New potential antitumor quinazolinones derived from dynamic 2-undecyl benzoxazinone: Synthesis and cytotoxic evaluation

Article abstract of DOI:10.1080/00397911.2018.1490433

Since the quinazoline and its derivatives have been considered as a novel class of cancer chemotherapeutic agents that show promising activity against different tumors, a new series of 6-iodo-2-undecylquinazolin-4(3H)-ones were prepared via reaction of 6-iodo-2-undecyl-4H-benzoxazin-4-one with nitrogen nucleophiles, namely, primary amines, 4-amino antipyrine, hydrazine hydrate, diamines, ethanol amine, and/or hydrazide derivatives and screened for their antitumor activity in vitro against a panel of three human tumor cell lines namely; hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, and mammary gland breast MCF-7. Compounds 14, 16, and 18 showed remarkable broad spectrum antitumor activity. All compounds were fully characterized by means of IR, MS, and ¹H-NMR spectra.

Full text of DOI:10.1080/00397911.2018.1490433

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
New potential antitumor quinazolinones derived
from dynamic 2-undecyl benzoxazinone: Synthesis
and cytotoxic evaluation
Mohamed H. Hekal & Fatma S. M. Abu El-Azm
To cite this article: Mohamed H. Hekal & Fatma S. M. Abu El-Azm (2018) New potential
antitumor quinazolinones derived from dynamic 2-undecyl benzoxazinone: Synthesis and cytotoxic
evaluation, Synthetic Communications, 48:18, 2391-2402, DOI: 10.1080/00397911.2018.1490433
To link to this article: https://doi.org/10.1080/00397911.2018.1490433
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2018, VOL. 48, NO. 18, 2391–2402
https://doi.org/10.1080/00397911.2018.1490433
New potential antitumor quinazolinones derived from
dynamic 2-undecyl benzoxazinone: Synthesis and
cytotoxic evaluation
Mohamed H. Hekal and Fatma S. M. Abu El-Azm
Department of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 19 May 2018
Since the quinazoline and its derivatives have been considered as a
novel class of cancer chemotherapeutic agents that show promising
activity against different tumors, a new series of 6-iodo-2-undecylqui-
nazolin-4(3H)-ones were prepared via reaction of 6-iodo-2-undecyl-4H-
benzoxazin-4-one with nitrogen nucleophiles, namely, primary amines,
4-amino antipyrine, hydrazine hydrate, diamines, ethanol amine, and/or
hydrazide derivatives and screened for their antitumor activity in vitro
against a panel of three human tumor cell lines namely; hepatocellular
carcinoma (liver) HepG2, colon cancer HCT-116, and mammary gland
breast MCF-7. Compounds 14, 16, and 18 showed remarkable broad
spectrum antitumor activity. All compounds were fully characterized by
KEYWORDS
Cytotoxic evaluation; lauroyl
chloride; quinazolinone;
triazolo[4,3-a]quinoline-4-
carbonitrile
1
means of IR, MS, and H-NMR spectra.
GRAPHICAL ABSTRACT
O
NC
NH
I
N
O
N
CH3
(CH2)10
I
O
O
H2N
CN
(17)
N
H
Δ
Dioxane /
N
CH3
(CH2)10
OH
N
(2)
I
CN
N
N
H
3C(H2C)10
(18)
Introduction
Cancer has become a major cause of human mortality and is considered a major world-
wide health problem. Cancer consists of a group of cells that originated from a single
CONTACT Mohamed H. Hekal
mohahekal2007@yahoo.com
Department of Chemistry, Faculty of Science, Ain
Shams University, Abbassia, Cairo 11566, Egypt.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher's website.
ß 2018 Taylor & Francis

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M. H. HEKAL AND F. S. M. ABU EL-AZM
cell with uncontrolled growth and rapid proliferation properties.[1,2] Presently, a wide
range of cytotoxic drugs, either alone or in combination, are used to treat cancer, and
several of these drugs are in different phases of clinical trials. Heterocyclic compounds
are widely investigated as bioactive molecules and are considered important synthetic
targets for the development of novel therapeutic agents.[3–5] Quinazoline is one of these
heterocycles for which considerable research has been done in order to examine its
biomedical applications.[6] In a number of biologically active compounds and drug
molecules, the quinazoline nucleus is used as a basic framework. Due to their broad
range of pharmacological activities, which include antimicrobial,[7,8] antimalarial,[9]
anti-inflammatory,[10–12] anticonvulsant,[13,14] antihypertensive,[15] antioxidant,[16] anti-
viral,[17] anti-HIV,[18] and anticancer,[19–22] quinazoline and its derivatives have attracted
the attention of biologists and medicinal chemists. Quinazoline and its derivatives have
been identified as a new class of cancer chemotherapeutic agents with significant thera-
peutic efficacy against solid tumors.[23–26] The Food and Drug Administration (FDA)
has approved several quinazoline derivatives for clinical use as anticancer drugs. These
include gefitinib, erlotinib, lapatinib, afatinib, and vandetanib (Fig. 1).[27]
In continuation of our program exploring the chemical reactivity of the oxazinone
moiety present in 4H-3,1-benzoxazin-4-one derivatives with saturated aliphatic substitu-
ents at position 2 (the so-called dynamic benzoxazinones),[28–30] and derivatives with
bulky substituents involving strong conjugation power (which are so-called static ben-
zoxazinones),[31,32] undecyl group has been chosen to be the alkyl group at position-2
in the synthesized benzoxazinone and the corresponding quinazolinones which are
expected to have interesting biological and medicinal activity toward different diseases.
The iodo derivatives were selected for study because iodine atom has received consider-
able attention in organic synthesis due to its high tolerance to air and moisture, low
cost, non-toxic nature and ready availability. The presence of iodine in heterocyclic
compounds increases the lipophilicity of the molecules more than fluorine, chlorine or
bromine (iodine atom is bigger and possesses high polarizability). In previous
studies,[33,34] we have synthesized several quinazolinones derivatives. Based on our
Figure 1. FDA approved quinazoline derivatives as anticancer drugs.

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results and on literature data, the present study aimed to synthesize and evaluate the
antitumor activity of some new quinazolinone derivatives.
Results and discussion
The aim of this work was to design and synthesize novel quinazolinone derivatives to
evaluate their anticancer activity. Thus, the reaction of 2-amino-5-iodobenzoic acid with
lauroyl chloride in the presence of pyridine at room temperature afforded the amide
analog 1 followed by ring closure in freshly distilled acetic anhydride to obtain the key
intermediate 6-iodo-2-undecyl-4H-benzo[d][1,3]oxazin-4-one 2 (Scheme 1). The struc-
1
ture of compound 2 was confirmed by complete analysis of IR, H NMR, and mass
spectrum besides the correct elemental analysis. Thus, the IR spectrum shows absorp-
1
tion bands for carbonyl group of oxazinone at 1764 cmꢀ1 and C¼N at 1643 cmꢀ1. H
NMR spectrum (DMSO-d6) of compound 2 revealed the presence of signals corre-
sponding to aromatic protons (3H) as multiplet in the region at d 8.52–7.30 ppm beside
the signals characteristic for the aliphatic chain which appeared as follows: 2.67 (t, 2H),
1.82 (m, 2H), 1.36-1.2 (m, 16H), 0.88 (t, 3H).
The starting intermediate 6-iodo-2-undecyl-4H-benzo[d][1,3]oxazin-4-one 2 was
allowed to react with primary amines such as cyclohexyl amine and/or sulfanilamide in
an attempt to obtain 3-substituted-quinazolin-4-ones in different reaction conditions, in
all cases; the reaction afforded the diamides 3 and 4 instead. Attempts to cyclize the
diamides 3 and 4 to the corresponding 4-(3H)-quinazolin-4-one using a variety of reac-
tion conditions, including fusion, were not successful. On the other hand, the ester 5
was obtained upon reaction of compound 2 with primary amines in refluxing ethanol
1
(Scheme 2). H NMR spectrum of compound 5 revealed the existence of triplet signal
at 1.43 ppm and quartet signal at 4.4 ppm characteristic for ethyl protons of ester group
which consistent with the structure 5. In contrast, the reaction of 2 with 4-aminoanti-
pyrine in boiling dioxane afforded the cyclized product 3-(1,5-dimethyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazol-4-yl)-6-iodo-2-undecylquinazolin-4(3H)-one 6 (Scheme 2).
Hydrazinolysis of the benzoxazinone 2 using hydrazine hydrate in boiling ethanol
yielded 3-amino quinazolinone derivative 7, via hetero ring opening followed by cycliza-
tion. The IR spectrum of compound 7 showed bands at 3319, 3210, and 1673 cmꢀ1
1
attributed to NH2 and C¼O groups. While the H NMR spectrum revealed the NH2
as a singlet at 4.84 ppm. Condensation of 3-amino quinazolinone derivative 7 with
Scheme 1. Synthesis of 6-iodo-2-undecyl-4H-benzo[d][1,3]oxazin-4-one 2.

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M. H. HEKAL AND F. S. M. ABU EL-AZM
Scheme 2. Reaction of benzoxazinone 2 with primary amines and hydrazine hydrate.
1,3-diphenyl pyrazole-4-carboxaldehyde in dioxane in the presence of catalytic amount
1
of triethylamine afforded the arylidene derivatives 8. The IR and H NMR spectra of
compound 8 were devoid of any signals for the NH2 group (Scheme 2).
The reactivity of benzoxazinone 2 towards bident nucleophiles such as 1,2-diamino-
ethane, 1,5-diaminopentane, and ethanolamine was also investigated. Thus, the reaction of 2
with 1,2-diaminoethane and/or 1,5-diaminopentane in refluxing ethanol afforded the quina-
zolinone derivatives 9a,b (Scheme 3). Similarly, ethanolamine reacted with compound 2 to
give 3-(2-hydroxyethyl)-6-iodo-2-undecylquinazolin-4(3H)-one (10) (Scheme 3).
The reaction of benzoxazinones with anilines containing a reactive functional group at
the ortho position adds another dimension to the basic transformation, that further cyc-
lization to another heterocyclic system is possible. Benzoxazinones are able to transfer its
carbon-2 and its attached substituents to another molecule.[35] An interesting example of
this is the reaction of the benzoxazinone 2 with o-phenylenediamine in refluxing pyridine
in which 2-undecyl-1H-benzo[d]imidazole 11 was formed in high yield along with a small
amount of 5-iodoanthranilic acid rather than compound 12 or 13. The 1H NMR (CDCl3)
spectrum of compound 11 revealed the presence of signals down field for (NH) proton as
singlet at 12.1 ppm, aromatic protons (4H) as multiplet in the region of d 7.56–7.20 ppm,
and signals characteristic for the aliphatic chain appeared as follows: 2.93 (t, 2H), 1.86 (m,
2H), 1.38-1.23 (m, 16H), 0.88 (t, 3H) (Scheme 3).

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The proclivity of the benzoxazinone 2 for undergoing nucleophilic addition with semi-
carbazide hydrochloride, 4-methylbenzenesulfonohydrazide, 4-oxo-3,4-dihydrophthalazine-
1-carbohydrazide, and/or 2-cyanoacetohydrazide has been investigated. Thus, the reaction
of compound 2 with semicarbazide hydrochloride in refluxing dioxane in the presence of
TEA afforded 1-(6-iodo-4-oxo-2-undecylquinazolin-3(4H)-yl)urea 14 (Scheme 4). Similarly,
Scheme 3. Reaction of benzoxazinone 2 with bident nucleophiles.
Scheme 4. Reaction of benzoxazinone 2 with some hydrazides.

2396
M. H. HEKAL AND F. S. M. ABU EL-AZM
when compound 2 reacted with 4-methylbenzenesulfonohydrazide in refluxing dioxane
afforded N-(6-iodo-4-oxo-2-undecylquinazolin-3(4H)-yl)-4-methylbenzenesulfonamide 15.
Also, the reaction of compound 2 with 4-oxo-3,4-dihydrophthalazine-1-carbohydrazide
in dioxane under reflux gave N-(6-iodo-4-oxo-2-undecylquinazolin-3(4H)-yl)-4-oxo-3,4-
dihydrophthalazine-1-carboxamide 16 (Scheme 4). In contrast, the reaction of 2 with
2-cyanoacetohydrazide in boiling dioxane afforded the unexpected product 5-hydroxy-7-
iodo-1-undecyl-[1,2,4]triazolo[4,3-a]quinoline-4-carbonitrile 18 rather than the pyra-
zolo[1,5-c]quinazoline derivative 17.[36] The appearances of a broad band at 3437 cmꢀ1
for OH group besides the absence of the frequency of the C¼O group in the IR
spectrum confirms the unexpected structure 18 (Scheme 4).
Cytotoxicity and antitumor evaluation
Most of the synthesized compounds were screened for their anticancer activity in vitro
against three representative cell lines, hepatocellular carcinoma (HePG-2), colon cancer
HCT-116, and mammary gland breast cancer (MCF-7). The results were expressed as
growth inhibitory concentration (IC50) values, which represent the compounds concen-
trations required to produce a 50% inhibition of cell growth after 72 h of incubation,
compared with untreated controls (Table 1, Fig. 2). In general, the cytotoxic activity of
the tested compounds ranged from very strong to weak activity. Compound 16 showed
approximately equal activity to the DOX as a standard for the three representative cell
lines with an IC50 value of 4.34 1.2, 5.16 1.4, and 7.9 0.5 mg/mL. The optimal results
were observed for compounds 14 and 16 (very strong activity) with an IC50 value of
9.62 0.9 and 4.34 1.2 lg/mL for HePG-2 cell line, respectively. Compounds 16 and
18 exhibited very strong activity with an IC50 value of 5.16 1.4 and 7.49 0.6 mg/mL
for HCT-116 cell line, respectively. Compounds 14, 16, and 18 showed very strong
activity with an IC50 value of 7.89 0.8, 7.9 0.5, and 9.91 0.9 lg/mL for MCF-7 cell
line. Compounds 15 and 18 showed strong activity towards HePG-2 cell with an IC50
Table 1. Cytotoxicity (IC50) of the tested compounds on different cell lines.
IC50 (mg/ml)a
Compound no.
HePG2
HCT-116
MCF-7
1
2
3
4
5
6
7
8
9a
9b
10
11
14
15
16
18
DOX
>100
>100
94.02 5.1
27.34 2.0
40.53 2.8
51.32 3.5
67.16 3.9
47.56 3.3
43.88 3.1
88.41 4.5
28.13 2.2
63.20 3.6
12.98 1.2
18.07 1.5
7.89 0.8
39.50 2.7
4.05 1.6
9.91 0.9
4.17 0.2
25.94 2.2
44.89 3.1
64.13 3.6
74.11 3.9
55.63 3.4
47.34 3.3
>100
31.12 2.3
79.64 4.0
17.08 1.6
23.85 1.9
9.62 0.9
16.73 1.4
4.34 1.2
13.78 1.1
4.50 0.2
33.42 2.3
50.92 2.9
70.46 3.8
86.60 4.4
68.49 3.8
54.95 3.2
>100
35.19 2.4
75.31 3.9
15.68 1.3
28.46 1.8
11.24 1.1
21.87 1.7
5.16 1.4
7.49 0.6
5.23 0.3
DOX: doxorubicin.
aIC50 (lg/mL): 1–10 (very strong); 11–20 (strong); 21–50 (moderate); 51–100 (weak); above 100 (non-cytotoxic).

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100
90
80
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
8
9a 9b 10 11 14 15 16 18 DOX
HePG2
HCT-116
MCF-7
Figure 2. Cytotoxic activity of the tested compounds on different cell lines.
value of 16.73 1.4 and 13.78 1.1 lg/mL, while compounds 10 and 14 showed strong
activity towards HCT-116 cell with an IC50 value of 15.68 1.3 and 11.24 1.1 lg/mL,
respectively. Also, strong activity towards MCF-7 cell line was observed with com-
pounds 10 and 11 with an IC50 value of 12.98 1.2 and 18.07 1.5 lg/mL, respectively.
Moderate activity towards HePG-2, HCT-116, and MCF-7 cell lines was observed with
compounds 2, 3, 7, 9a, 11, and 15.
Structure–activity relationship (SAR)
DNA is made of chemical building blocks called nucleotides. The four types of nitrogen
bases found in nucleotides are: adenine (A), thymine (T), guanine (G), and cytosine
(C). The base adenine always pairs with thymine, while guanine always pairs with cyto-
sine through a hydrogen bond. The cytotoxic activity of the tested compounds towards
different cell lines depends on two factors[37,38]: (i) the formation of an intermolecular
hydrogen bond with DNA bases; (ii) the positive charge on the tested compounds
attracted to the negative charge on the cell wall. By comparing the experimental cyto-
toxicity of the compounds reported in this study to their structures, the following SAR
was postulated:
Compounds 14, 16, and 18 showed very strong activity, this is due to the presence
of NH and NH2 groups in 14, two NH group in 16, and one OH group in 18
which may be added to any unsaturated moiety in DNA or forming hydrogen bond
with either one of the nucleobases of the DNA and causes it damage.
Compound 15 showed strong activity, this is due to the presence of NH group which
can form a hydrogen bond with either one of the nucleobases of the DNA and
causes it damage. Also, the presence of the SO2Ph group as a strong electron
attracting group rendered the molecule positively charged forming electrostatic
attraction with the DNA nucleobases. Moreover, the SO2 group acts on the mitotic
spindle (Fig. 3).[39]

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M. H. HEKAL AND F. S. M. ABU EL-AZM
Figure 3. Structure of doxorubicin and some of the designed target compounds.
Experimental
All melting points were taken on a Griffin and Geory melting-point apparatus and are
uncorrected. IR spectra were recorded on Pye Unicam SP1200 spectrophotometer using
1
the KBr wafer technique. H NMR experiments were run at 300 and 400 MHz on a
Varian Mercury VX-300 NMR spectrometer (Varian Inc., Palo Alto, CA) using tetrame-
thylsilane (TMS) as an internal standard in CDCl3 or dimethyl sulfoxide (DMSO-d6).
Chemical shifts are quoted as d. EI-MS were measured on a Schimadzu-GC-MS operating
at 70eV. Elemental analyses were carried out at the Microanalytical Unit, Faculty of
Science, Ain Shams University, using a Perkin-Elmer 2400 CHN elemental analyzer
(PerkinElmer, Waltham, MA), and satisfactory analytical data ( 0.4) were obtained for all
compounds. The homogeneity of the synthesized compounds was controlled by thin layer
chromatography (TLC) using aluminum sheet silica gel F254 (Merck, Kenilworth, NJ).
The Pharmacological activity assays were carried out at Pharmacology Department,
Faculty of Pharmacy, El-Mansoura University, El-Mansoura, Egypt.
2-Dodecanamido-5-iodobenzoic acid (1)
To a solution of iodoanthranilic acid (2.6 g, 10 mmole) in pyridine (50 ml), dodecanoyl
chloride (2.1 ml, 10 mmole) was added dropwise with stirring at room temperature for

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0.5 h. The solid product that precipitated down was filtered off, washed by cold water,
dried and then recrystallized from benzene to give 1 as white crystals, mp 132–134 ꢁC,
yield 84%. Anal. calcd. for C19H28INO3 (445.34): C, 51.24; H, 6.34; I, 28.50; N, 3.15.
Found: C, 51.13; H, 6.38; I, 28.23; N, 2.99. IR (t/cmꢀ1): br. 3339 (OH, NH), 2920, 2850
(CH aliphatic), 1674 (C ¼ O). MS m/z (%): 445 (M, 5.4), 401 (8.9), 263 (100), 245 (58). 1H
NMR (DMSO-d6) d (ppm): 10.91 (s, 1 H, NH, exchangeable with D2O), 8.57–7.84 (m,
3Harom.), 2.46 (t, 2H), 1.75 (m, 2H), 1.35–1.25 (m, 16H), 0.87 (t, 3H).
Pharmacological activity
Cytotoxicity assay
The cytotoxic activity of thirteen compounds was tested against three human tumor cell
lines namely hepatocellular carcinoma (liver) HePG-2, colon cancer HCT-116, and
mammary gland (breast) MCF-7. The cell lines were obtained from the ATCC via the
Holding Company for Biological Products and Vaccines (VACSERA, Cairo, Egypt).
Doxorubicin was used as a standard anticancer drug for comparison. The reagents used
were RPMI-1640 medium, MTT, DMSO and Doxorubicin (Sigma Co., St. Louis, MO),
and Fetal Bovine Serum (GIBCO, Paisley, UK).
The different cell lines[40,41] mentioned above were used to determine the inhibitory
effects of compounds on cell growth using the MTT assay. This colorimetric assay is
based on the conversion of the yellow tetrazolium bromide (MTT) to a purple formazan
derivative by mitochondrial succinate dehydrogenase in viable cells. The cells were
cultured in RPMI-1640 medium with 10% fetal bovine serum. Antibiotics added were
100 units/mL penicillin and 100 mg/mL streptomycin at 37 ꢁC in a 5% CO2 incubator.
The cell lines were seeded[42] in a 96-well plate at a density of 1.0 ꢂ 104 cells/well at
37 ꢁC for 48 h under 5% CO2 incubator. After incubation, the cells were treated with
different concentration of compounds and incubated for 24 h. After 24 h of drug treat-
ment, 20 mL of MTT solution at 5 mg/mL was added and incubated for 4 h. Dimethyl
sulfoxide (DMSO) in the volume of 100 mL was added into each well to dissolve the
purple formazan formed. The colorimetric assay is measured and recorded at an absorb-
ance of 570 nm using a plate reader (EXL 800, BioTech, Winoosky, VT).
The relative cell viability in percentage was calculated as (A570 of treated samples/
A570 of the untreated sample) ꢂ 100.
Calculation of the IC50 for each compound
Cytotoxicity was estimated as the concentration that caused approximately 50% loss of
the monolayer. The assay was used to examine the newly synthesized compounds.
Doxorubicin was used as a standard anticancer drug for comparison. To calculate IC50,
you would need a series of dose–response data (e.g. drug concentrations x1, x2, xn and
growth inhibition y1, y2, yn). The values of y are in the range of 0–1.
Supporting information
Full experimental details and spectroscopic data for compounds 1–18 can be accessed
on the publisher’s website.

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M. H. HEKAL AND F. S. M. ABU EL-AZM
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