Green synthesis of 1,3,4-oxadiazole derivatives based on N-arylidene-2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide as potential antitumor agents

Article abstract of DOI:10.1002/jhet.4181

Design of a new series of 1,3,4-oxadiazole derivatives was achieved in good yield via treatment of N-arylidene-2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide with cerium (IV) ammonium nitrate as a catalyst. They can be formulated also using one-pot reaction of 2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide, aromatic aldehyde and cerium (IV) ammonium nitrate in dichloromethane. The structural formulas of all synthesized products were elucidated based on their elemental and spectral analyses. In addition, MTT assay was used to evaluate antitumor activity of the synthesized molecules and some of them showed potent activity in comparison with Doxorubicin as a standard drug.

Full text of DOI:10.1002/jhet.4181

Green synthesis of 1,3,4-oxadiazole derivatives based on N-arylidene-
2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide as
potential antitumor agents
Mohamed S. Behalo*, Ebtsam S. El said
Chemistry Department, Faculty of Science, Benha University, Benha, P. O. Box
13518. Egypt
Corresponding author: mohamed.behalo@fsc.bu.edu.eg
Abstract:
Design of a new series of 1,3,4-oxadiazole derivatives was achieved in good yield via
treatment
of
N-arylidene-2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-
yl)acetohydrazide with cerium (IV) ammonium nitrate as a catalyst. They can be
formulated also using one-pot reaction of 2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-
2(1H)-yl)acetohydrazide, aromatic aldehyde and cerium (IV) ammonium nitrate in
dichloromethane. The structural formulas of all synthesized products were elucidated
based on their elemental and spectral analyses. In addition, MTT assay was used to
evaluate antitumor activity of the synthesized molecules and some of them showed
potent activity in comparison with Doxorubicin as a standard drug.
Keywords:
Phthalazine; hydrazide; cerium (IV) ammonium nitrate; oxadiazole; antitumor activity
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Introduction
Recently, cerium (IV) ammonium nitrate (CAN) gained great attention as one of the
most convenient and widely used inexpensive catalysts for several types of chemical
reactions. It is employed in the design of organic molecules via bond formation
between two carbons or carbon and heteroatom [1-3]. In addition, easy handling, the
low toxicity and good solubility of CAN in a large number of organic solvents
increase its use as an efficient green catalyst [4]. On the other hand, 2,5-disubstituted-
1,3,4-oxadiazoles constitute one of the most important class of nitrogen heterocyclic
molecules, they possess a variety of biological effects including antibacterial [5-7],
anti–inflammatory [8], antifungal [9], anticancer[10-14], antiviral [15] and
antitubercular [16,17] activities. It was reported that, 1,3,4-oxadiazoles can be used
also in various optoelectronic applications owing to their good blue fluorescent
properties with better quantum yield [18,19].
Oxadiazole moiety can be formulated through different synthetic pathways. Among
these, oxidation of acylhydrazone with oxidizing agents [20-22] or treatment of acid
hydrazide with carboxylic acids and acid halide derivatives [23]. In addition,
phthalazine derivatives were used as reactive starting targets in the design of novel
biologically active molecules that exert potent antimicrobial [24-26], antitumor [27-
30] analgesic and anti-inflammatory activities [31-33].
Based on the above mentioned observations and in continuation of our interest for
synthesis of bio-active heterocyclic molecules [34-39], the present work deals with
the synthesis of oxadiazole derivatives attached to phthalazine moiety in an attempt to
obtain new molecules with potent antitumor activity.
Results and discussion
Synthesis of (1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide
(4) as the key compound in this work proceeded via the following steps. Initially, 2-
(4-phenoxybenzoyl)benzoic acid (1) [prepared via Fridel- crafts acylation of diphenyl
ether with phthalic anhydride in the presence of anhydrous aluminium chloride in
tetrachloroethane as a solvent]30 was treated with hydroxyl amine in pyridine to give
4-(3-phenoxyphenyl)-1H-benzo[d][1,2]-oxazin-1-one (2).
2
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The structural formula of benzoxazinone 2 was confirmed on the basis of its
spectral data and elemental analyses. IR spectrum showed characteristic bands at
1734, 1615 cm-1 corresponding to CO and C=N absorptions respectively. On the other
1
hand, H NMR spectrum confirmed disappearance of acidic proton in acid 1 and
displayed only signals at 7.13-8.34 ppm corresponding to aromatic protons.
Benzoxazinone 2 reacted with ethyl glycinate in ethanol in the presence of
sodium acetate to afford ester 3. The latter reacted with hydrazine hydrate to give 2-
(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide (4), (Scheme 1). IR
spectrum of hydrazide 4 confirmed the presence of characteristic absorption bands of
2 CO, NH and NH2 at 1684-1670 and 3447-3155 cm-1 respectively and disappearance
of ester absorption band at 1733 cm-1. 1H NMR spectrum showed also signals at 12.80
and 7.13 ppm corresponding to NH and NH2 protons respectively.
Scheme 1: Synthesis of 2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide (4).
The hydrazide 4 was used as a reactive starting material to design a series of
substituted 1,3,4-oxadiazole derivatives using cerium (IV) ammonium nitrate (CAN)
as a catalyst followed by evaluation of their antitumor activity. Thus, it was allowed
to react with aromatic aldehydes such benzaldehyde, 4-chlorobenzaldehyde and
3
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thiophen-2-carboxaldehyde in ethanol in the presence of catalytic amounts of CAN to
give the corresponding hydrazone 5a-c. Grinding of hydrazones 5a-c with CAN under
solvent free conditions at room temperature resulted in formation of 2,5-diaryl-1,3,4-
oxadiazole derivatives 6a-c, (Scheme 2).
Scheme 2: Cyclization-oxidation reaction of hydrazones 5a-c with cerium (IV) ammonium nitrate
The reaction was performed using different ratios of CAN (0.0001, 0.0005,
0.001, 0.005, 0.01 and 0.02 mol) to study the effect of the catalyst ratio on the yield of
the produced oxadiazole. We observed higher yields of oxadiazole (73-87 %) in case
of 0.01 mol and 0.02 mol of the catalyst but other ratios decreased the yields to lower
than 60 %.
The conversion of hydrazone to oxadiazole moiety by the aid of CAN could
be explained on the basis of cyclization-oxidation reaction of hydrazones 5a-c that
probably takes place according to the following mechanism, (Figure 1). As shown in
the proposed mechanism CAN acts as an oxidant and Lewis acid [22].
According to the probable reaction mechanism, the carbonyl group of aldehyde could
be activated by CAN to which hydrazide could be added by nucleophilic addition to
form the hydrazone. The formation of oxadiazole moiety can be achieved via
intermolecular cyclization of hydrazone. The coordination of Ce(IV) assists to
activate C=N for nucleophilic addition of hydroxyl group to form intermediate X
followed by removing of hydrogen to generate oxadiazole moiety.
4
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Figure 1: A proposed mechanism for the synthesis of oxadiazoles 6a-c.
On the other hand, synthesis of oxadiazoles 6a-c in high yields can be
proceeded via one-pot reaction as alternative method involving 2-(1-oxo-4-(4-
phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide (4), aromatic aldehydes and CAN
in aqueous dichloromethane as a solvent, (Scheme 3).
Scheme 3: One-pot synthesis of oxadiazoles 6a-c
5
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Antitumor activity:
Most of the synthesized molecules were screened for their in vitro cytotoxicity
against four human tumor cell lines namely, hepatocellular carcinoma HePG-2,
mammary gland breast cancer MCF-7, Human prostate cancer PC3 and Colorectal
carcinoma HCT-116 using the colorimetric (3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazoliumbromide) (MTT assay) [40,41]. The cell lines were obtained
from ATCC via the Holding company for biological products and
vaccines (VACSERA) (Cairo, Egypt). Doxorubicin was used as a standard cytotoxic
drug for comparison.
MTT assay is used to determine cytotoxicity of potential medicinal agents and
other toxic materials. It is colorimetric assay for measuring cell growth based on the
conversion of the yellow tetrazolium bromide to a purple formazan derivative by
mitochondrial succinate dehydrogenase in viable cells [41].
As shown in table 1, there are varying degrees of inhibitory activity toward the
tested human tumor cell lines for the examined molecules in comparison with the
standard Doxorubicin. Oxadiazole 6c exhibited very strong cytotoxic activity among
the studied series towards the tumor cell lines HePG-2, PC-3 and HCT-116 and strong
activity towards MCF-7 with IC50 values 5.71, 7.26, 9.13 and 10.12 mg/mL
respectively. Oxadiazole 6b also showed strong activity towards HePG-2, MCF-7 and
HCT-116 and very strong cytotoxic activity against PC3 with IC50 value 8.65
mg/mL. In addition, hydrazone 5c revealed strong activity towards all the tested
tumor cell lines having IC50 values 14.63, 20.48, 18.11 and 12.38 mg/mL. Other
products showed cytotoxic activity that range from weak to moderate towards the
tested cell lines.
It is observed from the given data, attachment of thiophene moiety in the
hydrazone 5c and oxadiazole 6c and chlorophenyl group in oxadiazole 6b enhanced
their cytotoxic activity towards the tested tumor cell lines in comparison with the
starting hydrazide 4 that exhibited only strong activity against PC3.
6
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Table 1: Cytotoxic activity (IC50) of some compounds against human tumor cells.
In vitro Cytotoxicity IC50 (µg/ml)•
Compounds
HePG2
MCF-7
PC3
HCT-116
5.23±0.3
4.50±0.2
52.01±4.0
28.22±3.2
45.63±2.3
29.41±2.5
14.63±1.5
34.52±3.1
15.26±1.2
5.71±0.4
4.17±0.2
8.87±0.6
69.22±4.5
19.35±1.9
38.23±1.5
32.09±2.9
18.11±1.7
47.04±3.8
8.65±1.7
7.26±0.8
DOX•
3
42.65±3.5
24.13±3.2
33.18±1.6
53.44±3.9
20.48±1.9
36.97±3.4
18.53±2.2
10.12±1.1
26.22±2.3
36.52±2.2
23.47±1.1
40.30±3.5
12.38±1.3
16.13±1.7
11.71±3.1
9.13±1.0
4
5a
5b
5c
6a
6b
6c
• IC50 (µg/ml) : 1 – 10 (very strong). 11 – 20 (strong). 21 – 50 (moderate). 51 – 100 (weak) and above
100 (non-cytotoxic), • DOX : Doxorubicin
Conclusion
We have reported facile synthesis of 1,3,4-oxadiazole derivatives attached to
phthalazinone moiety using N-arylidene-2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-
2(1H)-yl)acetohydrazide as a reactive starting material in the presence of cerium (IV)
ammonium nitrate as a catalyst. Most of the synthesized products were investigated
also for their antitumor activities against four human tumor cell lines using MTT
assay, compounds 5c, 6b and 6c showed the most potent cytotoxic effect as concluded
from their IC50 values.
Experimental:
Melting points were measured in open capillaries using Gallen Kamp melting point
apparatus and are uncorrected. NMR, IR, Mass spectra were carried out by Micro
Analytical Unit at Cairo University. IR spectra were recorded on a JASCO IR 660
Plus spectrometer. NMR spectra were recorded on a Bruker Avance 400 (400 MHz)
using DMSO as a solvent. Mass spectra (EI) were recorded on a Shimadzu GCMS-
QP 1000 EX mass spectrometer. All reactions were monitors by thin layer
chromatography (TLC) and carried out on 0.2 mm silica gel 60 F254 (Mark) plates.
7
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4-(4-Phenoxyphenyl)-1H-benzo[d][1,2]-oxazin-1-one (2)
A mixture of acid 130 (0.01mol) and hydroxyl amine (0.01mol) in dry pyridine (20
mL) was refluxed for 6 hours. After cooling, the reaction mixture was poured on
crushed ice/HCl, the precipitated solid was filtered off, washed, dried and crystallized
from ethanol.
Yellowish white crystals, yield: 75 %; m.p. 120-122 oC. IR spectrum (KBr, ν, cm-1):
1
1615 (C=N), 1734 (CO); H NMR (DMSO-d6, δ ppm): 7.13-7.54 (m, 9H,
13
diphenylether-H), 7.65 -8.34 (m, 4H, benzoxazine-H); C NMR, 112.5 115.3, 117.1,
118.5, 122.5, 123.2, 123.6, 125.5, 127.9, 128.4, 129.5, 135.6, 155.3, 158.4, 172.3;
MS: m/z: 315 (M+); Anal. calcd. for C20H13NO3 (315.33): C, 76.18; H, 4.16; N, 4.44
%. Found: C, 76.07; H, 4.11; N, 4.35 %.
Ethyl 2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetate (3)
A mixture of benzoxazinone 2 (0.01 mol) and ethyl glycinate (0.01 mol) in ethanol
(20 mL) containing sodium acetate (0.01 mol) was heated under reflux for 3 hours.
The reaction mixture was allowed to cool then poured into crushed ice.
The precipitated solid was collected by filtration, dried and crystallized from ethanol.
Yellowish white crystals, yield: 69 %; m.p. 135-137 oC. IR spectrum (KBr, ν, cm-1):
1
1609 (C=N), 1678, 1733 (2 CO), 2940, 2860 (CH2); H NMR (DMSO-d6, δ ppm):
1.18 (t, 3H, CH3), 3.83 (s, 2H, NCH2), 4.32 (q, 2H ,CH2), 7.15-7.63 (m, 9H,
diphenylether-H), 7.90-8.36 (m, 4H, phthalazine-H); 13C NMR, 14.7, 63.5, 65.3,
114.5, 115.2, 118.3, 118.5, 120.5, 121.2, 122.7, 123.5, 125.5, 126.3, 127.5, 128.3,
128.6, 135.5, 153.1, 168.5, 176.8; MS: m/z: 400 (M+); Anal. calcd. for C24H20N2O4
(400.43): C, 71.99; H, 5.03; N, 7.00 %. Found: C, 71.86; H, 4.98; N, 6.82 %.
2-(1-Oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide (4)
An equimolar amount of ester 3 and hydrazine hydrate (0.01 mol) in ethanol (20 mL)
was refluxed for 3 hours. The reaction mixture was allowed to cool and the
precipitated solid was filtered, dried and crystallized from ethanol.
o
Yellow crystals, yield: 85 %; m.p. 233-235 C. IR spectrum (KBr, ν, cm-1): 1615
1
(C=N), 1670-1684 (2CO), 2937, 2900 (CH2), 3447-3155 (NH2, NH); H NMR
(DMSO-d6, δ ppm): 3.36 (s, 2H, NCH2), 7.13 (s, 2H ,NH2, exchangeable), 7.11-7.71
8
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(m, 9H, diphenylether-H), 7.78-8.35 (m, 4H, phthalazine-H), 12.80 (s, 1H, NH
13
exchangeable); C NMR, 65.5, 113.5, 114.8, 116.2, 118.7, 121.3, 123.5, 124.3,
127.5, 128.6, 128.9, 131.5, 133.5, 135.3, 153.5, 155.5, 169.5, 176.8; MS: m/z: 386
(M+); Anal. calcd. for C22H18N4O3 (386.41): C, 68.38; H, 4.70; N, 14.50 %. Found:
C, 68.27; H, 4.55; N, 14.32 %
General procedure for synthesis of hydrazones 5a-c
Cerium (IV) ammonium nitrate (0.01 mol) was added to a mixture of hydrazide 4
(0.01 mol) and aromatic aldehydes (0.01 mol) namely benzaldehyde, 4-
chlorobenzaldehyde and thiophene-2-carbaldehyde in ethanol (10 mL), the reaction
mixture was stirred and heated under reflux for 1h. Water (5 mL) was added and the
product solid was filtered, washed and recrystallized from proper solvent.
N-Benzylidene-2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)acetohydrazide
(5a)
o
Yellow powder, yield: 83 %; m.p. 215-217 C. IR spectrum (KBr, ν, cm-1): 1610
1
(C=N), 1680-1669 (2 CO), 2998, 2905 (CH2), 3431 (NH); H NMR (DMSO-d6, δ
ppm, 3.94 (s, 2H, NCH2), 7.08-7.88 (m, 18H, diphenylether and benzylidene-H),
7.95-8.32 (m, 4H, phthalazine-H), 8.82 (s, 1H, CH=N), 12.82 (s, 1H, NH,
exchangeable); 13C NMR, 63.5, 114.5, 115.3, 116.3, 116.7, 117.5, 118.3, 120.5,
121.7, 123.2, 126.5, 128.3, 129.5, 133.4, 132.5, 133.1, 135.5, 145.3, 148.3, 1542.5,
155.5, 169.5, 177.4; MS: m/z: 474 (M+); Anal. calcd. for C29H22N4O3 (474.52): C,
73.40; H, 4.67; N, 11.81 %. Found: C, 73.27; H, 4.51; N, 11.68 %.
N-(4-Chlorobenzylidene)-2-(1-oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)
acetohydrazide (5b)
o
Yellow powder, yield 84 %; m.p. 220-222 C. IR spectrum (KBr, ν, cm-1): 1620
1
(C=N), 1669-1677 (2 CO), 2903, 2980 (CH2), 3437 (NH); H NMR (DMSO-d6, δ
ppm):
3.74 (s, 2H, NCH2), 7.12-7.69 (m, 13H, diphenylether and 4-
chlorobenzylidene-H), 7.75-8.35 (m, 4H, phthalazine-H), 8.90 (s, 1H, CH=N), 12.81
(s, 1H, NH, exchangeable); 13C NMR, 62.7, 118.1, 119.6, 121.5, 122.1, 123.3, 124.4,
125.4, 126.9, 127.3, 127.7, 128.1, 128.6, 130.3, 131.4, 134.4, 135.3, 136.1, 155.6,
156.7, 158.7, 163.1, 171,5; MS: m/z: 508 (M+), 509 (M+1); Anal. calcd. for
9
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C29H21ClN4O3 (508.96): C, 68.44; H, 4.16; N, 11.01 %. Found: C, 68.28; H, 3.98; N,
10.87 %.
2-(1-Oxo-4-(4-phenoxyphenyl)phthalazin-2(1H)-yl)-N'-(thiophen-2-ylmethylene)
acetohydrazide 5c
o
Yellow crystals, yield: 87 %; m.p. 214-216 C. IR spectrum (KBr, ν, cm-1): 1605
1
(C=N), 1678-1665 (CO), 2950, 2899 (CH2), 3370 (NH); H NMR (DMSO-d6, δ
ppm): 3.65 (s, 2H, NCH2), 7.05-7.74 (m, 12H, diphenylether and 4-thiophene-H),
7.90-8.33 (m, 4H, phthalazine-H),
8.86 (s, 1H, CH=N), 11.74 (s, 1H, NH,
exchangeable); 13C NMR, 62.5, 113.2, 114.6, 115.5, 116.2, 118.1, 118.5, 119.5,
121.8, 122.5, 126.2, 128.3, 129.2, 129.6, 130.5, 131.5, 133.6, 135.2, 155.2, 167.5,
171.5 ; MS: m/z: 480 (M+); Anal. calcd. for C27H20N4O3S (480.54): C, 67.49; H,
4.20; N, 11.66 %. Found: C, 67.41; H, 4.12; N, 11.53 %.
General procedures for the synthesis of 2,5-disubstituted-1,3,4-oxadiazoles 6a-c
Method A: An equimolar amount of hydrazones 5a-c (0.01 mol) and cerium (IV)
ammonium nitrate (0.01 mol) was grinded together in mortar at room temperature for
30 min. Dichloromethane (10 mL) and water (10 mL) were added, then the organic
phase was separated and dried over magnesium sulfate. After evaporation of solvent,
the solid was collected and recrystallized from proper solvent to give oxadiazoles 6a-c.
Method B: Cerium (IV) ammonium nitrate (0.01 mol) was added to a mixture of
hydrazide 4 (0.01 mol), the same aromatic aldehydes (0.01 mol) in aqueous
dichloromethane (20 mL), the whole reaction mixture was stirred and heated under
reflux for 5 h. the progress of the reaction was monitored by TLC. Water (10 mL)
was added and the organic phase was separated and dried over magnesium sulfate.
After evaporation of solvent, the product solid was collected and recrystallized from
proper solvent to give oxadiazoles 6a-c.
4-(4-Phenoxyphenyl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl) phthalazin-1(2H)
-one (6a)
o
Yellow powder, Yield: 77 %; m.p. 230-232 C. IR (KBr, ν, cm-1): 1610 (C=N), 1671
(CO), 2940, 2901 (CH2); 1H NMR (DMSO-d6, δ ppm): 3.80 (s, 2H, NCH2), 7.12-7.76
13
(m, 14H, diphenylether and benzylidene-H), 7.82-8.34 (m, 4H, phthalazine-H); C
10
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NMR, 59.5, 115.5, 117.3, 118.1, 119.3, 121.5, 122.3, 124.1, 126.1, 126.6, 127.9,
128.2, 129.0, 129.5, 130.2, 131.2, 131.7, 133.7, 145.9, 156.0, 157.5, 159.2, 173.7 ;
MS: m/z: 472 (M+); Anal. calcd. for C29H20N4O3 (472.50): C, 73.72; H, 4.27; N,
11.86 %. Found: C, 73.66; H, 4.16; N, 11.72 %.
2-((5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)methyl)-4-(4-phenoxyphenyl)
phthalazin-1(2H)-one (6b)
o
Yellow powder, yield: 87 %; m.p. 240-242 C. IR (KBr, ν, cm-1): 1620 (C=N), 1677
(CO), 2901, 2880 (CH2); 1H NMR (DMSO-d6, δ ppm): 3.60 (s, 2H, NCH2), 7.12-7.76
(m, 13H, diphenylether and 4-chlorobenzylidene-H), 7.83-8.34 (m, 4H, phthalazine-
13
H); C NMR, 64.3, 116.5, 117.5, 118.3, 119.2, 122.2, 123.6, 126.4, 127.2, 128.6,
133.2, 135.3, 148.6, 150.5, 154.2, 155.2, 166.3; MS: m/z: 506 (M+), 507 (M+1); Anal.
calcd. for C29H19ClN4O3 (506.95): C, 68.71; H, 3.78; N, 11.05 %. Found: C, 68.67; H,
3.69; N, 11.02 %.
4-(4-Phenoxyphenyl)-2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)
phthalazin-1(2H)-one (6c)
Yellow powder, yield: 73 %; m.p.230-232 oC. IR (KBr, ν, cm-1): 1618 (C=N), 1683
1
(CO), 2918, 2856 (CH2); H NMR (DMSO-d6, δ ppm): 3.70 (s, 2H, NCH2), 7.22-
7.93 (m, 12H, diphenylether and thiophene-H), 7.75-8.34 (m, 4H, phthalazine-H); 13C
NMR, 62.5, 115.3, 117.2, 118.5, 120.5, 121.8, 122.5, 123.3, 126.1, 127.3, 128.5,
130.5, 133.2, 133.6, 135.5, 136.5, 148.6, 150.5, 154.2, 155.2, 166.3; MS: m/z: 478
(M+); Anal. calcd. for C27H18N4O3S (478.53): C, 67.77; H, 3.79; N, 11.71 %. Found:
C, 67.65; H, 3.68; N, 11.64 %.
Acknowledgments
The authors wish to thank Chemistry Department, Faculty of Science, Benha
University for the financial support.
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