Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: Search for anticancer agent

Article abstract of DOI:10.1016/j.ejmech.2011.03.015

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10^-5 M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzylideneamine)-2- (furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI₅₀ 1.82 & 2.14 μM respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.

Full text of DOI:10.1016/j.ejmech.2011.03.015

European Journal of Medicinal Chemistry 46 (2011) 2327e2346
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and in vitro antitumor activity of substituted quinazoline and
quinoxaline derivatives: Search for anticancer agent
*
Malleshappa N. Noolvi , Harun M. Patel, Varun Bhardwaj, Ankit Chauhan
Department of Pharmaceutical Chemistry, ASBASJSM College of Pharmacy, Bela (Ropar) 140111, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines
and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented
antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds
were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at
a single high dose (10ꢀ5 M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzy-
lideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the
series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with
Received 27 February 2011
Accepted 7 March 2011
Available online 15 March 2011
Keywords:
Synthesis 2-furano-4(3H)-quinazolinones
Diamides (open ring quinazolines)
Quinoxaline
Antitumor agents
QSAR
GI50 1.82 & 2.14
pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.
Ó 2011 Elsevier Masson SAS. All rights reserved.
mM respectively. Rational approach and QSAR techniques enabled the understanding of the
Rational design
1. Introduction
number of different structural classes of tyrosine kinase inhibitors
have been reported and reviewed [23e25]. The most promising
small-molecule selective EGFR-TK inhibitors include quinazolines
and quinoxalines. Chart 1 includes some examples that are currently
approved drugs or in clinical trials [19].
Cancer is continuing to be a major health problem in developing
as well as undeveloped countries [1e9]. Surpassing heart diseases, it
is taking the position number one killer due to various worldwide
factors. Although major advances have been made in the chemo-
therapeutic management of some patients, the continued commit-
ment to the laborious task of discovering new anticancer agents
remains critically important. In the course of identifying various
chemical substances which may serve as leads for designing novel
antitumor agents, we are particularly interested in the present work
with quinazoline and quinoxaline derivatives which have been
identified as a new class of cancer chemotherapeutic agents with
significant therapeutic efficacy against solid tumors [7e9]. It is well
known that quinazoline derivatives are potent inhibitors of
epidermal growth factor receptor (EGFR) [10e18]. The epidermal
growth factor receptor (EGFR) is cellular trans-membrane tyrosine
kinases that is over-expressed in a significant number of human
tumors (e.g., breast, ovarian, colon, and prostate), their expression
levels often correlate with vascularity, and is associated with poor
prognosis in patients [19e22]. Inhibitors of the EGFR PTK are
therefore expected to have great therapeutic potential in the treat-
ment of malignant and non -malignant epithelial diseases. A great
In May 2003, the FDA approved gefitinib (ZD1839, Iressa) as
monotherapy for the treatment of patients with locally advanced or
metastatic non-small celllung cancerafterchemotherapies hadfailed
[26]. Consequently, various approaches were adopted to enhance the
potency and selectivity of these inhibitors. These efforts led to
discovery of lapatinib, a dual EGFR and erbB2 inhibitor, which is
currently inphase III clinical trials [17]. Later, it has been reported that
somatic mutations in the tyrosine kinase domain of the EGFR gene
occur in a subset of patients with lung cancer who showed a dramatic
response to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib
[27e29]. Intensive research in the area of tyrosine kinase inhibitors
led to development of enormous number of active compounds
[30e36]. Apart from quinazolines, quinoxalines are also proved to be
selective ATP competitive inhibitors. AG 1295 (Chart 1), a quinoxaline
derivatives have been shown to block selectively EGFR kinase. This
molecule reverses the transformed phenotype of sis-trans-formed
NIH 3T3 cells and slow C6 glioma-induced tumors in nude mice [37].
In view of the previous rationale and in continuation of an
ongoing program aiming at finding new structure leads with
potential chemotherapeutic activities [38,39], in the present study
new series of quinazolinones and quinoxalines have been synthe-
sized and screened in vitro for antitumor activity at NCI. These series
* Corresponding author. Tel.: þ91 9417563874; fax: þ911881263655.
E-mail addresses: mnoolvi@yahoo.co.uk (M.N. Noolvi), hpatel_38@yahoo.com
(H.M. Patel).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.03.015

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2. Rational and design
In recent years, quinazolines have emerged as a versatile
template for inhibition of a diverse range of receptor tyrosine
kinases. The most widely studied of these is the epidermal growth
factor receptor (EGFR), with the small-molecule inhibitor gefitinib
being the first agent from this class to be approved for the treat-
ment of non-small cell lung cancer refractory to prior chemother-
apeutic intervention [43,44]. Subsequent research aimed at further
exploration of the SAR of this novel template has led to discovery of
highly selective compounds that target EGFR. These compounds act
via competing with ATP for binding at the catalytic domain of
tyrosine kinase. Later on, a great structural variety of compounds of
structurally diverse classes have proved to be highly potent and
selective ATP-competitive inhibitors. The ATP binding site has the
following features; Adenine region- Contains two key Hydrogen
bonds formed by the interaction of N-1 and N-6 amino group of the
adenine ring. Many potent inhibitors use one of these Hydrogen
bonds. Sugar region e A hydrophilic region, except a few e.g. EGFR.
Hydrophobic pocket e Though not used by ATP but plays an
important role in inhibitor selectivity. Hydrophobic channels e It is
not used by ATP and may be exploited for inhibitor specificity.
Phosphate binding region e This is used for improving inhibitor
selectivity [45]. In this study, we present a new sub-family of
compounds containing 2, 3-disubstituted quinazoline and qui-
noxaline core as EGFR inhibitors. Our strategy is directed toward
designing a variety of ligands with diverse chemical properties
hypothesizing that the potency of these molecules might be
enhanced by adding alternative binding group such as furan ring at
position 2-, urea, thiourea, thiosemicarbazide, phenyl hydrazine,
hydroxylamine, para amino benzoic acid, sulphonamide and imines
at position 3-of the quinazoline ring, substituted styryl at position 3
and thio methyl benzimidazole at position 2 of quinoxaline ring. In
this way, such substitution pattern could target different regions of
the ATP-binding site of the protein kinase domain to create differ-
entially selective molecules. The design of our ligands was done
based on previous Quntitive Structure Activity Relationship (QSAR)
of 4-anilinoquinazolines as EGFR inhibitor [40e42]. We introduced
larger moiety at 3 position of the quinazoline and quinoxalines such
as substituted arylidene, sulfonamide, substituted styryl, thio
methyl benzimidazole and substituted chalcone in ring opened
quinazolines [N-2-(phenyl carbamoyl) phenyl) furan-2-carbox-
amide and 2-benzamido-N-phenylbenzamide] moiety in a fashion
similar to lapatinib which binds in the ATP-binding cleft, so that the
bulky group could be oriented deep in the back of the ATP binding
site and makes predominantly hydrophobic interactions with the
protein mimicking the 30-chloro-40-[(3-fluorobenzyl)oxy]aniline
group of lapatinib (Fig. 2).
Chart 1. EGFR Tyrosine Kinase inhibitors.
comprise the derived 2,3-diubstituted quinazoline and quinoxaline
pharmacophore that are structurally related to Erlotinib and Lapa-
tinib (Fig.1). In the present study, the substitutionpattern at the 2, 3-
disubstituted quinazoline and quinoxaline pharmacophore were
selected so as to confer different electronic environment that would
affect the lipophilicity and hence the activity of the target molecules.
The objective of forming these hybrids is an attempt to reach an
active antitumor agent with potentiated activity and selectivity
toward cancerous cells. Moreover QSAR study was used to identify
the structural features required for the antitumor properties of these
new series [40e42]. However the results of this QSAR study could
support the postulation that our active compounds may act on the
same enzyme target where EGFR inhibitor acts confirming the
molecular design of the reported class of antitumor agents.
3. Chemistry
All the synthesized compounds were submitted to National
Cancer Institute (NCI) for anticancer screening. The tumor growth
inhibition properties of the seventeen compounds 5, 10, 11, 14, 15,
21, 39, 40, 41, 42, 48b, 48c, 48e, 48f, 48g, 48h and 48i with the NCI
codes NSC D-752812/1, NSC D-752813/1, D-753448/1, D-753446/1,
D-753445/1, D-753439/1, D-753786/1, D-753787/1, D-753788/1,
D-753789/1, D-753225/1, D-753230/1, D-532226/1, D-753231/1, D-
753227/1, D-753228/1 and D-753229/1 selected among 5e48(aei)
by the National Cancer Institute (NCI), USA, were screened on
human tumor cell lines at 10ꢀ5 M at the NIH, Bethesda, Maryland,
USA, under the drug discovery program of the NCI. Among the
selected seventeen compounds, compound 21 (NSC D-753439/1)
was further screened for 5-log dose molar range as it has shown
prominent cell growth inhibition at 10ꢀ5 M concentration against
variety of cell lines.
The reaction of anthranilic acid 1 and 2-furanocarbonylchloride
2 afforded the amide analog 3 which was then refluxed in acetic
anhydride to obtain the key intermediate 2-(furan-2-yl)- 4H-3,1-
benzoxazin-4-one 4 (Scheme 1).The reaction of thiosemicarbazide,
urea, thiourea, phenyl hydrazine and para amino benzoic acid with
2-( furan-2-yl)-4H-3,1-benzoxazin-4-one
4 by fusion at high
temperature afforded the corresponding quinazoline-4-one deriv-
atives 6e10 (Scheme 1).The benzoxazine derivative 4 was also
reacted with hydroxylamine hydrochloride in dry pyridine to afford
compound 5. Compound 4 was reacted with p-toludine and sul-
phanilamide by fusion in an attempt to obtain 3-substituted-qui-
nazolin-4-ones in different reaction conditions, in all cases; the
reaction afforded the diamides 11 (Scheme 1) and 12 (Scheme 2)
instead. Attempts to cyclize the diamides 11 and 12 to the

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2329
Fig. 1. Reported and proposed antitumor quinazoline derivatives.
corresponding 4-(3H)-quinazolin-4-one using variety of reaction
conditions, including fusion, were not successful. Condensation of
12 with different substituted aromatic aldehydes gave corre-
sponding chalcone derivatives of diamides 13e17 in acetic acid
(Scheme 2). Fusion of 4 with hydrazine hydrate at 200 ꢁC afforded
compound 18, which on further condensation with appropriate
aromatic aldehydes in glacial acetic acid afforded the arylidene
derivatives 19e34 (Scheme 3). Anthranilic acid 35 reaction with
benzoyl chloride 36 yielded 2-phenyl-4H-3, 1-Benzoxazin-4 one 37
by N-acylation via dehydrative cyclization mechanism. Subse-
quently which was fused with p-toludine at 200 ꢁC in an attempt to
obtain 3-substituted-quinazolin-4-ones in different reaction
conditions, in all cases; the reaction afforded the diamides 38
(Scheme 4) instead. Condensation of 38 with different substituted
aromatic aldehydes gave corresponding chalcone derivatives of
diamides 39e42 in acetic acid (Scheme 4). Condensation of
o-phenylenediamine 43 with pyruvic acid in an aqueous medium
alone yielded 3-methyl quinoxaline ꢀ2(1H)-one 45. The active

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M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
Fig. 2. Proposed hypothetical model of the highly active 2, 3-disubstituted quinazoline (Compound 21) bound to ATP binding site of EGFR protein tyrosine kinase.
methyl group of 45 condenses with different aromatic aldehydes in
acetic acid and catalytic amount of H2SO4 to afford the 46 (aei).
Chlorination of 46 (aei) with phosphorus oxychloride (POCl3) in
the presence of catalytic amount of dimethylformamide (DMF)
under refluxing condition yielded the corresponding chloro
compound 47 (aei), which on reaction with thio methyl 1H-
benzimidazole gave the corresponding nucleophillic substituted
product 48 (aei) (Scheme 5). It has been seen that benzoxazinones
undergo ring opening with different nucleophiles, allowing incor-
poration of substitution at the 3-position. It is a reported that the
benzoxazinones are liable to hydrolysis by water. The actual extent
to which this hydrolysis occurs varies greatly across a range of
molecules. A molecule of water would be able to open the ben-
zoxazinone ring by attacking the intracyclic carbonyl and effec-
tively hydrolyzing the cyclic ester (Chart 2) [46].
quinazolines) diamides 12 (Scheme 2) and 38 (Scheme 4) instead. The
reaction mechanism of ring opening is explained in Chart 4 and 5.
4. Pharmacology
4.1. In vitro cancer screen
The screening is a two-stage process, beginning with the eval-
uation of all compounds against the 60 cell lines at a single dose of
10ꢀ5 M. The output from the single dose screen is reported as
a mean graph and is available for analysis by the COMPARE
program. Compounds which exhibit significant growth inhibition
are evaluated against the 60 cell panel at five concentration levels.
The human tumor cell lines of the cancer-screening panel are
grown in RPMI 1640 medium containing 5% fetal bovine serum and
It is also been suggested that the nature of the substitution on the
benzoxazinone can modulate the reactivity of the carbonyl, in that
electron-donating groups cause the carbonyl to be less electrophilic
and reduce the reactivity of the benzoxazinone carbonyl to nucle-
ophillic attack [47]. This is desirable in terms of stability on storage,
or if they are to be final molecules themselves, but may be a factor
when these molecules are altered for further analog production.
An alkyl chain will act as an electron donor (þI effect); suggests
that the longer the chain gets, the more difficult a reaction and
insertion of the group that will constitute substitution at the
3-position of the corresponding quinazoline (Chart 3).
2 mM
L
-glutamine. For a typical screening experiment, cells are
inoculated into 96 well microtiter plates in 100
mL at plating
densities ranging from 5000 to 40,000 cells/well depending on the
doubling time of individual cell lines. After cell inoculation, the
microtiter plates are incubated at 37 ꢁC, 5% CO2, 95% air and 100%
relative humidity for 24 h prior to addition of experimental drugs.
After 24 h, two plates of each cell line are fixed in situ with TCA, to
representa measurementof thecell population foreachcell lineatthe
time of drug addition (Tz). Experimental drugs are solubilized in
dimethyl sulfoxide at 400-fold the desired final maximum test
concentration and stored frozen prior to use. At the time of drug
addition, an aliquot of frozen concentrate is thawed and diluted to
twice the desired final maximum test concentration with complete
Compound 4 and 37 was reacted with p-toludine by fusion in an
attempt to obtain 3-substituted-quinazolin-4-ones in different reac-
tion conditions, in all cases; the reaction afforded the (ring open
medium containing50
mg/ml gentamicin. Additionalfour,10-foldor½

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2331
Scheme1. Synthetic route for the preparation of the target compounds 5e11.
log serial dilutions are made to provide a total of five drug concen-
trations plus control. Aliquots of 100 l of these different drug dilu-
tions are added to the appropriate microtiter wells already containing
100 l of medium, resulting in the required final drug concentrations.
with 10 mM trizma base, and the absorbance is read on an auto-
mated plate reader at a wavelength of 515 nm. For suspension cells,
the methodology is the same except that the assay is terminated by
m
m
fixing settled cells at the bottom of the wells by gently adding 50 ml
Following drug addition, the plates are incubated for an addi-
tional 48 h at 37 ꢁC, 5% CO2, 95% air, and 100% relative humidity. For
adherent cells, the assay is terminated by the addition of cold TCA.
of 80% TCA (final concentration, 16% TCA). Using the seven absor-
bance measurements [time zero, (Tz), control growth, (C), and test
growth in the presence of drug at the five concentration levels (Ti)],
the percentage growth is calculated at each of the drug concen-
trations levels. Percentage growth inhibition is calculated as:
Cells are fixed in situ by the gentle addition of 50
v) TCA (final concentration, 10% TCA) and incubated for 60 min at
ꢁC. The supernatant is discarded, and the plates are washed five
times with tap water and air dried. Sulforhodamine B (SRB) solution
(100 l) at 0.4% (w/v) in 1% acetic acid is added to each well, and
ml of cold 50% (w/
4
½ðTiꢀTzÞ=ðCꢀTzÞꢂ ꢃ 100forconcentrationsforwhichTi>= ¼ Tz
½ðTi ꢀ TzÞ=Tzꢂ ꢃ 100 for concentrations for which Ti < Tz:
Three dose response parameters are calculated for each experi-
mental agent. Growth inhibition of 50% (GI50) is calculated from
m
plates are incubated for 10 min at room temperature. After staining,
unbound dye is removed by washing five times with 1% acetic acid
and the plates are air dried. Bound stain is subsequently solubilized

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M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
Scheme 2. Synthetic route for the preparation of the target compounds 13e17.
[(TiꢀTz)/(CꢀTz)] ꢃ 100 ¼ 50, which is the drug concentration
resulting in a 50% reduction in the net protein increase (as measured
by SRB staining) in control cells during the drug incubation. The drug
concentration resulting in total growth inhibition (TGI) is calculated
from Ti ¼ Tz. The LC50 (concentration of drug resulting in a 50%
reduction in the measured protein at the end of the drug treatment
as compared to that at the beginning) indicating a net loss of cells
following treatment is calculated from [(TiꢀTz)/Tz] ꢃ 100 ¼ ꢀ50.
Values are calculatedforeach of thesethreeparameters if the level of
activity is reached; however, if the effect is not reached or is
exceeded, the value for that parameter is expressed as greater or less
than the maximum or minimum concentration tested [48e50].
anticancer activity. Primary in vitro one dose anticancer assay was
performed in full NCI 60 cell panel representing leukemia, mela-
noma and cancers of lung, colon brain breast, ovary, kidney and
prostate in accordance with the protocol of the NCI, USA. The
compounds were added at a single concentration (10ꢀ5 M) and the
culture was incubated for 48 h. End point determinations were
made with a protein binding dye, Sulforhodamine B. Results for
each compound were reported as a mean graph of the percent
growth of the treated cells when compared to the untreated control
cells. There after obtaining the results for one dose assay, analysis of
historical Development Therapeutics Programme (DTP) was per-
formed and compound 21 (NSC D-753439/1) which satisfied pre-
determined threshold inhibition criteria was selected for NCI full
panel 5 dose assay.
4.2. Pharmacological (in vitro anticancer activity)
The tested quinazolines, diamides and quinoxalines analogs
showed a distinctive pattern of selectivity. With regard to sensi-
tivity against individual cell lines (Table 1). Compound 11 and 21
showed remarkably lowest cell growth promotion against Renal
A-498 and Non-small lung HOP-62 cancer cell line with cell growth
promotion of ꢀ23 and ꢀ34.84 respectively. Apart from this
compound 21 also exhibited broad spectrum cell growth inhibition
against Non Small Cell Lung Cancer NCI-H522 (cell growth
promotion 10.38%, inhibition 89.62%), Colon HCT-116 Cancer (cell
growth promotion 24.88%, inhibition 75.12%), CNS Cancer SNB-75
(cell growth promotion 32.38%, inhibition 67.62%), Melanoma LOX
IMVI (cell growth promotion 34.24%, inhibition 65.76%), Ovarian
OVCAR-4 Cancer cell line (cell growth promotion 4.38%, inhibition
95.62%), Renal ACHN Cancer Cell line (cell growth promotion
23.89%, inhibition 76.11%) and Breast BT -549 cancer cell line (cell
growth promotion 13.63%, inhibition 86.37%) at single dose assay
concentration of 10ꢀ5 M. The highest activity of this compound
might be because of its structural resemblance with lapatinib since
it contain 2-chloro benzylideneamine group at C-3 position of
The tumor growth inhibition properties of the seventeen
compounds 5, 10, 11, 14, 15, 21, 39, 40, 41, 42, 48b, 48c, 48e, 48f, 48g,
48h and 48i with the NCI codes NSC D-752812/1, NSC D-752813/1,
D-753448/1, D-753446/1, D-753445/1, D-753439/1, D-753786/1, D-
753787/1, D-753788/1, D-753789/1, D-753225/1, D-753230/1,
D-532226/1, D-753231/1, D-753227/1, D-753228/1 and D-753229/
1 selected among 5e48(aei) by the National Cancer Institute (NCI),
USA, were screened on human tumor cell lines at 10ꢀ5 M at the NIH,
Bethesda, Maryland, USA, under the drug discovery program of the
NCI. Among the selected seventeen compounds, compound 21 (NSC
D-753439/1) was further screened for 5-log dose molar range as it
has shown prominent cell growth inhibition at 10ꢀ5 M concentra-
tion against verity of cell lines.
4.2.1. Primary single high dose (10ꢀ5 M) full NCI 60 cell panel in
vitro assay
All the selected compounds submitted to National Cancer
Institute (NCI) for in vitro anticancer assay were evaluated for their

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2333
Scheme 3. Synthetic route for the preparation of the target compounds 19e34.
quinazoline which suppose to block the hydrophobic pocket of
Tyrosine kinase (Fig. 2). The third most-highest active compound
from the category of quinoxalines is no one but the 48g, which
showed significant cell growth inhibition against Ovarian OVCAR-4
(cell growth promotion 2.71%, inhibition 97.29%), Non-Small Cell
Lung EKVX (cell growth promotion 22.23%, inhibition 77.77%) and
Melanoma SK-MEL-5 Cancer Cell line (cell growth promotion
17.40%, inhibition 82.6%). With regard to broad spectrum antitumor
activity 48g was found to active against Ovarian, Non-Small Cell
Lung, Melanoma, Colon, Renal and Breast cancer subpanel cell lines.
Contrary compound 14, 48c has not shown any significant cell
growth inhibition while 5, 10, 15, 41, 48e and 48f was found to be
moderately active against subpanel of cell lines. From the category
of diamides (open quinazolines) compound 39 was emerged as
active compound which showed significant cell growth inhibition
against Leukemic Cancer Cell lines K-562 (cell growth promotion
40.21%, inhibition 59.79%), Melanoma UACC-62 (cell growth
promotion 40.16%, inhibition 59.84%) and Renal UO-31 (cell growth
promotion 39.29%, inhibition 60.71%). Apart from this it also
showed cell growth inhibition against Non Small Cell Lung, Colon,
CNS, Ovarian, Prostate and Breast Cancer subpanel cell lines.
Another diamides namely compound 40 and 42 showed up to 50%
cell growth inhibition against Renal UO-31 while individually
compound 40 also exhibited 51% cell inhibition against Colon HCT-
116 Cancer cell line. Another active candidate from quinoxalines
was 48i, which significantly cell growth inhibition against Ovarian
OVCAR-4 Cancer cell line (cell growth promotion 25.22%, inhibition
74.78%) and Leukemia HL-60(TB) (cell growth promotion 26.78%,
inhibition 73.22%).Compound 48h, another member of quinoxa-
lines showed up to 44% (56.15% cell growth promotion) cell growth
inhibition against Renal TK-10 Cancer cell line at single dose assay
(10ꢀ5 M concentration) as shown in Table 1.
4.2.2. In vitro 5 dose full NCI 60 cell panel assay
All the cell lines (about 60), representing nine tumor subpanels,
were incubated at five different concentrations (0.01, 0.1, 1, 10 &

2334
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
Scheme 4. Synthetic route for the preparation of the target compounds 39e42.
100 mM). The outcomes were used to create log concentration Vs %
growth inhibition curves and three response parameters (GI50, TGI
and LC50) were calculated for each cell line. The GI50 value (growth
inhibitory activity) corresponds to the concentration of the
compound causing 50% decrease in net cell growth, the TGI value
(cytostatic activity) is the concentration of the compound resulting
in total growth inhibition and LC50 value (cytotoxic activity) is the
concentration of the compound causing net 50% loss of initial cells at
the end of the incubation period of 48 h. Compound under investi-
gation 21 (NSC D-753439/1) exhibited remarkable anticancer
activity against most of the tested cell lines representing nine
Scheme 5. Synthetic route for the preparation of the target compounds 48 (aei).
obtained by dividing the full panel MID (the average sensitivity of all
cell lines toward the test agent) by their individual subpanel MID
(the average sensitivity of all cell lines of a particular subpanel
toward the test agent). Ratios between 3 and 6 refer to moderate
selectivity; ratios greater than 6 indicate high selectivity toward the
corresponding cell line, while compounds not meeting either of
these criteria rated non-selective [51]. As per this criterion,
compound in the study was found to be moderate selective toward
ovarian cancer subpanel only with selectivity ratio of 3.17, whereas it
was found to be non-selective against remaining cell panel (Table 2).
different subpanels with GI50 values between ‘‘1.82e15.24
except one HL-60 (TB) Cell line of Leukemia subpanel showing GI50
at a concentration of 23.89 M (Table 2), whereas four cell lines of
mM’’,
m
Leukemia subpanel namely K-562,MOLT-4,RPMI-8226 and SR were
found to be insensitive at the highest tested concentration i.e.
100 mM therefore a sign of ‘‘>’’ is used as prefix to the concentration.
5. Structure activity relationship
With regard to the sensitivity against some individual cell lines
(Table 2) the compound showed high activity against Ovarian
OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 &
Structure-activity correlation of the synthesized compounds
revealed that, in the diamide (open ring quinazolines) series 39, 40,
41 and 42 aromatic substitution, on the benzamide amide function,
favors the activity. Replacement of aromatic substitution by sul-
phonamide ring on the benzamide amide function resulting into
a potent compound. This is obvious upon comparing compound 11
2.14
profile toward ovarian subpanel (GI50 value ranging from 1.82 to
6.12 M), least for OVCAR-4 and maximum for IGROV1 cell line. The
criterion for selectivity of a compound depends upon the ratio
mM respectively. Obtained data revealed an obvious sensitivity
m

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2335
Chart 2. Ring opening of benzoxazinone by water.
(Renal A-498 cancer cell line ꢀ23% promoted) and compound 39
Renal UO-31(cell growth promotion 39.29%, inhibition 60.71%).
Introduction of eOH and benzoic acid group at position 3-of qui-
nazoline did not result into the very active compounds 5 and 10.
Introduction of 2-chloro benzylideneamine group at 3 position of
quinazoline markedly increased the activity that results into the
very potent and broad spectrum compound 21 (Non-small lung
HOP-62 cancercell line ꢀ34.84promotedatone dosewith GI50 value
position of quinoxaline improves the potency and broad spec-
trumness of compound as compared to substituted styryl. These
preliminary encouraging results of biological screening of the
tested compounds could offer an excellent framework in this field
that may lead to discovery of potent antitumor agent.
7. Experimental
of 1.82 mM against Ovarian OVCAR-4 cancer cell line at five dose
All chemicals and solvents were supplied by Merck, S.D. Fine
Chemical Limited, Mumbai. All the solvents were distilled and dried
before use. The reactions were monitored with the help of thin-layer
chromatography using pre-coated aluminum sheets with GF254
silica gel, 0.2 mm layer thickness (E. Merck). Melting points of the
synthesized compounds were recorded on the Veego (VMP-MP)
melting point apparatus. IR spectrum was acquired on a Shimadzu
Infra Red Spectrometer, (model FTIR-8400S). Both 1H NMR (DMSO)
and 13C NMR (DMSO) spectra of the synthesized compounds were
performed with Bruker Avance-II 400 NMR Spectrometer operating
at 400 MHz in SAIF, Punjab University (Chandigarh). Chemical shifts
assay). The highest activity of this compound might be because of its
structural resemblance with lapatinib since it contain 2-chloro
benzylideneamine group at 3-position of quinazoline which
suppose to block the hydrophobic pocket of Tyrosine kinase (Fig. 2).
In quinoxaline series, styryl substitution at 3-position of quinoxaline
favors the activity as well broad spectrumness rather than
substituted styryl substitution. This is obvious upon comparing
compound 48g [Ovarian OVCAR-4 (cell growth promotion 2.71%,
inhibition 97.29%), Non-Small Cell Lung EKVX (cell growth promo-
tion 22.23%, inhibition 77.77%) and Melanoma SK-MEL-5 Cancer Cell
line (cell growth promotion 17.40%, inhibition 82.6%)] and 48h [44%
cell growth inhibition against Renal TK-10 Cancer cell line].
were measured relative to internal standard TMS (d: 0). Chemical
shifts are reported in scale (ppm). Mass spectra of the synthesized
d
compounds were recorded at MAT 120 in SAIF, Punjab University.
6. Conclusion
7.1. 2-[(furan-2-ylcarbonyl) amino] benzoic acid (3)
All the compounds were submitted to screen for their anticancer
potential at NCI on the basis of results obtained it was found that 3-
(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-
one 21 (NSC D-753439/1) proved to be the most active member of
this study. Rational approach and QSAR techniques enabled the
understanding of the pharmacophoric requirement for quinazoline
and quinoxaline derivatives. The overall outcome of this model
revealed that: (i) the quinazoline ring is satisfactory backbone for
antitumor activity, (ii) the presence of 2-chloro benzylideneamine
group at 3 position of quinazoline and chalcone on the benzamide
amide function of diamides (open ring quinazolines) enhances the
activity as hydrophobic region, (iii) the presence of sulphonamide
group is necessary as H-bond region (iv) plane styryl group at 3-
2-Furoyl chloride 2 (0.01 mol) was added drop wise to a stirred
solution of anthranilic acid 1 (0.01 mol) in pyridine (50 ml) and the
reactionmixturewasstirredatroomtemperaturefor2h. Thereaction
mixture was poured into cold 5% dilute HCl, solution (100 ml). The
solid obtained was filtered, washed several times with water, dried
and crystallized from ethanol. Yield 67%; mp 190e192 ꢁC; IR (KBr)
ѵmax 3446, 3115, 2980, 1681, 1638,1598,1457 cmꢀ1; 1H NMR (DMSO-
d6)
d
ppm: 6.54e8.96 (m,7H, AreH and furan-H), 10.89 (s,1H,NHCO),
ppm: 170.1, 164.9, 148.5,
12.32 (s,1H, COOH); 13C NMR (DMSO-d6)
d
143.9, 140.3, 134.1, 130.6, 124.3, 118.4, 114.8; HRMS (EI) m/z calcd for
C12H9NO4: 231.0532; found: 231.0536.
7.2. 2-(furan-2-yl)-4H-3, 1-benzoxazin-4-one (4)
A mixture of 2-[(furan-2-ylcarbonyl) amino] benzoic acid 3
(0.01 mol) and acetic anhydride (0.1 mol) was heated under reflux for
4 h. The solvent was removed under reduced pressure. The residuewas
triturated with petroleum ether 40e60. The separated solid was
collected by filtration, washed with petroleum ether 40e60, dried and
crystallized from toluene. Yield 64%; mp 161e163 ꢁC; IR (KBr) ѵmax
Chart 3. Impact of electron donating group at C-2 over the reactivity of benzoxazinone.

2336
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2918, 1699, 1644, 1495, 1455, 1379 cmꢀ1; 1H NMR (DMSO-d6)
6.63e8.21 (m, 7H, AreH and furan-H); 13C NMR (DMSO-d6)
163.5, 159.3, 142.8, 143.4, 141.6, 134.1, 128.8, 126.4, 122.2, 118.8, 108.9,
d
d
ppm:
ppm:
223e227 ꢁC; IR (KBr) ѵmax 3418, 2918, 1649, 1623, 1550, 1451,
1320 cmꢀ1; 1H NMR (DMSO-d6)
ppm: 6.51e8.72 (m, 7H, AreH and
furan-H), 12.31 (s, 1H, OH); 13C NMR (DMSO-d6)
ppm: 160.2, 158.6,
d
d
108.4; HRMS (EI) m/z calcd for C12H7NO3: 213.0426; found: 213.0428.
142.7,141.7,140.7,133.4,128.3,124.7,121.8,108.8,108.6; HRMS (EI) m/z
calcd for C12H8N2O3: 228.0535; found: 228.0539.
7.3. 2-(furan-2-yl)-3-hydroxyquinazolin-4(3H)-one (5)
7.4. General procedure for the synthesis of 3(4H)-substituted 2-
Amixtureof2-(furan-2-yl)-4H-3,1-benzoxazin-4-one4(0.01mol)
and hydroxylamine hydrochloride (0.01 mol) in dry pyridine (30 ml)
was heated under reflux for 8 h and the reaction mixture was then
concentrated to half its volume. The separated solid was filtered,
washed with water and crystallized with ethanol. Yield 66%; mp
(furan-2-yl)-4-oxoquinazoline) (6e8)
Equimolaramount of 2-(furan-2-yl)-4H-3,1-benzoxazin-4-one 4
and different primary amino containing moieties like thiosemi-
carbazide, urea, and thiourea were fused together at 200 ꢁC in an oil
Chart 4. Reaction mechanism of ring opening of compound 12 in the synthesis of target compound 13e17 (Scheme 2).

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2337
Chart 5. Reaction mechanism of ring opening of compound 38 in the synthesis of target compound 39e42 (Scheme 4).
bath for 1 h. The mixture was cooled and methanol was added to the
mixture. The separatedsolid wascollected byfiltration, washed with
methanol, dried and crystallized from ethanol.
d
ppm: 7.11e8.80 (m, 7H, AreH and furan-H), 9.99 (s, 1H, NH), 12.32
(s, 2H, NH2); 13C NMR (DMSO-d6)
d
ppm: 180.3, 168.5, 154.3, 143.8,
141.3, 140.7, 132.4, 128.7, 126.8, 120.6, 108.9, 108.4; HRMS (EI) m/z
calcd for C13H10N4O2S: 286.0524; found: 286.0527.
7.4.1. 1- (2-Furan-2-yl)-4-oxoquinazoline-3(4H)-yl) thiourea (6)
This compound was prepared and purified as per the above
mentioned procedure: yield 24%; mp 228e231 ꢁC; IR (KBr) ѵmax
7.4.2. 2-(furan-2-yl)-4-oxoquinazoline-3(4H)-carboxamide (7)
This compound was prepared and purified as per the above
mentioned procedure: yield 18%; mp 215e218 ꢁC; IR (KBr) ѵmax
3648, 2918, 1658,1632,1504,1455, 1320 cmꢀ1 1H NMR (DMSO-d6)
;

2338
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
Table 1
Sixty human tumor cell line anticancer screening data at single dose assay (10ꢀ5 M concentration) as percent cell growth promotion of compound 5, 10, 11, 14, 15, 21, 39, 40, 41,
42, 48b, 48c, 48e, 48f, 48g, 48h, 48i.
5
10
11
14
15
21
39
40
41
42
48b
48c
48e
48f
48g
48h
48i
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
98.16
95.84
105.54 98.25
101.31 91.05
NT
94.70
87.86
94.52
98.87
93.06
95.39
87.33
117.5 108
101.4 109
96.43 103
83.12
89.12
40.37 52.41 79.93
50.34 94.11 97.49
40.21 57.81 96.88
44.21 59.17 86.81
53.22 56.24 79.36
53.89 99.77 93.78 77.99 81.79 89.58 81.59 41.14
92.43 96.53 94.70 84.38 87.19 77.83 91.21 26.78
84.98
94.72
96.67
95.66 101.3
62.47 79.20 99.20 107
77.32 84.40 88.59 75.47 84.64 63.07 69.92 57.51
63.43 108 102 85.51 100 47.73 77.53 63.38
105
61.44 90.78 77.33
99.10 100
99.12
92.65
94.12
NT
92.85
120
109
94.97 81.19 106.41 70.89 97.29 97.73 99.18 79.22 83.80 81.40 44.46
Non-Small Cell Lung Cancer
A549/ATCC
EKVX
HOP-62
113.82 104.77 106.3 101
109.13 98.39 97.23 88.81
112.74 107.05 106 111
97.88 78.42 114.6 107
105.41 98.82
97.18 97.61
108.52 95.38
NT
102
80.41
104
105
95.98
110
107
114
38.12
64.12
ꢀ34.84
53.52
64.87
36.23
28.38
10.38
75.71 70.02 99.78
85.24 86.68 100
91.49 100
93.12 85.66 97.05 64.03 90.64 77.16
87.70 79.01 99.04 92.68 92.96 22.23 81.90 60.40
93.96 97.73 99.49 101
84.69 96.35 95.59 99.33 105
91.39 93.86 105
81.13 95.01 120
95.55 105
94.69
100
88.30 87.33 73.71
65.68 87.18 79.35
52.23 92.16 76.93
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon Cancer
COLO 205
HCC-2998
HCT-116
HCT-15
79.29 85.77 95.46
91.38 73.51 105
71.88 89.27 91.92
92.10 72.92 107
69.87 70.95 99.45
110.8
119.5 102
115.5 116
94.62
102
NT
95.51 104
102
97.59 86.40 94.87 80.01
70.22 94.48 80.34
94.36 NT
70.10 NT
104
NT
109.67 90.78 106
NT
NT
NT
NT
NT
107.29 103.97 NT
124
128
96.83
32.76 101
124
115
121
119
105
119
123
110
75.70 104
96.37
102
119.50 120.31 103.3 105
34.89
24.88
62.36
52.78
26.67
94.19 78.38 99.70
70.71 49.35 92.70
57.75 65.81 98.82
97.64 89.94 121
67.28 64.38 106
93.69 99.44 NT
84.74 78.83 88.47 89.77 87.81 35.79 73.92 65.39
73.53 101
111 94.19 89.43 86.49 101
93.79 90.27 104 98.91 104
107 NT 98.13 95.64 102
90.32 86.35 NT
105.94 99.69
108.36 93.69
103.19 92.00
109.7 103
105.5 104
99.28 108
108
109
103
110
106
114
96.67 93.83 96.13 103
74.29
50.17 80.40 83.56
79.70 97.42 77.92
83.03 96.03 93.22
HT 29
KM 12
SW-620
110.22 104.99 108.4 107
107.69 106.15 101.9 106
34.38 101
99.16 109
CNS Cancer
SF-268
SF-295
SF-539
SNB-19
106.30 106.85 98.43 104
117.66 108.58 103.8 114
107
122
97.41
107
71.39
107
72.86
52.12
24.89
62.14
32.38
69.03 82.84 108
97.53 52.07 162
81.74 91.80 110
86.41 74.25 104
99.47 84.55 85.88
98.17 94.82 109
91.53 107
82.46 104
88.12 99.47 81.66
58.93 100
102 101
127
125
58.32 110
93.22
95.42
101.58 91.35
86.97 89.20
104.20 86.82 102
110.7 111
87.71 80
111
85.81 97.75 94.92 97.28
90.58 94.19 100
82.74 NT NT
95.87 90.27 107
97.81 96.81 82.87 98.90 76.60
93.68 NT
95.56 102
SNB-75
U251
NT
NT
NT
110.85 102.8
99.55 100
37.22 103
60.68 103
79.81 104
83.34
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian Cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
Renal Cancer
786-0
107.97 98.82
101.6 109
94.63
34.24
78.64
87.98
90.21
67.89
69.03 74.93 92.00
97.53 91.75 101
81.74 78.50 92.83
86.41 82.15 107
99.47 90.64 104
84.87 91.83 100
95.29 103
56.83 93.90 78.17
63.63 108 83.19
92.21 76.83 99.58 70.20
122.97 102.96 118.8 108
89.53 103.37 113.1 112
124.51 112.17 107.2 108
103.59 93.19 115.3 116
109.58 115.08 107.1 113
111.56 94.96 108.4 103
112.27 107.43 100.1 103
115
107
101
136
111
105
112
101
78.99 86.98 90.35 86.88 102
83.75 102 99.32 100
90.52 90.95 109 96.11 102
96.46 NT NT
86.57 88.08 102
88.93 105
NT NT
94.52 118
81.04
NT
95.95
NT
NT
38.98 103
101
115
107
124
48.82
82.72
62.82
76.71 82.15 86.16
94.49 94.73 104
40.16 79.67 98.83
77.57 96.24 101
95.26 97.96 17.40 75.46 68.43
117 102 67.72 111 81.10
96.99 84.34 61.37 80.62 58.04
103
93.79 113
92.42
84.67
107
99
84.87 79.86 100
103.91 91.67
114.53 105.38 108
117
110
107
117
109
101
108
100
104
116
71.23
27.98
4.38
37.89
26.87
12.24
25.85
85.60 89.85 96.30
89.47 86.93 107
82.05 85.63 NT
78.34 101
88.79 92.52 110
NT NT NT
99.95 94.90 104
103
71.03 116
87.44 79.39 59.92
102
107
102
100
100
NT
107
NT
102
108
106
NT
65.02 107
2.71 NT
95.41 101
81.53
25.22
86.09
114.55 100.60 98.00 100
100.49 98.22 99.82 105
110.28 104.87 103
112.30 102.28 111
106.84 107.59 110
96.06 123
116
106
109
111
86.46 88.85 105
71.73 95.06 117
92.69 95.35 96.53
104
112
97.32 103
89.75 103
82.17 92.09 75.12
53.22 95.82 82.43
73.61 85.70 NT
87.56 NT
NT
104.23 105.17 108
115
103
26.39
36.82
23.89
62.86
82.73
36.81
81.43 75.14 95.86
84.31 95.67 90.69 94.31 90.32 76.68 90.52 89.92
A-498
ACHN
CAKI-1
RXF-393
SN 12C
97.65
98.81
106.88 ꢀ23
94.62
104
83.31
69.42
100
89.89
117
103
127
85.08 NT
NT
NT
NT
105
100
88.72 88.48 71.11 95.89 92.56
93.62 103
76.71 107
101.24 101
58.96 82.68 97.71
70.25 90.60 95.90
97.37 82.15 95.14
80.93 79.73 96.62
87.29 102
76.83 94.36 69.99
77.88 83.86 56.68
102.81 102.24 100
117.15 109.93 113
83.56 69.32 111
98.83 105 107
87.79 88.36 94.09 94.78 100
114 103 86.49 107 113
114
104
126
106
99.96 97.82 87.00 87.29
98.60
98.03
68.92
99.34
94.73
68.61
105
102
104
74.42 88.34 78.21
44.74 56.15 43.48
TK-10
UO-31
73.98 100
62.12
123
97.64
84.80
83.88
39.29 52.88 68.52
49.85 63.70 86.51 85.96 84.96 58.60 60.33 49.71
Prostate Cancer
PC-3
DU-145
Breast Cancer
MCF7
MDA-MB-231/ATCC 93.48
HS 578T
BT -549
T-47D
91.05
86.25
118
109
104
115
112
78.23
56.23 100
61.81 65.20 94.13
75.75 125 103 96.98 119 NT 113 63.90
122.21 111.42 113
107
108
111
100
97.76 103
61.74 101
97.51 95.35 74.33 98.54 76.88
89.91 77.51 40.30 82.73 51.80
103.51 63.47 95.61
98.40
94.46 102
100
109
103
108
98.82
63.86
52.12
83.85 104
13.63
62.59
78.92
77.81 82.72 96.33
76.35 81.11 96.74
83.73
NT
102
118
87.48 93.29 97.02 95.18 89.23 77.23 96.56 53.69
NT
113
127
106
108
67.95 100
80.44 NT
86.19 NT
86.44 NT
81.99 101
107
NT
NT
110
NT
NT
119
NT
NT
90.10 87.08 48.80
NT NT NT
34.60 63.43 NT
103.70 100.59 111
106.81 83.00 103
115.34 101.43 106
65.95 76.41 95.53
66.17 82.14 89.85
77.87 83.46 95.39
MDA-MB-468
104
114
109
39.93 98.24 59.53
NT- Not Tested, 30-40% growth inhibition, 40-50% growth inhibition, 50-70% growth inhibition, 70-90% growth inhibition, 90-100% growth inhibition, Highly
potent compound.

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2339
3130, 2933, 1655, 1641, 1558, 1460, 1449 cmꢀ1; 1H NMR (DMSO-d6)
ppm: 7.43e8.10 (m, 7H, AreH and furan-H), 12.39 (s, 2H, NH2);
13C NMR (DMSO-d6)
ppm: 170.8, 158.4, 156.4, 143.7, 141.3, 140.7,
133.4, 127.3, 126.6, 118.8, 108.9, 108.6; HRMS (EI) m/z calcd for
C13H9N3O3: 255.0644; found: 255.0646.
7.4.3. 2-(furan-2-yl)-4-oxoquinazoline-3(4H)-carbothioamide (8)
d
This compound was prepared and purified as per the above
d
mentioned procedure: yield 23%; mp 222e224 ꢁC; IR (KBr) ѵmax
3124, 2916, 1675, 1642, 1549, 1458, cmꢀ1 1H NMR (DMSO-d6)
;
d C
ppm: 7.38e7.98 (m, 7H, AreH and furan-H), 12.17 (s, 2H, NH2); 13
Table 2
NCI in vitro testing result of compound 21 (NSC D-753439/1) at five dose level in mM.
Panel
Cell Line
GI50
TGI
LC50
Concentration
per cell line
Subpanel MIDb
Selectivity ratio
(MIDa: MIDb)
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
11.8
23.8
> 100
> 100
> 100
> 100
4.78
7.23
3.56
4.12
7.87
4.11
3.45
2.14
4.96
5.68
3.32
5.73
3.42
3.65
4.68
6.84
3.26
3.28
6.34
4.10
4.12
4.54
7.23
10.8
8.23
6.86
4.45
5.56
8.34
6.38
6.12
4.12
1.82
5.12
3.98
2.45
3.68
3.94
5.76
3.12
7.99
11.6
4.89
7.84
6.12
8.23
4.38
5.29
3.13
15.2
2.92
6.89
9.96
12.36
72.63
0.170
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
13.7
> 100
> 100
76.86
8.41
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
82.9
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
52.7
Non-Small Cell
Lung Cancer
A549/ATCC
EKVX
4.65
2.65
HOP-62
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
COLO 205
HCC-2998
HCT-116
HCT-15
HT 29
KM 12
SW-620
SF-268
SF-295
6.45
34.1
Colon Cancer
4.49
2.75
> 100
23.6
> 100
> 100
25.4
12.7
CNS Cancer
Melanoma
4.65
6.94
2.65
1.78
> 100
> 100
21.2
12.8
7.51
SF-539
SNB-19
SNB-75
U251
32.3
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
786e0
A-498
ACHN
CAKI-1
RXF-393
SN 12C
TK-10
UO-31
PC-3
DU-145
> 100
> 100
> 100
16.96
> 100
18.6
31.8
> 100
> 100
> 100
6.87
6.48
> 100
25.8
8.78
14.8
14.9
16.7
> 100
34.8
42.6
> 100
> 100
> 100
> 100
> 100
> 100
7.84
Ovarian Cancer
Renal Cancer
3.89
6.41
3.17
1.92
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
72.4
Prostate Cancer
Breast Cancer
6.30
7.23
1.96
1.70
MCF7
MDA-MB-231/ATCC
HS 578T
BT -549
T-47D
> 100
6.8
> 100
> 100
> 100
> 100
MDA-MB-468
MIDa
MIDa ¼ Average sensitivity of all cell line in
mM.
MIDb ¼ Average sensitivity of all cell line of a particular subpanel in
mM.

2340
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
NMR (DMSO-d6)
d
ppm: 180.4, 172.4, 158.2, 143.7, 141.3, 140.7, 132.6,
132.8, 128.4, 126.6, 124.4, 122.5, 120.5, 118.4, 116.7, 112.6, 23.6;
128.8, 126.6, 118.7, 108.8, 108.2; HRMS (EI) m/z calcd for
HRMS (EI) m/z calcd for C19H16N2O3: 320.1161; found: 320.1165.
C13H9N3O2S: 271.0415; found: 271.0418.
7.9. General procedure for the synthesis of N-(2-(4- substituted
styryl phenyl carbamoyl) phenyl) furan-2-carboxamides (13e17)
7.5. 2-(furan-2-yl)-3-(phenylamino) quinazolin-4(3H)-one (9)
A
mixture of 2-(furan-2-yl)-3-(4-methylphenyl)quinazolin-4
A mixture of 2-(furan-2-yl)-3-hydroxyquinazolin-4(3H)-one 4
(0.01 mol) and phenyl hydrazide (0.01 mol) in ethanol (20 ml) was
heated under reflux for 10 h. The reaction mixture was concen-
trated, cooled and the separated solid was crystallized out from
acetone to afford compound 9.Yield 68%; mp 158e162 ꢁC; IR (KBr)
(3H)-one 12 (0.01 mol) and substituted aromatic aldehydes in
equimolar quantities (0.01 mol) in glacial acetic acid (50 ml) with
few drops of concentrated sulphuric acid was heated under reflux
for 4 h. Subsequently, mixture was poured into water and the
residual solid was filtered, washed repeatedly with water. It was
dried and crystallized from ethanol.
ѵmax 3114, 2913, 1673, 1640, 1543, 1458 cmꢀ1 1H NMR (DMSO-d6)
;
d
ppm: 7.28e8.10 (m, 12H, AreH and furan-H), 10.37(s, 1H, NH); 13
C
NMR (DMSO-d6) d ppm: 163.8,158.6,148.5,142.7,141.6,140.6,133.2,
132.4, 129.2, 127.9, 126.8, 121.6, 118.8, 108.8, 108.4; HRMS (EI) m/z
calcd for C18H13N3O2: 303.1008; found: 303.1011.
7.9.1. N-(2-(4-styryl phenyl carbamoyl) phenyl) furan-2-
carboxamide (13)
This compound was prepared and purified as per the above
mentioned procedure: yield 40%; mp 231e233 ꢁC; IR (KBr) ѵmax 3241,
7.6. 4-[2-(furan-2-yl)-4-oxoquinazolin-3(4H)-yl] benzoic acid (10)
2821, 1660, 1649, 1454, 1412 cmꢀ1; 1H NMR (DMSO-d6)
d ppm: 7.72 (d,
1H, J ¼ 16.6 Hz, olefinic CH), 6.74e8.70 (a set of signals, 17 H, AreH,
Equimolar amount of 2-(furan-2-yl)-4H-3, 1-benzoxazin-4-one
4 and p-amino benzoic acid was fused together at 200 ꢁC in an oil
bath for 1 h. The mixture was cooled and methanol was added to
the mixture. The separated solid was collected by filtration, washed
with methanol, dried and crystallized from acetic acid. Yield 56%;
mp 184e186 ꢁC; IR (KBr) ѵmax 3450, 2851, 1668, 1614, 1502, 1438,
furan-H and olefinicCH),10.19 (s,1H,eNHCOe),12.08(s,1H,eCONHe);
13C NMR (DMSO-d6)
d ppm:168.7,163.2,146.7,144.4,138.5,136.5,134.7,
132.8, 129.8, 128.8, 128.5, 126.9, 126.2, 124.5, 122.7, 120.8, 118.6, 114.4,
112.4; HRMS (EI) m/z calcd for C26H20N2O3: 408.1474; found: 408.1476.
7.9.2. N-(2-(4-(4 e cyano styryl) phenyl carbamoyl) phenyl) furan-
2-carboxamide (14)
1374 cmꢀ1; 1H NMR (DMSO-d6)
H), 7.19e8.68 (m, 10H, AreH and furan-H), 11.68(s, 1H, COOH); 13C
NMR (DMSO-d6) ppm: 168.8, 161.8, 158.6, 143.6, 142.1, 141.8, 138.4,
d
ppm: 6.99 (t, 1H, J ¼ 4.0 Hz, furan-
This compound was prepared and purified as per the above
d
mentioned procedure: yield 46%; mp 204e208 ꢁC; IR (KBr) ѵmax
132.4, 130.5, 128.3, 126.8, 124.8, 124.3, 118.6, 108.8, 108.3; HRMS (EI)
m/z calcd for C19H12N2O4: 332.0797; found: 332.0799.
3238, 2818, 2215, 1665, 1641, 1460, 1421, 1416 cmꢀ1 1H NMR
;
(DMSO-d6)
set of signals, 16H, AreH, furan-H and olefinic CH), 10.27 (s,
1H,eNHCOe), 11.89 (s, 1H,eCONHe); 13C NMR (DMSO-d6)
ppm:
d
ppm: 7.67 (d, 2H, J ¼ 16.6 Hz, olefinic CH), 6.31e8.25 (a
7.7. N-{2-[(4-sulfamoylphenyl) carbamoyl] phenyl} furan-2-
carboxamide (11)
d
168.2, 163.1, 146.7, 144.9, 142.3, 136.6, 135.5, 132.1, 129.7, 128.7,
128.5, 126.7, 126.2, 125.2, 124.6, 120.5, 119.6, 118.4, 114.2, 111.8;
HRMS (EI) m/z calcd for C27H19N3O3: 433.1426; found:433.1429.
Equimolar amount of 2-(furan-2-yl)-4H-3, 1-benzoxazin-4-one
4 and sulphanilamide were fused together at 200 ꢁC in an oil bath
for 1 h. The mixture was cooled and methanol was added to the
mixture. The separated solid was collected by filtration, washed
with methanol, dried and crystallized from 1,4 dioxane. Yield 72%;
mp 188e189 ꢁC; IR (KBr) ѵmax 3350, 2913, 1676, 1624,1606, 1505,
7.9.3. N-(2-(4-(4 e chloro styryl) phenyl carbamoyl) phenyl) furan-
2-carboxamide (15)
This compound was prepared and purified as per the above
mentioned procedure: yield 32%; mp 190e193 ꢁC; IR (KBr) ѵmax
1453, 1328,1140 cmꢀ1; 1H NMR (DMSO-d6)
d ppm: 3.43 (s, 2H, NH2),
3237, 2833, 1660, 1638, 1575, 1406, 777 cmꢀ1 1H NMR (DMSO-d6)
;
7.68 (d, 1H, J ¼ 8.0 Hz, AreH), 6.57e7.98 (m, 10H, AreH and furan-
d
ppm: 7.52 (d, 2H, J ¼ 16.6 Hz, olefinic CH), 6.83e8.45 (a set of
signals, 16H, AreH, furan-H and olefinic CH), 9.48 (s, 1H,eNHCOe),
12.17 (s, 1H,eCONHe); 13C NMR (DMSO-d6)
ppm: 168.1, 163.4,
H) 10.53 (s,1H,eNHCOe), 11.71(s,1H,eCONHe); 13C NMR (DMSO-
d6) d ppm; 168.5, 163.7, 146.7, 142.8, 141.4, 136.4, 135.5, 130.2, 128.7,
127.6, 124.4, 122.3, 118.6, 116.3, 114.4, 112.3; HRMS (EI) m/z calcd for
C18H15N3O5S: 385.0732; found: 385.0735.
d
149.2, 144.2, 138.4, 136.3, 134.7, 133.3, 132.1, 130.1, 128.9, 128.2,
126.4, 126.1, 125.3, 122.5, 121.5, 118.2, 114.3, 111.4; HRMS (EI) m/z
calcd for C26H19ClN2O3: 442.1084; found: 442.1088.
7.8. N-(2-(p-tolyl carbamoyl) phenyl) furan-2-carboxamide (12)
7.9.4. N-(2-(4-(4 e methyl styryl) phenyl carbamoyl) phenyl)
furan-2-carboxamide (16)
Method A: A mixture of 2-furanyl-4H-3, 1-benzoxazin-4-one
4 and 4-methyl aniline was fused together equimolarly at 200 ꢁC in
an oil bath for 1 h. The mixture was cooled and methanol was
added to the mixture. The separated solid was collected by filtra-
tion, washed with methanol, dried and crystallized from acetic acid.
Method B: A mixture of 2-furanyl-4H-3, 1-benzoxazin-4-one
4 (0.01 mol) and 4-methyl aniline (0.01 mol) in dry pyridine (50 ml)
was heated under reflux for 8 h. Subsequently, mixture was poured
into water (containing few drops of HCl) solid thus separated was
filtered, washed repeatedly with water. It was dried and crystal-
lized from acetic acid. Yield 52%; mp 141e142 ꢁC; IR (KBr) ѵmax 3111,
This compound was prepared and purified as per the above
mentioned procedure: yield 23%; mp 221e224 ꢁC; IR (KBr) ѵmax
3203, 2910,1633,1456 cmꢀ1; 1H NMR (DMSO-d6)
d ppm: 3.37(s, 3H,
CH3), 7.45 (d, 2H, J ¼ 16.6 Hz, olefinic CH), 6.81e8.48 (a set of
signals, 16H, AreH, furan-H and olefinic CH), 9.41 (s, 1H,eNHCOe),
12.10 (s, 1H,eCONHe); 13C NMR (DMSO-d6)
d ppm: 168.1, 163.9,
149.1, 142.6, 138.8, 138.1, 137.6, 135.8, 134.2, 129.8, 128.8, 128.6,
128.1, 126.3, 126.3, 124.7, 122.1, 120.2, 118.6, 114.6, 111.4, 23.3; HRMS
(EI) m/z calcd for C27H22N2O3: 422.1630; found: 422.1633.
2951, 1687,1632,1458, 1442 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 3.69
7.9.5. N-(2-(4-(4-nitro styryl) phenyl carbamoyl) phenyl) furan-2-
carboxamide (17)
(s,3H, CH3), 7.45 (d,1H, J ¼ 8.0 Hz, AreH), 6.55e8.06 (m,10H, AreH
and furan-H), 10.26 (s,1H,eNHCOe), 11.72(s,1H,eCONHe); 13C NMR
This compound was prepared and purified as per the above
(DMSO-d6)
d ppm: 168.8, 163.4, 146.5, 142.6, 138.7, 136.8, 134.4,
mentioned procedure: yield 21%; mp 238e240 ꢁC; IR (KBr) ѵmax

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2341
3301,2902,1647,1560, 1556, 1401, 1353, cmꢀ1; 1H NMR (DMSO-d6)
7.11.4. 3-(benzylideneamino))-2-(furan-2-yl) quinazoline-4(3H)
one (22)
d
ppm: 7.71 (d, 2H, J ¼ 16.6 Hz, olefinic CH), 6.75e8.72 (a set
of signals, 16H, AreH, furan-H and olefinic CH), 10.29
This compound was prepared and purified as per the above
(s, 1H,eNHCOe), 12.11 (s, 1H,eCONHe); 13C NMR (DMSO-d6)
mentioned procedure: yield 51%; mp 206e207 ꢁC; IR (KBr) ѵmax
d
ppm: 168.5, 163.7, 146.4, 144.2, 142.6, 142.3, 136.8, 136.3, 132.6,
2927, 1682, 1536,1394 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 6.60 (t,1H,
J ¼ 4.0 Hz, furan-H), 7.10e8.26 (m, 11 H, AreH and furan-H), 8.78 (s,
1H, N]CH); 13C NMR(DMSO-d6)
ppm: 169.9, 160.4, 144.1, 141.3,
129.3, 128.6, 126.4, 126.7, 125.3, 122.7, 122.2, 121.5, 118.2, 114.3,
111.6; HRMS (EI) m/z calcd for C26H19N3O5: 453.1325; found:
453.1328.
d
140.1, 132.7, 132.4, 131.3, 129.4, 128.1, 127.7, 125.1, 120.9, 108.8, 108.4;
HRMS (EI) m/z calcd for C19H13N3O2: 315.1008; found: 315.1010.
7.10. 3-amino-2-(furan-2-yl) quinazolin-4(3H)-one (18)
7.11.5. 3-(4-hydroxy-3-methoxy benzylideneamino))-2-(furan-2-
yl) quinazoline-4(3H) one (23)
3-amino-2-(furan-2-yl) quinazolin-4(3H)-one (0.01 mol) 4 was
heated to melt and excess of hydrazine hydrate was added. The
mixture was fused together at 200 ꢁC in an oil bath for 1 h. The
separated solid was cooled and acetone was added to the mixture.
The separated solid was collected by filtration, washed with
methanol, dried and crystallized from acetone. Yield 42%; mp
197e199 ꢁC; IR (KBr) ѵmax 3390, 2980, 1656, 1638, 1579, 1472,
This compound was prepared and purified as per the above
mentioned procedure: yield 32%; mp 270e273 ꢁC; IR (KBr) ѵmax
3344, 2944, 1674, 1470, 1379 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 3.94
(s, 3H, OCH3), 7.51e8.15 (m, 10H, AreH and furan-H), 8.89 (s, 1H,
N]CH), 11 (s, 1H, OH); 13C NMR (DMSO-d6)
ppm: 169.8, 160.5,
d
156.2, 152.1, 148.2, 143.3, 142.3, 140.8, 132.3, 131.6, 128.2, 126.3,
122.2, 120.2, 118.2, 114.4, 108.4, 108.1, 54.4; HRMS (EI) m/z calcd for
C20H15N3O4: 361.1063; found: 361.1066.
1450 cmꢀ1; 1H NMR (DMSO-d6)
d ppm: 5.18 (s, 2H, NH2), 7.86 (t, 1H,
J ¼ 4.0 Hz, furan-H), 6.61e7.98 (m, 6H, AreH and furan-H); 13C NMR
(DMSO-d6)
d ppm: 164.8, 158.9, 146.6, 142.2, 141.6, 132.8, 126.3,
7.11.6. 3-(4-hydroxy benzylideneamino))-2-(furan-2-yl)
quinazoline-4(3H) one (24)
125.8, 116.2, 108.4, 108.2; HRMS (EI) m/z calcd for C12H9N3O2:
227.0695; found: 227.0699.
This compound was prepared and purified as per the above
mentioned procedure: yield 38%; mp 199e202 ꢁC; IR (KBr) ѵmax
7.11. General procedure for the synthesis of 2-(furan-2-yl)-3-
substituted arylideneamino-3, 4 dihydro-quinazoline-4-ones
(19e34)
3330, 2921, 1641, 1466 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 6.56e8.70
(m, 11H, AreH and furan-H), 8.78 (s, 1H, N]CH), 11.99 (s, 1H, OH);
13C NMR (DMSO-d6)
ppm: 170.7, 160.4, 148.4, 142.4, 140.6, 132.6,
d
130.6, 128.6, 126.2, 126.1, 120.8, 118.2, 108.4, 108.2; HRMS (EI) m/z
Equimolar amount of 3-amino-2-(furan-2-yl) quinazolin-4(3H)-
one 18 (0.01 mol) and the appropriate aromatic aldehydes
(0.015 mol) in glacial acetic acid was heated under reflux for 4 h.
The separated solid was poured into water, filtered, washed with
water and crystallized from ethanol to give required products.
calcd for C19H13N3O3: 331.0957; found: 331.0960.
7.11.7. 3-(4-methyl benzylideneamino))-2-(furan-2-yl)
quinazoline-4(3H) one (25)
This compound was prepared and purified as per the above
mentioned procedure: yield 32%; mp 218e220 ꢁC; IR (KBr) ѵmax
7.11.1. 3-(anthracene-9-yl methylene amino)-2-(furan-2-yl)
quinazoline-4(3H) one (19)
2919,1650,1460,1413 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 2.48 (s, 3H,
CH3), 6.56e7.87 (m, 11H, AreH and furan-H), 8.87 (s, 1H, N]CH);
13C NMR (DMSO-d6)
ppm: 169.8, 160.9, 146.8, 143.6, 142.4, 140.8,
This compound was prepared and purified as per the above
d
mentioned procedure: yield 62%; mp 289e291 ꢁC; IR (KBr) ѵmax
132.2, 130.4, 128.4, 126.2, 125.8, 125.6, 120.4, 108.4, 108.2, 22.5;
HRMS (EI) m/z calcd for C20H15N3O2: 329.1164; found: 329.1168.
3050, 1684, 1582, 1530, 1448 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
6.54e8.65 (m, 16H, AreH and furan-H), 8.77 (s, 1H, N]CH); 13C
NMR (DMSO-d6) ppm: 169.7, 160.2, 144.5, 142.6, 141.2, 140.4,
d
7.11.8. 3-(3-bromo benzylideneamino))-2-(furan-2-yl) quinazoline-
4(3H) one (26)
132.4, 130.3, 128.6, 128.4, 127.6, 126.2, 124.2, 120.2, 108.9, 108.4;
HRMS (EI) m/z calcd for C27H17N3O2: 415.1321; found: 415.1323.
This compound was prepared and purified as per the above
mentioned procedure: yield 38%; mp 213e214 ꢁC; IR (KBr) ѵmax
7.11.2. 3-(4-chloro benzylideneamine))-2-(furan-2-yl) quinazoline-
4(3H) one (20)
2927, 1677, 1521, 11456, 670 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
6.57e7.96 (m,11H, AreH and furan-H), 8.86 (s,1H, N]CH); 13C NMR
(DMSO-d6) ppm: 169.6, 160.6, 144.9, 143.8, 142.6, 140.6, 136.4,
This compound was prepared and purified as per the above
d
mentioned procedure: yield 48%; mp 210e212 ꢁC; IR (KBr) ѵmax
132.6,131.6,129.4,128.6,127.7,127.5,125.3,122.5,120.5,108.6,108.4;
HRMS (EI) m/z calcd for C19H12BrN3O2: 393.0113 found: 393.0116.
2931, 1648, 1502, 1355, 560 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
7.16e7.94 (m, 11H, AreH), 8.78 (s, 1H, N]CH); 13C NMR (DMSO-d6)
ppm: 169.4, 160.5, 144.1, 142.3, 140.4, 138.2, 132.4, 131.3, 129.4,
d
7.11.9. 3-(4-cyano benzylideneamino))-2-(furan-2-yl) quinazoline-
4(3H) one (27)
128.7, 127.1, 125.3, 120.4, 108.6, 108.4; HRMS (EI) m/z calcd for
C19H12ClN3O2: 349.0618; found: 349.0621.
This compound was prepared and purified as per the above
mentioned procedure: yield 62%; mp 222e225 ꢁC; IR (KBr) ѵmax 3057,
7.11.3. 3-(2-chloro benzylideneamine))-2-(furan-2-yl) quinazoline-
4(3H) one (21)
2226, 1684, 1534, 1393 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 6.60 (t, 1H,
J¼ 4.0Hz, furan-H),7.10e8.26(m,10H, AreHandfuran-H),8.79(s,1H,
N]CH); 13C NMR (DMSO-d6)
ppm: 169.9, 160.6, 144.2, 142.8, 141.6,
This compound was prepared and purified as per the above
d
mentioned procedure: yield 53%; mp 201e204 ꢁC; IR (KBr) ѵmax
136.2, 133.2,131.2, 127.3, 126.8, 126.4,116.6,114.4,108.4, 108.2; HRMS
(EI) m/z calcd for C20H12N4O2: 340.0960; found: 340.0964.
2920, 1650, 1488, 1399, 554 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 7.09
(t, 1H, J ¼ 4.0 Hz, furan-H), 7.50e8.25 (m, 10H, AreH and furan-H),
8.79 (s, 1H, N]CH); 13C NMR (DMSO-d6)
ppm: 169.1, 160.4, 144.2,
d
7.11.10. 3-(2, 5-dimethoxy benzylideneamino))-2-(furan-2-yl)
quinazoline-4(3H) one (28)
142.3, 141.8, 140.3, 134.6, 132.2, 132.1, 131.4, 130.4, 127.4, 127.1, 125.6,
125.9, 120.3, 108.8, 108.9; HRMS (EI) m/z calcd for C19H12ClN3O2:
349.0618; found:349.0622.
This compound was prepared and purified as per the above
mentioned procedure: yield 28%; mp 251e254 ꢁC; IR (KBr) ѵmax

2342
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2958, 1685, 1489, 1395 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 3.96 (s,
6.55e8.32 (a set of signals, 14H, AreH, furan-H and olefinic CH]
CH), 8.88 (s, 1H, N]CH); 13C NMR (DMSO-d6)
ppm: 169.4, 160.4,
158.6, 146.6, 144.2, 140.4, 138.4, 136.2, 134.1, 132.4, 128.6, 128.2,
127.8,127.4,126.8,126.6,120.8,108.4,108.2; HRMS (EI) m/z calcd for
C21H15N3O2: 341.1164; found: 341.1167.
6H, OCH3), 7.10e8.26 (m, 10H, AreH and furan-H), 8.88 (s, 1H, N]
d
CH); 13C NMR (DMSO-d6)
d
ppm: 169.2, 160.4, 152.3, 148.4, 142.3,
142.4, 141.4, 140.2, 132.2, 127.4, 126.6, 120.4, 116.4, 114.2, 112.4,
108.4, 108.1, 58.2; HRMS (EI) m/z calcd for C21H17N3O4: 375.1219;
found: 375.1221.
7.12. Synthesis of 2-phenyl-4H-benzo[d] [1,3] oxazine-4-one (37)
7.11.11. 3-(4-nitro benzylideneamino))-2-(furan-2-yl) quinazoline-
4(3H) one (29)
Anthranilic acid 35 (0.1 mol) was dissolved in minimum volume
of dry pyridine (30 mL) by shaking. To this solution an ice-cold
solution of benzoyl chloride 36 (0.2 mol) taken in dry pyridine
(30 mL), was added slowly with constant stirring. When the addi-
tion was completed (the operation of addition required half an
hour), the resultant solution was subjected to vigorous stirring for
1 h mechanically subsequently, it was left as such for 1 h at room
temperature and treated with a solution of sodium bicarbonate
(10%). Addition of sodium bicarbonate solution was continued till
the effervescence due to the evolution of carbon-dioxide ceased.
The separated solid was allowed to settle down and filtered off. It
was washed with cold water repeatedly till there was no smell of
pyridine and unreacted benzoyl chloride. The crude benzo-oxazine
was dried in vacuum overnight and recrystallization from diluted
ethanol afforded analytically pure sample of 2-phenyl benzo[d]
[1,3] oxazin-4-one 37 as white crystalline mass. Yield 82%; mp
109e112 ꢁC; IR (KBr) ѵmax 2910, 1765,1610,1510,1256 cmꢀ1; 1H NMR
This compound was prepared and purified as per the above
mentioned procedure: yield 30%; mp 246e250 ꢁC; IR (KBr) ѵmax
3013, 1669, 1478, 1386, 1391 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 7.90
(t, 1H, J ¼ 4.0 Hz, furan-H), 6.65e7.83 (m, 10H, AreH and furan-H),
8.82 (s, 1H, N]CH); 13C NMR (DMSO-d6)
ppm: 169.8, 160.9, 152.4,
d
146.6, 144.2, 142.4, 138.6, 132.2, 128.2, 126.2, 124.4, 124.1, 108.8,
108.2; HRMS (EI) m/z calcd for C19H12N4O4: 360.0859; found:
360.0862.
7.11.12. 3-(2-nitro benzylideneamino))-2-(furan-2-yl) quinazoline-
4(3H) one (30)
This compound was prepared and purified as per the above
mentioned procedure: yield 32%; mp 250e252 ꢁC; IR (KBr) ѵmax
3025, 1670, 1465, 1362, 1342 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
6.70e7.83 (m, 11H, AreH and furan-H), 8.62 (s, 1H, N]CH); 13C
NMR (DMSO-d6) ppm: 169.4, 160.1, 150.6, 146.2, 143.6, 142.4,
d
140.4, 136.4, 132.6, 132.4, 128.2, 127.5, 125.2, 124.2, 120.2, 108.6,
108.4; HRMS (EI) m/z calcd for C19H12N4O4: 360.0859; found:
360.0861.
(DMSO-d6)
ppm: 162.6, 158.4, 148.2, 134.6, 132.8, 129.9, 128.8, 128.2, 128.2,
d
ppm: 7.60e8.21 (m, 9H, AreH); 13C NMR (DMSO-d6)
d
127.4, 122.8, 118.6.
7.11.13. 3-(4-bromo benzylideneamino))-2-(furan-2-yl)
quinazoline-4(3H) one (31)
7.13. 2-benzamido-N-p-tolylbenzamide (38)
This compound was prepared and purified as per the above
Method A: A mixture of 2-phenyl-benzo[d] [1,3] oxazine-4-one
37 and 4-methyl aniline was fused together at 200 ꢁC in an oil bath
for 1 h. The mixture was cooled and methanol was added to the
mixture. The separated solid was collected by filtration, washed
with methanol, dried and crystallized from acetic acid.
mentioned procedure: yield 42%; mp 262e265 ꢁC; IR (KBr) ѵmax
2917, 1667, 1520, 1453, 669 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
7.16e7.94 (m,11H, AreH and furan-H), 8.75 (s,1H, N]CH); 13C NMR
(DMSO-d6) ppm: 169.8, 160.4, 144.2, 143.2, 140.2, 133.4, 132.8,
d
130.4, 128.4, 127.4, 126.2, 124.3, 120.4, 108.9, 108.6; HRMS (EI) m/z
calcd for C19H12BrN3O2: 393.0113; found: 393.0116.
Method B: A mixture of 2-phenyl-benzo[d] [1,3] oxazine-4-one
37 (0.01 mol) and 4-methyl aniline (0.01 mol) in dry pyridine
(50 ml) was heated under reflux for 10 h. Subsequently, mixture
was poured into water (containing few drops of HCl) solid thus
separated was filtered, washed repeatedly with water. It was dried
and crystallized from acetic acid. Yield 71%; mp 206e208 ꢁC; IR
7.11.14. 3-(4-fluro benzylideneamino))-2-(furan-2-yl) quinazoline-
4(3H) one (32)
This compound was prepared and purified as per the above
mentioned procedure: yield 24%; mp 201e204 ꢁC; IR (KBr) ѵmax
(KBr) ѵmax 2940, 1760, 1624, 1518, 1370, 1265 cmꢀ1
(DMSO-d6) ppm: 2.33 (s, 3H, CH3), 7.14e7.98 (m, 13H, AreH),
10.22 (s, 1H,eNHCOe), 12.11 (s, 1H,eCONHe); 13C NMR (DMSO-d6)
ppm: 164.8, 161.4, 150.2, 138.6, 132.2, 130.1, 129.7, 129.4, 128.9,
;
1H NMR
2939, 1655, 1467, 1376, 1010 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
6.55e7.94 (m, 11H, AreH and furan-H), 8.74 (s, 1H, N]CH); 13C
NMR (DMSO-d6) ppm: 168.6, 166.8, 158.4, 143.4, 140.2, 132.6,
d
d
d
130.6, 128.2, 126.8, 126.6, 120.8, 114.2, 108.8, 108.4; HRMS (EI) m/z
128.8, 128.4, 127.6, 127.4, 126.4, 126.2, 24.4; HRMS (EI) m/z calcd for
calcd for C19H12FN3O2: 333.0914; found: 333.0918.
C21H18N2O2: 330.1368; found: 330.1371.
7.11.15. 3-(3-nitro benzylideneamino))-2-(furan-2-yl) quinazoline-
4(3H) one (33)
7.14. General procedure for the synthesis of 2-benzamido-N-
(substituted styryl phenyl) benzamide (39e42)
This compound was prepared and purified as per the above
mentioned procedure: yield 30%; mp 244e246 ꢁC; IR (KBr) ѵmax
A mixture of 2-benzamido-N-p-tolylbenzamide 38 (0.01 mol)
and substituted aromatic aldehydes in equimolar quantities
(0.01 mol) in glacial acetic acid (50 ml) with few drops of concen-
trated sulphuric acid was heated under reflux for 4 h. Subsequently,
mixture was poured into water and the residual solid was filtered,
washed repeatedly with water. It was dried and crystallized from
ethanol.
3003, 1672, 1468, 1393, 1360 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
6.65e7.91 (m, 11H, AreH and furan-H), 9.19 (s, 1H, N]CH); 13C
NMR (DMSO-d6) ppm: 169.6, 160.4, 156.4, 150.0, 146.6, 144.2,
d
141.6, 136.2, 134.8, 132.6, 128.6, 127.4, 126.6, 126.2, 122.8, 122.5,
108.8, 108.2; HRMS (EI) m/z calcd for C19H12N4O4: 360.0859; found:
360.0863.
7.11.16. 3-(3-phenyl allyllidene amino))-2-(furan-2-yl)
quinazoline-4(3H) one (34)
7.14.1. 2-benzamido-N-(4-(4-hydroxy styryl) phenyl) benzamide
(39)
This compound was prepared and purified as per the above
This compound was prepared and purified as per the above
mentioned procedure: yield 28%; mp 283e284 ꢁC; IR (KBr) ѵmax
mentioned procedure: yield 44%; mp 258e261 ꢁC; IR (KBr) ѵmax
2939, 1649, 1521, 1468, 1386 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm:
3561, 3223, 2921, 1670, 1667, 1445 cmꢀ1 1H NMR (DMSO-d6)
;

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2343
d
ppm: 6.68 (d, 2H, J ¼ 15.8 Hz, olefinic CH) 6.89e8.45 (a set of
Latter the reaction mass was cooled to RT, the separated solid was
filtered, washed with water and dried to obtained next compounds
by using different aldehydes. The acetic acid mother liquor on
dilution with water gave a gummy solid, which was extracted into
chloroform (50 ml) the chloroform layer was separated and evap-
orated to obtain a residue, which on recrystallization from acetone
gave purified compound 46 (aei).
signals, 18H, aromatic protons and olefinic CH), 10.20 (s,
1H,eNHCOe), 10.84 (s, 1H, OH), 12.07 (s, 1H,eCONHe); 13C NMR
(DMSO-d6)
d ppm: 169.8, 166.6, 158.4, 138.5, 136.2, 134.6, 132.8,
132.4, 131.6, 130.4, 129.6, 128.8, 128.4, 127.8, 127.4, 126.2, 125.2,
122.4, 120.6, 118.6, 116.4; HRMS (EI) m/z calcd for C28H22N2O3:
434.1630; found: 434.1633.
7.14.2. 2-benzamido-N-(4-(4-chloro styryl) phenyl) benzamide
(40)
7.16.1. 3- (3-nitro styryl) quinoxalin-2 (1H)-one (46a)
This compound was prepared and purified as per the above
mentioned procedure: yield 70%; mp 287e290 ꢁC; IR (KBr) ѵmax
3310, 2945, 1662, 1642, 1540, 1510, 1524, 1452, 1353 cmꢀ1; 1H NMR
This compound was prepared and purified as per the above
mentioned procedure: yield 38%; mp 240e244 ꢁC; IR (KBr) ѵmax
3253, 2971, 1676, 1445,743 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 6.71
(DMSO-d6)
set of signals, 8H, aromatic protons and olefinic CH), 12.60 (s, 1H,
NH); 13C NMR (DMSO-d6)
ppm: 161.2, 158.6, 149.9, 139.2, 138.8,
d
ppm: 6.21 (d,1H, J ¼ 15.2 Hz, olefinic CH), 7.28e8.50 (a
(d, 2H, J ¼ 15.8 Hz, olefinic CH) 7.05e8.38 (a set of signals, 14H,
aromatic protons and olefinic CH); 10.51 (s, 1H,eNHCOe), 12.00 (s,
d
1H,eCONHe); 13C NMR (DMSO-d6)
d
ppm: 168.2, 166.8, 138.9,
136.2, 134.6, 132.7, 130.5, 130.1, 126.9, 124.5, 124.2, 123.4, 122.3,
118.2; HRMS (EI) m/z calcd for C16H11N3O3: 293.0800; found:
293.0804.
138.4, 136.8, 135.4, 133.4, 132.4, 132.2, 130.1, 129.8, 128.6, 128.1,
127.6, 127.4, 127.2, 126.4, 124.2, 122.6, 118.8; HRMS (EI) m/z calcd for
C28H21ClN2O2: 452.1292; found: 452.1295.
7.16.2. 3- (3-bromo styryl) quinoxalin-2 (1H)-one (46b)
7.14.3. 2-benzamido-N-(4-(4-hydroxy-3-methoxy styryl) phenyl)
benzamide (41)
This compound was prepared and purified as per the above
mentioned procedure: 3-Bromo Benzaldehyde yield 73%; mp
237e240 ꢁC; IR (KBr) ѵmax 3320, 2975, 1670, 1640, 1580, 1512, 1461,
This compound was prepared and purified as per the above
mentioned procedure: yield 46%; mp 248e251 ꢁC; IR (KBr) ѵmax
660 cmꢀ1
;
1H NMR (DMSO-d6)
d
ppm: 5.80 (d, 1H, J ¼ 15.2 Hz,
olefinic CH), 7.20e8.10 (a set of signals, 8H, aromatic protons and
olefinic CH), 12.40 (s, 1H, NH); 13C NMR (DMSO-d6)
ppm: 161.4,
3565, 3240, 2941, 1667, 1430 cmꢀ1; 1H NMR (DMSO-d6)
d ppm: 3.89
(d, 3H, OCH3), 6.56 (s, 2H, J ¼ 15.8 Hz, olefinic CH), 7.08e8.39 (a set
of signals, 17H, aromatic protons and olefinic CH), 9.78 (s,
1H,eNHCOe), 10.56 (s, 1H, OH), 12.04 (s, 1H,eCONHe); 13C NMR
d
158.8, 139.4, 138.5, 136.6, 132.4, 131.4, 130.8, 129.5, 129.2, 128.7,
126.6, 124.6, 124.2, 122.1, 116.4; HRMS (EI) m/z calcd for
C16H11BrN2O: 326.0055; found: 326.0058.
(DMSO-d6)
d ppm: 168.6, 166.6, 148.8, 148.6, 138.8, 137.6, 135.6,
134.4, 132.4, 130.4, 129.12, 128.9, 128.6, 126.7, 126.5, 125.2, 124.4,
123.4, 122.6, 121.4, 118.6, 116.2, 108.4, 54.6; HRMS (EI) m/z calcd for
C29H24N2O4: 464.1736; found: 464.1739.
7.16.3. 3- (4-cyano styryl) quinoxalin-2 (1H)-one (46c)
This compound was prepared and purified as per the above
mentioned procedure: yield 69%; mp 242e244 ꢁC; IR (KBr) ѵmax
7.14.4. 2-benzamido-N-(4-(4-phenyl buta-1, 3-dienyl) phenyl)
benzamide (42)
3310, 2985, 2215, 1660, 1648, 1508, 1570, 1448 cmꢀ1 1H NMR
;
(DMSO-d6)
set of signals, 8H, aromatic protons and olefinic CH), 12.10 (s, 1H,
NH); 13C NMR (DMSO-d6)
ppm: 161.5, 158.9, 140.6, 139.3, 133.5,
d
ppm: 6.10 (d, 1H, J ¼ 15.2 Hz, olefinic CH), 7.10e8.25 (a
This compound was prepared and purified as per the above
mentioned procedure: yield 38%; mp 261e264 ꢁC; IR (KBr) ѵmax
d
3240, 2951, 1670, 1569, 1445 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 6.70
132.6, 131.3, 130.2, 128.3, 126.4, 124.6, 122.2, 119.7, 112.9, 114.3;
and 6.89 (d, 2H, J ¼ 15.8 Hz, olefinic CH), 7.11e8.37 (a set of signals,
HRMS (EI) m/z calcd for C17H11N3O: 273.0902; found: 273.0905.
21H, aromatic protons and olefinic CH), 10.34 (s, 1H,eNHCOe),
12.09 (s, 1H,eCONHe); 13C NMR (DMSO-d6)
d
ppm: 168.8, 166.5,
7.16.4. 3- (4-methyl styryl) quinoxalin-2 (1H)-one (46d)
136.8, 136.2, 135.4, 134.4, 133.4, 132.2, 132.8, 130.0, 129.9, 129.8,
126.6, 126.4, 125.1, 124.6, 122.6, 120.6, 120.6; HRMS (EI) m/z calcd
for C30H24N2O2: 444.1838; found: 444.1841.
This compound was prepared and purified as per the above
mentioned procedure: yield 65%; mp 234e236 ꢁC; IR (KBr) ѵmax
3314, 2990, 1665, 1639, 1509, 1580, 1456 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 5.60 (d, 1H, J ¼ 15.2 Hz, olefinic CH), 7.09e8.30 (a set of
signals, 8H, aromatic protons and olefinic CH), 12.23 (s, 1H, NH); 13C
NMR (DMSO-d6) ppm: 161.6, 158.3, 140.2, 138.8, 134.6, 133.5,
7.15. 3-methylquinoxalin-2(1H)-one (45)
d
To a solution of o-phenylenediamine 43 (50 mM) in H2O (60 ml)
was added to a solution of pyruvic acid 44 (50 mM) in H2O (20 ml).
The mixture was stirred at RT for 10 min. At the end of this period,
the separated product was filtered, washed with water and
recrystallized from hot water. Yield 88%; mp 181e182 ꢁC; IR (KBr)
ѵmax 3325, 2980, 1660, 1640, 1568, 1502, 1458 1370 cmꢀ1; 1H NMR
132.6, 130.1, 128.4, 128.1, 126.3, 124.2, 122.2, 114.1, 23.2; HRMS (EI)
m/z calcd for C17H14N2O: 262.1106; found: 262.1109.
7.16.5. 3- (4-hydroxy styryl) quinoxalin-2 (1H)-one (46e)
This compound was prepared and purified as per the above
mentioned procedure: yield 78%; mp 248e249 ꢁC; IR (KBr) ѵmax
(DMSO-d6)
d
ppm: 2.41 (s, 3H, CH3), 7.2e8.6 (m, 4H, AreH),12.35 (s,
3410, 3335, 2920, 1664, 1641, 1553, 1502, 1458 cmꢀ1 1H NMR
;
1H, NH); 13C NMR (DMSO-d6)
d
ppm: 161.2, 156.8, 134.6, 132.4,
(DMSO-d6)
CH), 7.21e8.41 (a set of signals, 8H, aromatic protons and olefinic
CH), 12.00 (s, 1H, NH); 13C NMR (DMSO-d6)
ppm: 161.8, 158.6,
d
ppm: 4.78 (s, 1H, OH), 6.30 (d, 1H, J ¼ 15.2 Hz, olefinic
130.4, 128.6, 124.7, 116.2, 22.4.
d
7.16. General procedure for the synthesis of 3-(4-substituted styryl)
quinoxalines-2(1H)-ones 46 (aei)
155.6, 140.2, 135.6, 132.6, 130.4, 128.2, 127.9, 126.8, 125.6, 122.4,
116.9, 116.4; HRMS (EI) m/z calcd for C16H12N2O2: 264.0899; found:
264.0903.
In the three necked round bottom flask, equipped with
a mechanical stirrer, thermometer socket and condenser and,
7.16.6. 3- (4-dimethylamino styryl) quinoxalin-2 (1H)-one (46f)
This compound was prepared and purified as per the above
mentioned procedure: yield 63%; mp 240e244 ꢁC; IR (KBr) ѵmax
a
mixture of compound(3-methyl quinoxaline-2(1H)-one 45,
(10 mM), substituted aromatic aldehydes (11 mM) in acetic acid
with catalytic amount of sulphuric acid was refluxed (118ꢁc) for 1 h.
3323, 2967, 1665, 1644, 1578, 1509, 1457, 1372 cmꢀ1 1H NMR
;

2344
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
(DMSO-d6)
d
ppm: 3.08 (s, 6H, CH3), 5.30 (d, 1H, J ¼ 15.2 Hz, olefinic
129.8, 129.3, 129.1, 128.4, 128.1, 124.3, 122.1; HRMS (EI) m/z calcd for
CH), 6.88e8.10 (a set of signals, 8H, aromatic protons and olefinic
C16H10BrClN2: 343.9716; found: 343.9719.
CH), 12.18 (s, 1H, NH); 13C NMR (DMSO-d6)
d
ppm: 161.6, 158.6,
154.2,140.2,136.6,133.6,130.2,128.4,126.5,122.4,116.7,112.4, 38.2;
7.17.3. 2-chloro-3-(4-cyano styryl) quinoxaline (47c)
HRMS (EI) m/z calcd for C18H17N3O: 291.1372; found: 291.1376.
This compound was prepared and purified as per the above
mentioned procedure: yield 44%; mp 137e139 ꢁC; IR (KBr) ѵmax
7.16.7. 3- styryl quinoxalin-2 (1H)-one (46g)
3075, 2215, 1638, 1504, 1452, 873, 610 cmꢀ1 1H NMR (DMSO-d6)
;
This compound was prepared and purified as per the above
mentioned procedure: yield 73%; mp 228e231 ꢁC; IR (KBr) ѵmax
3340, 2985, 1650, 1638, 1518, 1503, 1462 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 6.90 (d, 1H, J ¼ 15.2 Hz, olefinic CH), 7.40e8.45 (a set of
signals, 8H, aromatic protons and olefinic CH); 13C NMR (DMSO-d6)
ppm: 159.8, 149.5, 142.4, 140.4, 139.4, 133.3, 132.4, 131.2, 131.5,
d
d
ppm: 5.89 (d, 1H, J ¼ 15.2 Hz, olefinic CH), 7.20e8.25 (a set of
signals, 9H, aromatic protons and olefinic CH), 12.21 (s, 1H, NH); 13C
NMR (DMSO-d6) ppm: 161.8,158.2, 140.2,136.1,134.6,132.5,130.2,
130.4, 129.8, 128.4, 125.6, 119.4, 113.8; HRMS (EI) m/z calcd for
C17H10ClN3: 291.0563; found: 291.0566.
d
129.8, 128.8, 126.6, 125.8, 124.4, 122.4, 116.4; HRMS (EI) m/z calcd
7.17.4. 2-chloro-3-(4-methyl styryl) quinoxaline (47d)
for C16H12N2O: 248.0950; found: 248.0954.
This compound was prepared and purified as per the above
mentioned procedure: yield 38%; mp 143e147 ꢁC; IR (KBr) ѵmax
3071, 1375, 1636, 1508, 1452, 1372, 860, 620 cmꢀ1; 1H NMR (DMSO-
7.16.8. 3- (2, 5-dimethoxy styryl) quinoxalin-2 (1H)-one (46h)
This compound was prepared and purified as per the above
mentioned procedure: yield 66%; mp 224e227 ꢁC; IR (KBr) ѵmax
3345, 2987, 1666, 1648, 1588, 1510, 1461 cmꢀ1; 1H NMR (DMSO-d6)
d6)
signals, 8H, aromatic protons and olefinic CH); 13C NMR (DMSO-d6)
ppm: 159.2, 149.4, 143.3, 141.4, 140.2, 138.2, 132.4, 130.6, 130.2,
d
ppm: 5.94 (d, 1H, J ¼ 15.2 Hz, olefinic CH), 7.18e8.20 (a set of
d
d
ppm: 3.89 (s, 6H, OCH3), 6.30 (d, 1H, J ¼ 15.2 Hz, olefinic CH),
7.34e8.45 (a set of signals, 7H, aromatic protons and olefinic CH),
12.16 (s, 1H, NH); 13C NMR (DMSO-d6)
ppm: 161.8, 158.4, 156.6,
129.4, 128.9, 128.5, 127.4, 123.3, 23.3; HRMS (EI) m/z calcd for
C17H13ClN2: 280.0767; found: 280.0770.
d
152.8,140.6,132.6,130.3,128.9,125.6,123.4,116.8,115.1,114.6,110.4,
58.4, 54.2; HRMS (EI) m/z calcd for C18H16N2O3: 308.1161; found:
308.1163.
7.17.5. 2-chloro-3-(4-hydroxyl styryl) quinoxaline (47e)
This compound was prepared and purified as per the above
mentioned procedure: yield 52%; mp 145e147 ꢁC; IR (KBr) ѵmax
3440, 3062, 1642, 1504, 1458, 895, 640 cmꢀ1 1H NMR (DMSO-d6)
;
7.16.9. 3- (2 hydroxy styryl) quinoxalin-2 (1H)-one (46i)
d
ppm: 5.35 (s, 1H, OH), 5.80 (d, 1H, J ¼ 15.2 Hz, olefinic CH),
6.90e8.10 (a set of signals, 8H, aromatic protons and olefinic CH);
13C NMR (DMSO-d6)
ppm: 160.8, 149.5, 147.5, 142.3, 138.4, 132.6,
This compound was prepared and purified as per the above
mentioned procedure: yield 72%; mp 243e246 ꢁC; IR (KBr) ѵmax
d
3421, 3321, 2965, 1678, 1641, 1584, 1511, 1450 cmꢀ1
;
1H NMR
131.4, 131.2, 130.5, 130.1, 129.2, 127.8, 124.4, 114.2: HRMS (EI) m/z
(DMSO-d6)
CH), 7.12e8.30 (a set of signals, 8H, aromatic protons and olefinic
CH), 12.12 (s, 1H, NH); 13C NMR (DMSO-d6)
ppm: 163.4, 158.2,
154.6, 134.6, 132.6, 130.4, 129.4, 128.4, 126.2, 124.5, 124.6, 123.3,
120.7, 120.5, 118.4, 114.1; HRMS (EI) m/z calcd for C16H12N2O2:
264.0899; found: 264.0901.
d
ppm: 4.89 (s, 1H, OH), 5.75 (d, 1H, J ¼ 15.2 Hz, olefinic
calcd for C16H11ClN2O: 282.0560; found: 282.0564.
d
7.17.6. 2-chloro-3-(4-dimethyl amino styryl) quinoxaline (47f)
This compound was prepared and purified as per the above
mentioned procedure: yield 51%; mp 137e140 ꢁC; IR (KBr) ѵmax
3050, 1642, 1504, 1461, 1370, 900, 680 cmꢀ1 1H NMR (DMSO-d6)
;
d
ppm: 3.06 (s, 6H, CH3), 6.90 (d, 1H, J ¼ 15.2 Hz, olefinic CH),
7.12e8.30 (a set of signals, 8H, aromatic protons and olefinic CH);
13C NMR (DMSO-d6)
ppm: 159.8, 152.5, 148.2, 140.3, 138.2, 132,
7.17. General procedure for the synthesis of 2- chloro-3-substituted
styryl quinoxalines 47 (aei)
d
130.5, 130.2, 129.4, 128.3, 125.4, 124.2, 118.4, 44.2; HRMS (EI) m/z
A mixture of 3-(4-substituted styryl) quinoxalines-2(1H)-ones
46 (aei) (50 mM), POCl3 (100 ml) and DMF (0.3 ml), was refluxed at
105ꢁc for 45 min. The reaction mixture was then cooled to RT and
treated with ice water. The separated solid was filtered washed with
water and dried to obtained crude solid. A portion of this solid was
recrystallized from hexane to obtained pure compound 47 (aei).
calcd for C18H16ClN3: 309.1033; found: 309.1037.
7.17.7. 2-chloro-3-(styryl) quinoxaline (47g)
This compound was prepared and purified as per the above
mentioned procedure: yield 39%; mp 128e130 ꢁC; IR (KBr) ѵmax 3050,
1638, 1510, 1453, 873,760 cmꢀ1; 1H NMR (DMSO-d6)
d
ppm: 6.80 (d,
1H, J ¼ 15.2 Hz, olefinic CH), 7.35e8.30 (a set of signals, 8H, aromatic
protons and olefinic CH); 13C NMR (DMSO-d6)
ppm: 159.6, 149.3,
7.17.1. 2-chloro-3-(3-nitro styryl) quinoxaline (47a)
d
This compound was prepared and purified as per the above
mentioned procedure: yield 45%; mp 179e182 ꢁC; IR (KBr) ѵmax
3021, 1639, 1556, 1510, 1456, 1353, 890,784 cmꢀ1; 1H NMR (DMSO-
141.3, 140.8, 138.5, 134.2, 131.5, 131.2, 130.3, 128.8, 128.4, 127.9, 127.5,
120.4; HRMS (EI) m/zcalcdforC16H11ClN2:266.0611;found:266.0614.
d6)
signals, 8H, aromatic protons and olefinic CH); 13C NMR (DMSO-d6)
ppm: 159.5, 149.6, 148.2, 141.2, 140.2, 138.3, 134.6, 132.4, 130.6,
d
ppm: 7.08 (d, 1H, J ¼ 15.2 Hz, olefinic CH), 7.50e8.50 (a set of
7.17.8. 2-chloro-3-(2, 5-dimethoxy styryl) quinoxaline (47h)
This compound was prepared and purified as per the above
mentioned procedure: yield 47%; mp 161e164 ꢁC; IR (KBr) ѵmax
d
130.2, 129.6, 129.5, 128.2, 124.5, 124.2, 122.5; HRMS (EI) m/z calcd
3090, 1648, 1509, 1459, 880, 780 cmꢀ1; 1H NMR (DMSO-d6)
d ppm:
for C16H10ClN3O2: 311.0462; found: 311.0465.
3.85 (s, 6H, OCH3), 6.80 (d, 1H, J ¼ 15.2 Hz, olefinic CH), 7.20e8.10 (a
set of signals, 7H, aromatic protons and olefinic CH); 13C NMR
7.17.2. 2-chloro-3-(3-bromo styryl) quinoxaline (47b)
(DMSO-d6) d ppm: 159.3, 154.2, 152.4, 148.2, 140.2, 138.2, 130.4,
This compound was prepared and purified as per the above
130.1, 128.2, 127.4, 127.1, 124.2, 116.3, 115.4, 114.3, 110.6, 52.4, 55.8;
HRMS (EI) m/z calcd for C18H15ClN2O2: 326.0822; found: 326.0825.
mentioned procedure: yield 38%; mp 148e150 ꢁC; IR (KBr) ѵmax
3058,1639,1505,1460, 884, 780, 650 cmꢀ1 1H NMR (DMSO-d6)
;
d
ppm: 6.85 (d, 1H, J ¼ 15.2 Hz, olefinic CH), 7.10e8.20 (a set of
signals, 8H, aromatic protons and olefinic CH); 13C NMR (DMSO-d6)
ppm: 159.3, 149.2, 143.4, 140.2, 138.2, 132.4, 130.7, 130.6, 130.0,
7.17.9. 2-chloro-3-(2-hydroxy styryl) quinoxaline (47i)
This compound was prepared and purified as per the above
d
mentioned procedure: yield 53%; mp 132e133 ꢁC; IR (KBr) ѵmax

M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
2345
3440, 1641, 1510, 1455, 3078, 895, 745 cmꢀ1
ppm: 5.14 (s, 1H, OH), 6.89 (d, 1H, J ¼ 15.2 Hz, olefinic CH),
7.26e8.40 (a set of signals, 8H, aromatic protons and olefinic
CH); 13C NMR (DMSO-d6)
ppm: 159.4, 156.6, 148.2, 140.4,
138.6, 132.4, 131.8, 131.4, 130.6, 130.2, 129.4, 128.6, 124.3, 115.2;
HRMS (EI) m/z calcd for C16H11ClN2O: 282.0560; found:
282.0562.
;
1H NMR (DMSO-d6)
7.18.5. 2-((1H-benzo[d]imidazol-2-yl) methylthio) 3-(4-hydroxyl
styryl) quinoxaline (48e)
This compound was prepared and purified as per the above
mentioned procedure: yield 55%; mp 214e218 ꢁC; IR (KBr) ѵmax
3580, 3417, 3010, 1626, 1505, 1451, 834,751 cmꢀ1; 1H NMR (DMSO-
d
d
d6)
1H, J ¼ 15.2 Hz, olefinic CH), 7.26e8.41 (a set of signals, 12H,
aromatic protons and olefinic CH); 13C NMR (DMSO-d6)
ppm:
d ppm: 4.93 (s, 2H, CH2), 5.10 (s, H, OH), 5.21 (s, H, NH), 6.68 (d,
d
7.18. General procedure for the synthesis of 2-((1H-benzimidazole-
2-yl) methyl thio)-3-(3-substituted styryl) quinoxalines 48 (aei)
161.6, 158.3, 148.2, 146.2, 142.4, 140.2, 138.2, 132.4, 131.5, 131.2,
130.8, 130.4, 130.3, 128.4, 123.6, 123.4, 123.1, 114.2, 34.2; HRMS (EI)
m/z calcd for C24H18N4OS: 410.1201; found: 410.1203.
A mixture of 1H-benzimidazole-2-ylmethanethiol (11 mM),
triethylamine (20 mM) and 2- chloro-3-substituted styryl qui-
noxalines 47 (aei) (10 mM) in methanol was refluxed for 8 h. It was
then cooled to RT the separated solid was filtered, washed and
recrystallized with ethanol to obtain 48 (aei).
7.18.6. 2-((1H-benzo[d]imidazol-2-yl) methylthio) 3-(4-dimethyl
amino styryl) quinoxaline (48f)
This compound was prepared and purified as per the above
mentioned procedure: yield 49%; mp 274e276 ꢁC; IR (KBr) ѵmax
3427, 3020,1601,1502,154,1370,810,753 cmꢀ1; 1H NMR (DMSO-d6)
7.18.1. 2-((1H-benzo[d] imidazol-2-yl) methylthio) 3-(3-nitrostyryl)
quinoxaline (48a)
d
ppm: 3.09 (s, 3H, CH3), 3.49 (s, 2H, CH2), 5.10 (s, H, NH), 6.60 (d,
1H, J ¼ 15.2 Hz, olefinic CH), 6.88e8.55 (a set of signals, 12H,
aromatic protons and olefinic CH); 13C NMR (DMSO-d6)
ppm:
This compound was prepared and purified as per the above
d
mentioned procedure: yield 73%; mp 226e230 ꢁC; IR (KBr) ѵmax
161.6, 152.4, 150.2, 146.8, 144.2, 142.4, 138.2, 132.4, 129.8, 129.4,
129.3,127.8,126.4,123.6,123.2,114.1,110.4, 44.2, 34.2; HRMS (EI) m/
z calcd for C26H25N5S: 437.1674; found: 437.1677.
3400, 3084, 1599,1550, 1527,1461,1350, 849, 739 cmꢀ1 1H NMR
;
(DMSO-d6)
d ppm: 4.99 (s, 2H, CH2), 5.27 (s, H, NH), 7.23e8.45 (a
set of signals, 12H, aromatic protons and olefinic CH), 7.06 (d,
1H, J ¼ 15.2 Hz, olefinic CH); 13C NMR (DMSO-d6)
d
ppm: 161.7,
7.18.7. 2-((1H-benzo[d]imidazol-2-yl) methylthio) 3-(styryl)
quinoxaline (48g)
152.3, 148.4, 144.3, 143.4, 142.4, 138.4, 135.4, 134.4, 132.4, 131.8,
131.5, 129.4, 129.3, 126.4, 123.4, 123.2, 123.1, 120.7, 116.2, 34.3;
HRMS (EI) m/z calcd for C24H17N5O2S: 439.1103; found:
439.1107.
This compound was prepared and purified as per the above
mentioned procedure: yield 37%; mp 216e220 ꢁC; IR (KBr) ѵmax
3436, 3054, 1625, 1522, 1451, 847, 745 cmꢀ1 1H NMR (DMSO-d6)
;
d
ppm: 5.21 (s, 2H, CH2), 5.61 (s, H, NH), 6.61 (d, 1H, J ¼ 15.2 Hz,
olefinic CH), 6.99e8.28 (a set of signals, 13H, aromatic protons and
olefinic CH); 13C NMR (DMSO-d6)
ppm: 161.8, 152.4, 148.4, 142.4,
7.18.2. 2-((1H-benzo[d]imidazol-2-yl) methylthio) 3-(3-bromo
styryl) quinoxaline (48b)
d
This compound was prepared and purified as per the above
mentioned procedure: yield 69%; mp 234e238 ꢁC; IR (KBr) ѵmax
3400, 3055, 1625, 1522, 1454, 870, 846, 747 cmꢀ1; 1H NMR (DMSO-
140.5, 138.4, 136.3, 132.4, 131.8, 131.4, 129.8, 129.2, 128.6, 128.5,
126.4, 124.5, 124.0, 114.5, 34.6; HRMS (EI) m/z calcd for C24H18N4S:
394.1252; found: 394.1256.
d6)
olefinic CH), 7.20e8.02 (a set of signals, 12H, aromatic protons and
olefinic CH); 13C NMR (DMSO-d6)
ppm: 161.5, 152.1, 144.4, 142.2,
d
ppm: 4.93 (s, 2H, CH2), 5.45 (s, H, NH), 6.80 (d, 1H, J ¼ 15.2 Hz,
7.18.8. 2-((1H-benzo[d]imidazol-2-yl) methylthio) 3-(2, 5-
dimethoxy styryl) quinoxaline (48h)
d
140.2, 138.4, 136.5, 132.4, 130.6, 131.9, 131.8, 129.5, 129.2, 129.1,
128.4, 126.4, 124.4, 124.2, 116.2, 34.2; HRMS (EI) m/z calcd for
C24H17BrN4S: 475.0357; found: 475.0359.
This compound was prepared and purified as per the above
mentioned procedure: yield 62%; mp 207e210 ꢁC; IR (KBr) ѵmax
3400, 3054, 1620, 1510, 1451, 842,761, cmꢀ1 1H NMR (DMSO-d6)
;
d
ppm: 3.89 (s, 6H, OCH3), 4.60 (s, 2H, CH2), 5.44 (s, H, NH), 6.81 (d,
1H, J ¼ 15.2 Hz, olefinic CH), 7.14e8.28 (a set of signals, 11H,
aromatic protons and olefinic CH); 13C NMR (DMSO-d6)
ppm:
7.18.3. 2-((1H-benzo[d]imidazol-2-yl) methylthio) 3-(4-cyano
styryl) quinoxaline (48c)
d
This compound was prepared and purified as per the above
161.5, 156.4, 152.4, 150.4, 149.4, 146.4, 142.4, 141.2, 138.4, 129.9,
129.6, 129.2, 128.4, 123.6, 123.2, 116.6, 116.3, 114.3, 110.2, 56.4, 55.1,
34.4; HRMS (EI) m/z calcd for C26H22N4O2S: 454.1463; found:
454.1467.
mentioned procedure: yield 55%; mp 266e268 ꢁC; IR (KBr) ѵmax
3400, 3000, 2224, 1628, 1522, 1455, 821, 758 cmꢀ1 1H NMR
;
(DMSO-d6)
J ¼ 15.2 Hz, olefinic CH), 7.34e8.05 (a set of signals, 12H, aromatic
protons and olefinic CH); 13C NMR (DMSO-d6)
ppm: 161.4, 152.8,
d ppm: 4.80 (s, H, NH), 5.10 (s, 2H, CH2), 6.87 (d, 1H,
d
7.18.9. 2-((1H-benzo[d]imidazol-2-yl) methylthio) 3-(2-hydroxy
styryl) quinoxaline (48i)
146.4, 143.4, 142.6, 142.2, 138.4, 132.2, 131.3, 131.8, 131.4, 129.3,
128.6, 128.2, 123.5, 123.2, 116.6, 114.5, 112.4, 34.5; HRMS(EI) m/z
calcd for C25H17N5S: 419.1205; found: 419.1208.
This compound was prepared and purified as per the above
mentioned procedure: yield 68%; mp 201e204 ꢁC; IR (KBr) ѵmax
3420, 3150, 1612, 1523, 1452, 873, 751 cmꢀ1 1H NMR (DMSO-d6)
;
7.18.4. 2-((1H-benzo[d]imidazol-2-yl) methylthio) 3-(4-methyl
styryl) quinoxaline (48d)
d
ppm: 3.76 (s, 2H, CH2), 4.34 (s, H, NH), 4.89 (s, H, OH), 6.64 (d, 1H,
J ¼ 15.2 Hz, olefinic CH), 6.95e8.45 (a set of signals, 12H, aromatic
protons and olefinic CH); 13C NMR (DMSO-d6)
ppm: 161.5, 158.1,
150.4, 148.4, 146.2, 140.5, 138.4, 129.8, 129.4, 129.3, 128.4, 127.2,
124.4, 123.6, 123.3, 118.3, 114.4, 34.1; HRMS (EI) m/z calcd for
C24H18N4OS: 410.1201; found: 410.1204.
This compound was prepared and purified as per the above
d
mentioned procedure: yield 45%; mp 207e210 ꢁC; IR (KBr) ѵmax
3423, 3053, 1618, 1542,1452, 856, 750 cmꢀ1 1H NMR (DMSO-d6)
;
d
ppm: 3.42 (s, 2H, CH2), 4.94 (s, H, NH), 6.67 (d, 1H, J ¼ 15.2 Hz,
olefinic CH), 7.15e8.04 (a set of signals, 12H, aromatic protons and
olefinic CH); 13C NMR (DMSO-d6)
ppm: 161.7, 152.3, 146.5, 144.5,
d
Acknowledgment
142.4, 140.1, 138.4, 137.2, 132.1, 131.6, 131.2, 129.9, 128.4, 128.1, 124.5,
124.0, 114.2, 34.4, 21.3; HRMS (EI) m/z calcd for C25H20N4S:
408.1409; found: 408.1412.
The authors would like to thank Director General, Department
of Science and Technology, New Delhi for funding the project

2346
M.N. Noolvi et al. / European Journal of Medicinal Chemistry 46 (2011) 2327e2346
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