (76 ), 384.09 (30), 358.10
(100), 357.07 (83); Analysis calcd. for C32H24FN5O3 (545.57): C, 70.45; H, 4.43; F, 3.48; N, 12.84; Found: C, 70.39; H,
4.38; F, 3.43; N, 12.92.
Acetic-N'-acetyl-2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-
yl)oxy)acetohydrazonic anhydride (15). A mixture of acetohydrazide 7 (0.416 g, 0.001 mol) and acetic
anhydride (5 mL) was heated at reflux for 6 h. After cooling, the reaction mixture was treated with ethanol
and the formed precipitate was filtered, washed with ethanol. The dried crude product was crystallized
from EtOH/DMF to give 15.
Yield % 80; colorless crystals; m.p.200-202 °C; IR spectrum (KBr, cm-1): 3301 (NH), 2938 (CH, alicyclic), 2224
(CN), 1742 (acetoxy C=O), 1670 (amide C=O), 1590 (C=N), 1204 (C-F); 1HNMR (300MHz, DMSO-d6, δ ppm):
1.71 (br. s, 4H, 2CH2 of tetrahydronaphthalene), 2.34 (s, 3H, NHCO-CH3), 2.35 (s, 3H, OCOCH3), 2.72 (m,
4H, 2CH2 of tetrahydronaphthalene), 5.69 (s, 2H, CH2), 7.12 (d, J 7.8Hz ,1H, Ar-H), 7.39 (t, J 8.7 Hz, 2H, Ar-
H), 7.68 (s, 1H, Ar-H), 7.73-7.80 (m, 4H, Ar-H+Pyridine-H5), 10.59 (s, 1H, NH exchangeable with D2O); 13C
NMR (101 MHz, DMSO) δ: 22.49, 22.58 (2CH3), 24.48 (2CH2), 28.68 (2CH2), 65.93 (OCH2), 114.78 (CN),
162.84 (C=NNH), (91.57, 104.31, 115.77, 115.98, 124.72, 128.25, 129.37, 129.74, 131.19, 131.59, 133.29,
136.24, 137.22, 156.44, 157.48, 163.31, 164.41) (18C, Ar-C), 168.63, 170.78 (2C=O); MS, m/z (%): 500.23
(M+, 14), 458.40 (9), 385.18 (23.44), 344.15 (33.16), 98.02 (57.31), 56.08 (100); Analysis Calcd. for
C28H25FN4O4 (500.53), C, 67.19; H, 5.03; F, 3.80; N, 11.19; Found: C, 67.08; H, 4.95; F, 3.74; N, 11.28.
N'-(2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-
yl)oxy)acetyl)benzohydrazide (17). A mixture of hydrazide 7 (0.416 g , 0.001 mol) and benzoyl chloride 16
(0.1405 g, 0.001 mol) in 10 mL pyridine was heated at reflux for 24 h then cooled and poured onto
ice/water acidified with HCl. The obtained solid was filtered off, washed with water, dried and crystalized
from EtOH/DMF to give the benzohydrazide derivative 17.
Yield 81%; pale yellow crystals; m.p. 272-274 °C; IR (KBr, cm-1): 3432, 3230 (2NH), 2925 (CH, alicyclic),
1
2222 (CN), 1728, 1716 (2C=O), 1607 (C=N), 1232 (C-F); H NMR (300MHz, DMSO-d6, δppm): 1.77 (br s, 4H,
2CH2 of tetrahydronaphthalene), 2.81 (m, 4H, 2CH2 of tetrahydonaphthalene), 5.22 (s, 2H, OCH2 ), 7.16 (d,
J =8.4 Hz, 1H, Ar-H), 7.45-7.51 (m, 5H, Ar-H), 7.81-7.99 (m, 7H, Ar-H+Pyridine-H5), 10.37 (s, 1H, NH
exchangeable with D2O), 10.46 (s, 1H, NH exchangeable with D2O); 13C NMR (101 MHz, DMSO) δ: 21.57,
22.61(2CH2), 28.55, 29.18 (2CH2), 65.98 (OCH2), 115.78 (CN), (95.04, 108.72, 116.59, 123.29, 127.45,
128.48, 129.10, 130.61, 130.97, 133.11, 135.17, 136.76, 155.02, 155.64, 162.96) (23 C, Ar-C), 165.36,
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168.08 (2 C=O); MS, m/z (%): 521.18 (M++1, 2), 520.19 (M+, 5), 519.26 (M+-1, 2), 516.20 (2), 515.12 (3),
514.12 (2), 445.14 (37), 444.14 (100); Analysis calcd. for: C31H25FN4O3 (520.19): C, 71.53; H, 4.84; F, 3.65;
N, 10.76; Found: C,71.41; H,4.78; F, 3.59; N, 10.88.
2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)-N'-formylaceto-
hydrazide (19). A mixture of 7 (0.832 g, 0.002 mol) and formic acid 17 (10 mL) was heated at reflux for 6
h. The resulting solid on heating was collected by filtration, washed with hot ethanol, dried and
recrystallized from ethanol/DMF to give 19.
Yield 78%; off white crystals; m.p:244-246 oC; IR (KBr, cm-1): 3440 (br, NH), 2922 (CH , alicyclic), 2220 (CN),
1
1724 (C=O), 1622 (C=O), 1247 (C-F); HNMR (400 MHz, DMSO-d6, δppm): 1.76 (br.s, 4H, 2CH2 of
tetrahydronaphthalene), 2.77 (br.s, 4H, 2CH2 of tetrahydronaphthalene), 5.08 (s, 2H, OCH2), 7.15 (d, J 8.0
Hz, 1H, Ar-H) ,7.44 (t, J 8.0 Hz, 2H, Ar-H), 7.81 –7.91 (m, 5H, Ar-H+Pyridine-H5), 8.04 (s, 1H, –CH=O
aldehydic proton), 10.23, 10.51 (2s, 2NH, exchangeable with D2O), 13C NMR (101 MHz, DMSO) δ: 22.48
(2CH2), 28.72 (2CH2), 65.50 (OCH2), 115.75 (CN), (97.13, 107.43, 115.96, 123.48, 128.04, 129.48, 131.08,
131.17, 133.50, 136.57, 137.23, 154.45, 155.29, 163.00) (17C, Ar-C),161.63, 169.70 (2C=O); MS, m/z (%):
445.15 (M++1, 2), 444.12 (M+, 7), 403.08 (20), 402.08 (100), 358.11 (26), 357.09 (95), 344.20 (26), 343.06
(22); Analysis Calcd. for C25H21FN4O3 (444.47): C, 67.56; H, 4.76; F, 4.27; N, 12.61; Found: C, 67.58; H, 4.69;
F, 4.23; N, 12.68
Methyl2-(2-((3-cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)acetyl)-
hydrazine-1-carbodithioate (20). To a mixture of acetohydrazide 7 (0.416 g, 0.001 mol) and triethylamine
(0.14 mL, 0.001 mol) in ethanol (15 mL), carbon disulfide (0.80 mL, 0.001 mol) was added dropwise.
Methyl iodide (0.062 mL, 0.001 mol) was then added and the reaction mixture was stirred at room
temperature for 30 min. Water (50 mL) was then added and the formed precipitate was filtered off,
washed with water, dried and recrystallized from EtOH/DMF to give 20.
Yield 68%; light brown crystals; m.p: 210-212 oC; IR (KBr, cm-1): 3439 (NH), 2925 (CH, alicyclic), 2219 (CN),
1
1717 (C=O), 1624 (C=N), 1232 (C-F); HNMR (300 MHz, DMSO-d6, δppm): 1.76 (br.s, 4H, 2CH2 of
tetrahydronaphthalene), 2.56 (s, 3H, SCH3), 2.76 (br.s, 4H, 2CH2 of tetrahydronaphthalene), 5.16, 5.46
(2s, 2H, OCH2), 7.15 (d, J = 8.1 Hz, 1H, Ar-H), 7.44 (t, J = 8.7 Hz, 2H, Ar-H), 7.78 –7.90 (m, 5H, Ar-H +
Pyridine-H5), 10.69 (s, 1H, NH, exchangeable with D2O), 10.75(s, 1H, NH, exchangeable with D2O); 13C
NMR (101 MHz, DMSO) δ: 19.56 (SCH3), 22.49 (2CH2), 28.72, 29.74 (2CH2), 64.30 (OCH2), 113.55 (CN),
(93.84, 105.54, 115.98, 122.39, 128.82, 129.10, 131.15, 132.28, 134.91, 136.43, 137.19, 155.98, 158.06,
163.11, 164.07) (17C, Ar-C), 168.14 (C=O), 201.65 (C=S); MS, m/z(%) : 510.68 (M++4, 52.52), 506.30 (M+,
100); Analysis calcd. for: C26H23FN4O2S2 (506.61): C, 61.64; H, 4.58; F, 3.75; N, 11.06; S, 12.66; Found: C,
61.56; H, 4.49; F, 3.67; N, 11.19; S, 12.64.
2-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-oxoethoxy)-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-
2-yl)nicotinonitrile (23). A mixture of acetohydrazide 7 (0.416 g, 0.001 mol) and acetyl acetone 20 (2 mL)
was heated at reflux for 12 h. After cooling the fused mixture was treated with ethanol and filtered. The
crude product was crystallized from ethanol to give compound 23.
Yield: 65 %; Light brown crystals; m.p.: 190‐192 °C; IR spectrum (KBr, cm-1): 2929 (CH, alicyclic), 2219 (CN),
1
1726 (C=O), 1594 (C=N), 1227 (C-F); HNMR (400 MHz, DMSO-d6, δ ppm): 1.76 (m, 4H, 2CH2 of
tetrahydronaphthalene), 2.29 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.72 (br. s, 4H, 2CH2 of
tetrahydronaphthalene), 5.90 (s, 2H, OCH2), 6.35 (s, 1H, CH pyrazole), 7.05 (d, J 8.0 Hz, 1H, Ar-H), 7.46 (t, J
8.0 Hz, 2H, Ar-H), 7.60 (s, 1H, Ar-H), 7.68 (d, J 8.0 Hz, 1H, Ar-H), 7.69-7.87 (m, 3H, Ar-H + pyridine-H5); 13C
NMR (101 MHz, DMSO) δ: 13.56, 13.60 (2CH3), 22.50 (2CH2), 28.61 (2CH2), 68.55 (OCH2), 113.31 (CN),
(92.26,102.64, 110.31, 115.77, 115.98, 121.57, 127.72, 129.80, 129.80, 131.12, 132.76, 134.30, 135.65,
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136.71, 150.45, 154.54, 156.53, 159.39, 163.83, 165.99) (20C, Ar-C), 168.16 (C=O); MS, m/z (%): 482.25
(M++2, 5), 480.79 (M+, 9), 478.74 (M+-2, 7), 292.15 (26), 210.13 (100), 57.11 (42); Analysis Calcd. For
C29H25FN4O2: (480.54), C, 72.48; H, 5.24; F, 3.95; N, 11.66; Found: C, 72.35; H, 5.19; F, 3.89; N, 11.73.
N-(2-(2-((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)acetyl)-5-
oxo-2,5-dihydro-1H-pyrazol-3-yl)acetamide (26). To a solution of acetohyrazide 7 (0.416 g, 0.001 mol) in
10% KOH solution (10 mL), ethyl cyanoacetate 3 (0.113 g, 0.001 mol) was refluxed in absolute ethanol (20
ml) for 10 h, then glacial acetic acid (5 mL) was added and the reaction mixture was heated at reflux for
another 2 h. The solid obtained upon cooling, dilution with water, acidification with conc. HCl and leaving
in the fridge till next day was filtered, washed with water, dried and crystallized from acetic acid.
Yield 76%; off colorless crystals; m. p. 298-300 °C; IR spectrum (KBr, cm-1): 3440 (OH), 3196 (NH), 2926
(CH, alicyclic), 2218 (CN), 1606 (br 2 C=O), 1230 (C-F); 1HNMR (300 MHz, DMSO-d6, δppm): 1.77 (br. s,
4H, 2CH2 of tetrahydronaphthalene), 1.87 (s, 3H, COCH3), 2.78 (m, 4H, 2CH2 of tetrahydronaphthalene),
5.11 (s, 2H, OCH2), 7.18 (d, J 8.4 Hz, 1H, Ar-H), 7.42-7.95 (m, 8H, Ar-H, CH-pyrazoleand Pyridine-H5), 9.89
13
(s, 1H, NH exchangeable with D2O), 10.21 (s, 1H, OH exchangeable with D2O); CNMR (101 MHz, DMSO)
δ: 20.90 (CH3), 23.03, 23.10 (2CH2), 28.69, 29.26 (2CH2), 64.26 (OCH2), 114.29 (CN), (92.28, 93.02, 106.69,
116.48, 123.83, 128.71, 129.96, 131.62, 132.67, 134.00, 136.02, 137.72, 140.44, 155.62, 157.61 163.58,
164.85) (19C, Ar-C), 166.49, 168.35 (2 C=O); MS, m/z (%): 525.35 (M+, 5), 385.15 (30), 357.16 (33), 85.10
(24),74.12 (100); Analysis Calcd. for: C29H24FN5O4 (525.54):C, 66.28; H, 4.60; F, 3.62; N, 13.33; Found: C,
66.19; H, 4.53; F, 3.58; N, 13.39.
2-(5-(((3-Cyano-4-(4-fluorophenyl)-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)oxy)methyl)-1,3,4-
oxadiazol-2(3H)-ylidene)malononitrile (30). A mixture of the acetohydrazide 7 (0.416 g, 0.001 mol) and
[bis(methylthio)methylene]-malononitrile (0.174 g, 0.001 mol), in absolute ethanol (30 mL) was heated at
reflux for 12 h. The crystalline precipitate so formed under reflux was filtered off, washed with hot
ethanol and crystallized from DMF to give the 1,3,4-oxadiazole 30.
Yield 76%; Orange crystals; m.p. > 340 oC; IR spectrum (KBr, cm-1): 3172 (NH), 2926 (CH, alicyclic), 2219
(CN), 1614 (C=N), 1228 (C-F), 1141 (C-O-C); 1H NMR (300 MHz, DMSO-d6, δ ppm): 1.63 (m, 4H, 2CH2 of
tetrahydronaphthalene), 2.72 (m, 4H, 2CH2 of tetrahydronaphthalene), 5.13, 4.87, 5.26 (3s, 2H, OCH2),
6.81, 6.98, 7.07 (3d, J 7.5 Hz, J 8.1 Hz, J = 8.1 Hz, 1H, C-4 of tetrahydronaphthalene), 7.44-7.54 (m, 3H, Ar-
H), 7.70- 7.90 (m, 4H, Ar-H + Pyridine-H5), 9.48, 10.46, 10.49 (3s, 1H, NH oxadiazole, exchangeable with
D2O); 13C NMR (101 MHz, DMSO) δ: 22.97 (2CH2), 25.66 (CN-C-CN), 29.27 (2CH2), 71.19, 71.48, 71.74
(OCH2), 113.55 (2CN), 113.98 (CN), (93.60, 109.75, 116.32, 122.41, 126.60, 126.39, 127.78, 128.46,
130.91, 133.44, 134.28, 135.34, 136.09, 155.95, 156.78, 163.84, 164.48) (17C, Ar-C), 157.82 (C5 of
oxadiazole), 208.62 (C2 of oxadiazole); MS: m/z (%): 490.50 (M+, 26), 358.15 (64), 357.14 (66), 344.13
(100), 343.12 (94.86); Analysis Calcd. for C28H19FN6O2 (490.50): C, 68.56; H, 3.90; F, 3.87; N, 17.13; Found:
C, 68.49; H, 3.87; F, 3.83; N, 17.21.
2. In-vitro anticancer activities
The cytotoxicity activities on HCT116 (colorectal carcinoma) and MCF-7 (human breast adenocarcinoma)
human cell lines was assessed using the 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide
(MTT) assay.46-48 These cancer cell lines were purchased from ATCC (Rockville, MD, USA). The cells were
cultured in a 96-well sterile microplate (5 × 104 cells per well) at 37°C in Dulbecco's Modified Eagle's
medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 100 U/mL of
both penicillin and streptomycin in a 5% CO2 humidified atmosphere. After 24 hours, the media were
removed and a fresh serum-free medium (90 uL / well) were added together with 10 uL of series of each
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compound or doxorubicin® (positive control) concentrations in DMSO for 48 hours. Then, media were
removed, MTT (40 µL of 2.5 mg/mL) was added to each well and incubated for 4 hours. 200 µL of DMSO
were added to solubilize the formazan dye crystals (purple color). Using a SpectraMax® Paradigm®Multi-
Mode microplate reader, the absorbance was measured at 570 nm. Each experiment was repeated on
three different days and conducted in triplicate. The relative cell cytotoxicity was measured according to
the following equation:
% cytotoxicity = (1 – As/Ab)*100
Where; As = Absorbance of each sample and Ab = Absorbance of the blank. The probit analysis using
the SPSS software program (version 20, SPSS Inc., Chicago, IL, USA) was used to determine each IC50.
Acknowledgements
The authors thank the management and the authorities of National Research Centre, Dokki, Cairo, Egypt,
for their kind support and constant encouragement. The authors are gratefully acknowledge the school of
Chemical Engineering at Aalto University, Finland and German Research Foundation (DFG), Germany for
performing NMR analyses.
Supplementary Material
Supplementary material related to this article, including Nuclear Magnetic Resonance (1H and 13C NMR)
figures for compounds 8b; 8c; 8d; 8e; 11c; 11d; 15; 17 and 23 are available in the online version of the
text.
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