EGFR tyrosine kinase targeted compounds: Synthesis, docking study, and in vitro antitumor activity of some new quinazoline and benzo[d]isothiazole derivatives

Article abstract of DOI:10.1007/s00044-010-9437-8

The preparation of new quinazoline and benzo[d]isothiazole-based antitumor agents is described. The target compounds fall into three groups including the N-substituted derivatives 2a-d, the substituted amino derivatives 4-6a-d, and the dimeric compounds 7-9a,b. Docking study of the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) tyrosine kinase was performed to compare the binding mode of these compounds to the known EGFR inhibitor, lapatinib. All compounds were tested, in vitro, for their activity against human mammary carcinoma cell line (MCF7) in which EGFR is highly expressed. All compounds showed significant growth inhibitory activity. The remarkable activity of the bis quinazoline derivative 8a (IC50 = 0.06 lg/ml; 1.64 nmol/ml) is to be noted. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9437-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1042–1053
DOI 10.1007/s00044-010-9437-8
ORIGINAL RESEARCH
EGFR tyrosine kinase targeted compounds: synthesis, docking
study, and in vitro antitumor activity of some new quinazoline
and benzo[d]isothiazole derivatives
•
Kamelia M. Amin Hanan H. Georgey
•
Fadi M. Awadallah
Received: 21 April 2010 / Accepted: 15 September 2010 / Published online: 2 October 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The preparation of new quinazoline and
benzo[d]isothiazole-based antitumor agents is described.
The target compounds fall into three groups including the
N-substituted derivatives 2a–d, the substituted amino
derivatives 4–6a–d, and the dimeric compounds 7–9a,b.
Docking study of the designed compounds into the ATP
binding site of epidermal growth factor receptor (EGFR)
tyrosine kinase was performed to compare the binding
mode of these compounds to the known EGFR inhibitor,
lapatinib. All compounds were tested, in vitro, for their
activity against human mammary carcinoma cell line
(MCF7) in which EGFR is highly expressed. All com-
pounds showed significant growth inhibitory activity. The
remarkable activity of the bis quinazoline derivative 8a
(IC50 = 0.06 lg/ml; 1.64 nmol/ml) is to be noted.
Protein tyrosine kinases (PTKs) are enzymes involved in
many cellular processes such as cell proliferation, metabo-
lism, and apoptosis. Several protein tyrosine kinases are
activated in cancer cells resulting in tumor growth and
progression (Jordan et al., 2000). Inappropriate or uncon-
trolled activation of many of these kinases, by over-
expression, constitutive activation or mutation has shown to
result in uncontrolled cell growth. PTKs can be broadly
classified as receptor (EGFR) or non-receptor kinases
Blume-Jensen and Hunter, 2001). Over-expression of these
receptors was found in many cancers such as breast, ovarian,
colon, and prostate cancer. Therefore, blocking of tyrosine
kinase activity represents a rational approach to cancer
therapy and several drug discovery efforts have targeted this
aberrant kinase activity in cancer (Abouzid and Shouman,
2008). Intensive research in the field of tyrosine kinase
inhibitors led to the development of enormous number of
active compounds among which are the FDA approved
geftinib I (ZD1839, IressaÒ) (Wakeling et al., 2002) and
lapatinib II (Higa and Abraham, 2007) (Fig. 1).
Keywords Quinazoline ꢀ Benzo[d]isothiazole ꢀ
EGFR tyrosine kinase ꢀ Docking study ꢀ
Antitumor activity ꢀ Human mammary carcinoma
One of the major classes of benzoheterocyclic com-
pounds that have drawn much attention in the field of
cancer chemotherapy, besides other pharmacological
activities, is the quinazoline ring (Morin, 2000; Bridges,
2001; Xia et al., 2001; Al-Rashood et al., 2006; Bavetsias
et al., 2007; Raghavendra et al., 2009). Many 4-quinaz-
olinone derivatives reveal potent anticancer activity med-
iated through the inhibition of dihydrofolate reductase
enzyme (DHFR) (Masur, 1990; Berman and Werbel, 1991;
Al-Rashood et al., 2006; Al-Omary et al., 2010) or through
inhibition of Chk1 kinase (Converso et al., 2009). Fur-
thermore, 4-substituted quinazoline derivatives such as
4-pyrazolylamino-substituted quinazolines are found to be
selective inhibitors of Aurora B kinase with potent antitu-
mor activity (Foote et al., 2008). In last decade, 4-
Introduction
The control of disseminated tumor growth by systemically
active chemotherapeutic agents remains a major challenge
for cancer chemotherapy despite decades of focused
efforts. Although there are some notable successes with
certain forms of cancer, drug therapy has only limited
impact against the three major killers: carcinoma of the
lung, breast, and colorectal system (Schnur et al., 1991).
K. M. Amin ꢀ H. H. Georgey ꢀ F. M. Awadallah (&)
Pharmaceutical Chemistry Department, Faculty of Pharmacy
Cairo University, Kasr ElEini, 11562 Cairo, Egypt
e-mail: Fadi_mae@hotmail.com
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Med Chem Res (2011) 20:1042–1053
1043
F
Cl
Cl
F
O
O
HN
N
HN
N
N
O
O
N
N
O
H
OMe
S
N
O
Lapatinib II
Geftinib (Iressa) I
CH3
O
S
N
O H
N
O
S
CH3
O
N
O
N
N
N
N
OMe
OMe
OMe
N
Cl
N
Cl
OMe
IV
III
MeO
MeO
F
N
S
V
Fig. 1 Examples of some EGFR-TK inhibitors
anilinoquinazolines have emerged as a versatile template
for inhibition of a diverse range of receptor tyrosine
kinases (Szczepankiewicz et al., 2000; Tobe et al., 2003).
The most widely studied of these are the inhibitors of the
epidermal growth factor receptor (EGFR) tyrosine kinase
and that have found wide clinical applications (Wakeling
et al., 1996; Gru¨nwald and Hidalgo, 2003; Wakeling, 2005;
derivatives exhibit their antitumor activity through differ-
ent mechanisms including inhibition of raf-1 (Song et al.,
2008), protein tyrosine phosphatase-1b (Sparks et al.,
2007), topoisomerase II (Choi et al., 2006), and lyso-
phosphatidic acid acyltransferase-b (Gong et al., 2004).
Moreover, the 2-arylbenzothiazole derivative V shows
potent inhibitory activity against lung, colon, and breast
cancer; an action that is mediated through inhibition of
EGFR tyrosine kinase (Mortimer et al., 2006) (Fig. 1). In
addition, many 1,1-dioxobenzo[d]isothiazol-3(2H)-one
(saccharin) derivatives show potent in vitro activity against
various tumor cell lines (Gu¨zel and Salamn, 2006).
¨
Wedge et al., 2005; Liu et al., 2007; Lu¨th and Lowe, 2008;
Li et al., 2010). In a recent approach, the antitumor activity
of quinazoline derivatives has shown to be enhanced by
introducing sulfonamide-containing moieties substituted at
position 4, as revealed in compounds III and IV which are
potent inhibitors of EGFR PTK (Abouzid and Shouman,
2008) (Fig. 1). Evidently, the aforementioned geftinib and
lapatinib are also derivatives of 4-anilinoquinazoline that
exert their antitumor action by competing with ATP for
binding at the catalytic domain of EGFR tyrosine kinase.
On the other hand, the non-classical bioisosteric ben-
zothiazole ring system was revealed as a new promising
skeleton for new anticancer agents. Many benzothiazole
In this study, we present new compounds having the
quinazoline core as promising potent EGFR inhibitors. The
target compounds were designed as to enhance the activity
of the quinazoline nucleus by adding alternative binding
groups such as the thiadiazolyl and sulfonamide moieties
which are known to enhance the antitumor activity
of compounds bearing them (Invidiata et al., 1991;
´
Al-Rashood et al., 2006; Sławinski and Brzozowski, 2006).
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Med Chem Res (2011) 20:1042–1053
In a similar approach, the 1,1-dioxobenzo[d]isothiazole
scaffold was used as a non-classical bioisosteric substitute for
the quinazoline ring in the design of analogous compounds,
hoping to introduce this new ring system in the field of anti-
cancer chemotherapy. Accordingly, 3-substituted quinaz-
olin-4(3H)-ones 2a,b, 4-substituted quinazolines 4–6a,b,
2-substituted 1,1-dioxobenzo[d]isothiazol-3(2H)ones 2c,d,
and 3-substitued 1,1-dioxobenzo[d]isothiazoles 4–6c,d were
prepared. Moreover, and for further exploration of the activity
of the quinazoline and benzo[d]isothiazole ring systems, bis
compounds of these agents have been prepared using different
linker groups such as 1,3-diaminophenyl 7a,b, 1,4-diamin-
ophenyl 8a,b, and 1,2-diaminoethyl groups 9a,b.
On the other hand, the chloro compounds 3a,b were
prepared according to the previously reported procedure
using phosphorous oxychloride (Endicott et al., 1946;
Meadoe and Reid, 1943). Reaction of the chloro deriva-
tives with an appropriate sulfonamide iia,b, 4-hydrazino-
sulfonamide iiia,b, and 2-amino-5((4-chlorophenyl/phenyl)
1,3,4-thiadiazole iva,b afforded 4a–d, 5a–d, and 6a–d,
respectively (Scheme 2). IR spectra revealed the appear-
ance of NHs in 4a–d and 5a–d (=3461–3121 cm-1) and
1
NH in 6a–d (=3276–3267 cm-1). H-NMR revealed, in
addition to the corresponding integration for the aromatic
protons, the presence of NHs or NH protons. Also, mass
spectra are concomitant with the molecular weight of the
synthesized compounds.
The binding mode of the designed compounds in EGFR
homology model could be a helpful tool for predicting their
mechanism of antitumor activity.
Moreover, the bis diamino derivatives 7a,b, 8a,b, and
9a were synthesized by reacting one mole equivalent of
1,3-phenylenediamine, 1,4-phenylenediamine, or 1,2-eth-
ylenediamine with two mole equivalents of 3a,b in a
suitable solvent in the presence of a basic catalyst as
depicted in Scheme 3. IR revealed the presence of NH
group (=3364–3285 cm-1). 1H-NMR naked, besides
the corresponding integration for the aromatic protons, the
presence of NH protons. In addition, mass spectra are
concomitant with the calculated molecular weights of the
compounds. In an attempt to prepare 9b by reacting one
mole equivalent of 1,2-ethylenediamine with two mole
equivalents of 3b, an un-separated water soluble product
was obtained. Trials to isolate the product by extracting
with different organic solvents failed. Alternatively, fusion
of the two reactants with the same mentioned ratio fol-
lowed by neutralization with sodium carbonate solution,
extraction with chloroform to remove any organic impu-
rities and evaporation of the aqueous solution afforded 9b
as an oily product together with the inorganic impurities.
The pure product 9b was obtained by centrifugation to
leave out the inorganic impurities as a residue from which
the product was decanted. 1H-NMR was performed in D2O
and it revealed the presence of singlet signal at 3.40 ppm
integrated for four protons corresponding to the CH2CH2
protons.
Results and discussion
Chemistry
To verify the effects of structural modifications on the
antitumor activity, substituted quinazoline and 1,1-diox-
obenzo[d]isothiazole 2, 4–9 were synthesized.
Compounds 2a–d were synthesized via the reaction of
1a; previously synthesized according to the literature
method (Endicott et al., 1946), or the commercially
available saccharine 1b with N-[(4-chloro/methyl
phenyl)sulfonyl]carbamic acid methyl ester ia,b in a suit-
able solvent (Scheme 1). The structure of the obtained
compounds was established through spectroscopic (IR, 1H-
NMR, Mass) as well as elemental analyses data. IR spectra
revealed the presence of an additional carbonyl group
(=1722–1660 cm-1). 1H-NMR showed the presence of
singlet signal integrated for three protons of CH3 at 2.18
and 2.50 ppm for 2b and 2d, respectively. Mass spectra of
compounds 2a, 2b, and 2d showed the molecular ion peaks
of the compounds (=364 (M?), 341 (M - 2), and 382
(M ? 2), respectively).
O
H
N
O
O
O
MeO
S
R
O
O
O
S
O
ia R=Cl, ib R=CH3
NH
N
N
H
X
X
1a X=-N=CH-
1b X=SO2
2a X=-N=CH- R=Cl
2b X=-N=CH- R= CH3
R
2c X=SO2
2d X=SO2
R= Cl
R= CH3
Scheme 1 Preparation of compounds 2a–d
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Med Chem Res (2011) 20:1042–1053
1045
Cl
POCl3
N
1a,b
N
N
X
H2N
S
R
3a X=-N=CH-
3b X=SO2
iva R=H, ivb R=Cl
O
O
N
N
N
H2N
S
O
S
NHR
H
O
R
HN
N
S
NH2
iia R=H, iib R=
HN
H2N
NHR
HN
O
O
NH2
iiia R=H, iiib R=
S
NHR
X
H
N
HN
6a X=-N=CH- R=H
6b X=-N=CH- R=Cl
HN
O
O
6c X=SO2
6d X=SO2
R=H
R=Cl
N
S
N
X
NHR
X
5a X=-N=CH-
5b X=-N=CH-
4a X=-N=CH-
4b X=-N=CH-
R= H
R= H
HN
HN
NH2
R=
NH2
R=
R= H
R= HN
4c X=SO2
4d X=SO2
R= H
5c X=SO2
5d X=SO2
HN
NH2
NH2
R=
Scheme 2 Preparation of compounds 4a–d, 5a–d and 6a–d
Cl
NH
HN
H2N
NH2
N
N
N
X
H2N
X
X
3a X=-N=CH-
3b X=SO2
7a X=-N=CH-
NH2
7b X=SO2
H
H
N
NH2
H2N
N
N
N
X
X
X
H
N
8a X=-N=CH-
8b X=SO2
N
N
H
N
X
9a X=-N=CH-
9b X=SO2
Scheme 3 Preparation of compounds 7a,b, 8a,b and 9a,b
Antitumor activity
surviving fraction of the compound-treated cell lines compared
by untreated control using Sulforhodamie B (SRB) colori-
metric assay. Sulforhodamie B is a bright pink aminoxanthene
anionic dye with two sulfonic acid groups that bind electro-
statically to protein basic amino acid residues of trichloroacetic
acid fixed cells under mild acidic conditions. Cultures fixed
The newly synthesized compounds were tested for their anti-
tumor activity against human mammary carcinoma cell line
(MCF7) in the National Cancer Institute, Cairo University. The
screening involved calculation of the percentage growth of
123

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Med Chem Res (2011) 20:1042–1053
The results of the preliminary antitumor activity against
human mammary carcinoma cell line (Table 1) revealed
that all newly synthesized derivatives showed significant
antitumor activity.
with trichloroacetic acid were stained for 30 min with 0.4% w/
v Sulforhodamie B dissolved in 1% acetic acid, and protein-
bound dye was extracted with 10 mM tris base for determi-
nation of optical density in a computer-interfaced, 96-well
microtiter plate reader (Skehan et al., 1990).
In general, it could be noticed that the activity of the
quinazoline derivatives was superior to that of the
benzo[d]isothiazole ones. The most active compounds are
among the quinazoline series especially compounds 5a, 5b,
and 8a with IC50 equal to 3.58, 4.61, and 1.64 nmol,
respectively. In the benzoisothiazole series, the most active
compound is 8b having an IC50 equal to 6.29 nmol. It
could also be revealed that the N-substituted derivatives
2a–d were less active than the substituted amino deriva-
tives 4–6a–d.
The optical density measured is linear to the cell number
of the surviving fraction. Therefore, the assay is a sensitive
measure of compound-induced cytotoxicity with the best
signal to noise ratio. The assay also, provides a colori-
metric end point that is non-destructive, indefinitely stable
and visible to naked eye.
Data were collected, revised, and analyzed by SPSS
statistical package version 11. Excel computer program
was used to tabulate the results (Table 1). Probit regression
analysis procedure had been introduced to select the best
model that described the relationship between the probit
(percentages of protection) as a dependant variable in order
to be used for prediction of the concentration of the com-
pound that caused inhibition of 50% (IC50) of cancer cells.
The in vitro growth inhibition properties of each compound
were described by IC50 and the degree of inhibition of
cancer cell line was described by the equation:
Regarding the effect of the substituent on the amino
derivatives 4–6a–d, the results showed that the sulfa-
moylphenylamino derivatives 4a–d were less active than
their hydrazino analogs 5a–d. Moreover, substitution at
position 4 of the quinazoline ring with the thiadiazolyla-
mino group, as in compounds 6a,b, led to decrease in
activity compared to compounds 4a,b; while the reverse is
true for the 3-thiadiazolylamino substituted benzo[d]iso-
thiazoles 6c,d which are more active than 4c,d.
The probit ðPÞ ¼ intercept
As for the bis products 7–9a,b, the derivatives having
the 1,4-diaminophenyl linker group 8a,b were found to be
more active than those with the 1,3-diaminophenyl 7a,b
and 1,2-diaminoethyl spacers 9a,b. It is noteworthy that
compound 8a exhibited the highest activity, having an IC50
of 0.06 lg/ml; 1.64 nmol/ml.
þ ðregression coefficient ꢁ concÞ
Table 1 Antitumor activity of the newly synthesized compounds
Compound
IC50 (lg/ml)
IC50(nmol/ml)
2a
2b
2c
2d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
8a
8b
9a
9b
3.74
3.96
6.03
5.65
2.40
1.85
4.17
4.30
1.13
1.65
3.73
4.35
3.61
2.04
2.92
2.92
2.04
3.14
0.06
2.76
2.04
3.69
10.27
11.52
15.04
14.85
7.98
Docking study
Docking study of the designed compounds into EPFR
tyrosine kinase was performed using ‘‘Molecular Operating
Environment (MOE) version 2008.10 release of Chemical
Computing Group’s’’. The crystal structure of the enzyme
with lapatinib was obtained from the protein data bank;
PDB code: 1XKK.
5.39
12.35
11.33
3.58
To study the binding interactions of the reference ligand,
redocking of lapatinib in the ATP binding region of the
kinase active site was carried out, revealing that two amino
acids are involved in the interaction: Thr-830 and Met-769.
The quinazoline ring binds to a narrow hydrophobic pocket
in the N-terminal domain of EGFR TK where N-1 of the
quinazoline ring interacts with the backbone NH of Met-
4.61
10.58
11.02
11.82
6.00
8.52
˚
769 via a hydrogen bond (H-acceptor; bond length 2.42 A),
7.74
and similarly, a water molecule-mediated hydrogen bond-
ing interaction was observed with the S=O and Thr-830
˚
(H-acceptor; bond length 3.03 A).
5.59
7.16
1.64
The target compounds were modeled by positioning
them in the lapatinib binding site. The results for the most
active compound 8a showed two hydrogen bonding inter-
actions with Thr-830: one with N-3 of the quinazoline ring
6.29
6.44
9.30
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Med Chem Res (2011) 20:1042–1053
1047
˚
˚
2.25 A) and the other with the backbone Asp 831
˚
(H-acceptor; bond length 2.71 A) (Fig. 3).
(H-acceptor; bond length 2.57 A) and the other with the
4-NH group of the same ring (H-donor; bond length
˚
0.91 A). Additional hydrogen bonding interaction of N-3
Comparing the docking modes of our compounds with
lapatinib, it could be postulated that the designed com-
pounds might act on the same enzyme target where lapat-
inib acted.
of the same quinazoline ring with Thr 766 (H-acceptor;
˚
bond length 2.18 A) was observed. The 4-NH group of the
other quinazoline ring interacts with the backbone Met-769
˚
(H-donor; bond length 1.38 A) (Fig. 2).
The binding mode of compound 9b, revealed the
involvement of the S=O moiety of both benzoisothiazole
rings by hydrogen bonding interaction with both amino
acids. The study revealed a backbone hydrogen bonding
interaction between S=O of one ring and Met-769
Experimental
Chemistry
˚
(H-acceptor; bond length 2.40 A). The S=O of the other
Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification.
Melting points were performed on Stuart SMP3 version 5
ring was found to be involved into two hydrogen bonding
interactions: one with Thr-830 (H-acceptor; bond length
Fig. 2 Simplified structure of 8a docked in the ATP binding site of EGFR TK. a interaction with Thr-830; (b) interaction with Met-769
Fig. 3 Binding mode of compound 9b in the ATP binding site of EGFR TK
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Med Chem Res (2011) 20:1042–1053
digital melting point apparatus and were uncorrected. Ele-
mental microanalyses were performed at the microanalytical
center, Faculty of Science, Cairo University. 1H-NMR
spectra were recorded on Varian Gemini 200 spectropho-
tometer at 200 MHz in DMSO-d6, unless otherwise noted;
using tetramethylsilane (TMS) as internal reference.
Chemical shift values were given in ppm. Mass spectra
were performed on Fennigan MAT, SSQ 7000 mass
spectrophotometer at 70 eV. IR spectra were recorded on
Bruker FT-IR spectrophotometer as potassium bromide
disc. Sulfanilamide iia and sulfaguanidine iib were pur-
chased from Sigma Chemical Co. (St. Louis, MO, USA).
Compounds 1a, 3a (Endicott et al., 1946), 3b (Meadoe and
Reid, 1943), ia, ib (Lange et al., 2004), iiia (Itano, 1955),
iiib (Takeda, 1954), and iva, ivb (Jatav et al., 2008) were
prepared according to the reported procedure.
H), 8.75 (1H,s, NH). MS: m/z (%) 364(M?, 100). Anal.
Calcd. for C15H10ClN3O4S (363.95): C, 49.50; H 2.70; N,
11.55. Found: C, 49.80; H, 2.70; N, 11.55.
4-Methyl-N-((4-oxo-4H-quinazolin-3-
yl)carbonyl)benzenesulfonamide (2b)
This compound was prepared according to method C. m.p.
175–177°C (from ethanol), yield 83%. IR (KBr, cm-1):
3203 (NH), 3038 (CH aromatic), 2976–2923 (CH ali-
phatic), 1702 (CO), 1661 (CO), 1610 (NH bending), 1321,
1167 (SO2). 1H-NMR (200 MHz, DMSO-d6: d, ppm): 2.18
(3H, s, CH3), 7.30–8.13 (9H, m. aromatic H), 8.17 (1H, s,
NH). MS: m/z (%) 341(M-2, 65), 91 (100). Anal. Calcd. for
C16H13N3O4S (343.53): C, 55.94; H, 3.81; N, 12.28.
Found: C, 56.06; H, 3.70; N, 12.20.
General methods for the preparation of the target
compounds
4-Chloro-N-((1,1,3-trioxo-2,3-
dihydrobenzo[d]isothiazol-2yl)carbonyl)benzene-
sulfonamide (2c)
Method A A mixture of the chloro derivative 3a
(5 mmol), the appropriate amine (5 mmol), and anhydrous
potassium carbonate (10 mmol) in dry acetone (15 ml) was
heated under reflux for 24 h. The reaction mixture was
filtered while hot, and the filtrate was evaporated till dry-
ness under vacuum. The residue was treated with cold
water, and the suspension was filtered to yield the crude
product which was dried and recrystallized from the
appropriate solvent.
This compound was prepared according to method B. m.p.
145–147°C (from DMF), yield 55%. IR (KBr, cm-1): 3335
(NH), 3118 (CH aromatic), 1660 (CO), 1630 (CO), 1572
(NH bending), 1331, 1152 (SO2). 1H-NMR (200 MHz,
DMSO-d6: d, ppm): 7.50–8.18 (8H, m, aromatic H), 8.21
(1H, s, NH). Anal. Calcd. for C14H9ClN2O6S2 (400.82): C,
41.95; H, 2.26; N, 6.99. Found: C, 42.34; H, 2.41; N, 7.22.
4-Methyl-N-((1,1,3-trioxo-2,3-dihydrobenzo[d]
isothiazol-2yl)carbonyl)benzenesulfonamide (2d)
Method B A solution of 1b or 3a/3b (5 mmol) in dry
dimethyl formamide (DMF) (5 ml) was heated at 120° with
the appropriate ester or amine (5 mmol), respectively, in
the presence of triethylamine (3 ml) for 10 h. The solution
was concentrated under vacuum and the residue was trit-
urated with cold water. The precipitated solid was filtered,
dried, and recrystallized from the appropriate solvent.
This compound was prepared according to method B. m.p.
215–218°C (from DMF), yield 59%. IR (KBr, cm-1): 3361
(NH), 3093 (CH aromatic), 2926–2855 (CH aliphatic),
1722 (CO), 1654 (CO), 1592 (NH bending), 1337, 1178
(SO2). 1H-NMR (200 MHz, DMSO-d6: d, ppm): 2.50 (3H,
s, CH3), 6.97–8.11 (8H, m, aromatic H), 8.14 (1H, s, NH).
MS: m/z (%) 382 (M ? 2, 4.9), 64(100). Anal. Calcd. for
C15H12N2O6S2 (380.40): C, 47.36; H; 3.18; N, 7.36. Found:
C, 47.60; H, 3.50; N, 7.81.
Method C A solution of 1a or the chloro derivative 3a
(5 mmol) and the appropriate ester or amine (5 mmol),
respectively, in dry toluene (15 ml) was refluxed for 8 h.
The solvent was removed under vacuum and the residue
was recrystallized from the appropriate solvent.
4-(Quinazolin-4-ylamino)benzenesulfonamide (4a)
4-Chloro-N-((4-oxo-4H-quinazolin-3-
yl)carbonyl)benzenesulfonamide (2a)
This compound was prepared according to method A. m.p.
217–218°C (from ethanol), yield 62%. IR (KBr, cm-1):
3181–3121 (NH), 3061 (CH aromatic), 1609 (NH bend-
ing), 1309, 1149 (SO2). 1H-NMR (200 MHz, DMSO-d6: d,
ppm): 6.57–8.11 (10H, m, aromatic H and aniline NH),
12.2 (2H, s, NH2). MS: m/z (%) 303 (M ? 3, 3.25), 63.9
(100). Anal. Calcd. for C14H12N4O2S (300.57): C, 55.94;
H, 4.02; N, 18.72. Found: C, 56.30; H, 4.00; N, 18.70.
This compound was prepared according to method C. m.p.
128–129°C (from ethanol), yield 78%. IR (KBr, cm-1):
3203 (NH), 3039 (CH aromatic), 1702 (CO), 1663 (CO),
1610 (NH bending), 1323, 1169 (SO2). 1H-NMR
(200 MHz, DMSO-d6: d, ppm):7.54–8.12 (9H, m, aromatic
123

Med Chem Res (2011) 20:1042–1053
1049
1-(4-(Quinazolin-4-ylamino)phenylsulfonyl)guanidine
3420–3187 (NH), 3062 (CH aromatic), 1614 (NH bend-
ing), 1313, 1137 (SO2). 1H-NMR (200 MHz, DMSO-d6: d,
ppm): 6.77 (2H, br s, NHNH), 7.26–8.69 (9H, m, aromatic
H), 12.01 (4H, br s, NHs, NH2). MS: m/z (%) 356 (M-1,
38), 57 (100) Anal. Calcd. for C15H15N7O2S (357.81): C,
50.35; H, 4.22; N, 27.51. Found: C, 50.59; H, 4.09; N,
27.51.
(4b)
This compound was prepared according to method A. m.p.
161–163°C (from ethanol), yield 60%. IR (KBr, cm-1):
3428–3340 (NH), 3040 (CH aromatic), 1620 (NH bending),
1307, 1132 (SO2). 1H-NMR (200 MHz, DMSO-d6: d, ppm):
6.53–8.08 (10H, m, aromatic H and aniline NH), 10.10 (4H,
br s, NHs, NH2). MS: m/z (%) 341 (M?, 36), 63.9 (100). Anal.
Calcd. for C15H14N6O2S (342.73): C, 52.56; H, 4.11; N,
24.62. Found: C, 52.63; H, 4.10; N, 25.32.
4-(N-(1,1-Dioxobenzo[d]isothiazol-3-
yl)hydrazino)benzenesulfonamide (5c)
This compound was prepared according to method B. m.p.
136–137°C (from ethanol), yield 66%. IR (KBr, cm-1):
3351–3258 (NH), 3067 (CH aromatic), 1628 (NH bend-
4-(1,1-Dioxobenzo[d]isothiazol-3-
ylamino)benzenesulfonamide (4c)
1
ing), 1334, 1159 (SO2). H-NMR (200 MHz, CDCl3: d,
This compound was prepared according to method B. m.p.
[350°C (from DMF), yield 65%. IR (KBr, cm-1): 3332–
3246 (NH), 3090 (CH aromatic), 1619 (NH bending),
1319, 1161 (SO2). 1H-NMR (200 MHz, CDCl3: d,
ppm):5.02 (1H, s, NH), 7.26–7.80 (8H, m, aromatic H),
11.85 (2H, br s, NH2). MS: m/z (%) 337 (M?, 0.98), 57
(100). Anal. Calcd. for C13H11N3O4S2 (337.38): C, 46.28;
H, 3.29; N, 12.45. Found: C, 46.74; H, 4.06; N, 12.25.
ppm): 5.40 (2H, br s, NHNH), 7.48–8.10 (10H, m, aromatic
H and NH2). MS: m/z (%) 353 (M ? 1, 0.26), 237 (100).
Anal. Calcd. for C13H12N4O4S2 (352.39): C, 44.31; H,
3.43; N, 15.90. Found: C, 44.50; H, 4.20; N, 15.80.
1-(4-(N-(1,1-Dioxobenzo[d]isothiazol-3-
yl)hydrazino)phenylsulfonyl) guanidine (5d)
This compound was prepared according to method B. m.p.
165–168°C (from ethanol), yield 72%. IR (KBr, cm-1):
3422–3220 (NH), 3050 (CH aromatic), 1625 (NH bend-
1-(4-(1,1-Dioxobenzo[d]isothiazol-3-
ylamino)phenylsulfonyl)guanidine (4d)
1
ing), 1338, 1142 (SO2). H-NMR (200 MHz, CDCl3: d,
This compound was prepared according to method B. m.p.
[350°C (from DMF), yield 43%. IR (KBr, cm-1): 3461–
3344 (NH), 3050 (CH aromatic), 1623 (NH bending),
1301, 1162 (SO2). 1H-NMR (200 MHz, DMSO-d6: d,
ppm): 6.73–8.52 (11H, m, aromatic H and NHs), 11.03
(2H, br s, NH2). MS: m/z (%) 379 (M?, 64.71), 97.4 (100).
Anal. Calcd. for C14H13N5O4S2 (379.42): C, 44.32; H,
3.45; N, 18.46. Found: C, 44.00; H, 3.20; N, 17.92.
ppm): 5.60 (2H, br s, NHNH), 7.35–8.15 (12H, m, aromatic
H, NHs and NH2). MS: m/z (%) 394 (M?, 3.76), 76 (100).
Anal. Calcd. for C14H14N6O4S2 (394.43): C, 42.63; H,
3.58; N, 21.31. Found: C, 42.50; H, 4.10; N, 21.77.
4-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)quinazoline
(6a)
This compound was prepared according to method A. m.p.
216–217°C (from ethanol), yield 81%. IR (KBr, cm-1):
3275 (NH), 3085 (CH aromatic), 1631 (NH bending). H-
4-(N-(Quinazolin-4-yl)hydrazino)benzenesulfonamide
(5a)
1
NMR (200 MHz, DMSO-d6: d, ppm): 7.43–8.38 (11H, m,
aromatic H and NH). MS: m/z (%) 305 (M?, 5.8), 60 (100).
Anal. Calcd. for C16H11N5S (305.37): C, 62.93; H, 3.63; N,
22.93. Found: C, 62.58; H, 3.34; N, 22.60.
This compound was prepared according to method B. m.p.
295–297°C (from ethanol), yield 56%. IR (KBr, cm-1):
3340–3187 (NH), 3063 (CH aromatic), 1606 (NH bend-
ing), 1311, 1152 (SO2). 1H-NMR (200 MHz, DMSO-d6: d,
ppm): 6.80 (2H, br s, NHNH), 7.29–8.62 (9H, m, aromatic
H), 12.10 (2H, br s, NH2). MS: m/z (%) 315 (M?, 0.17), 73
(100). Anal. Calcd. for C14H13N5O2S (315.65): C, 53.27;
H, 4.15; N, 22.28. Found: C, 53.10; H, 4.01; N, 23.10.
4-(5-(4-Chlorophenyl)-1,3,4-thiadiazol-2-
ylamino)quinazoline (6b)
This compound was prepared according to method A. m.p.
339–340°C(from ethanol), yield 84%. IR (KBr, cm-1):
3267 (NH), 3087 (CH aromatic), 1613 (NH bending). H-
1
1-(4-(N-(Quinazolin-4-
yl)hydrazino)phenylsulfonyl)guanidine (5b)
NMR (200 MHz, DMSO-d6: d, ppm): 7.50–8.29 (9H, m,
aromatic H), 9.30 (1H, s, NH). Anal. Calcd. for
C16H10ClN5S (339.80): C, 56.55; H, 2.97; N, 20.61. Found:
C, 56.64; H, 3.57; N, 20.20.
This compound was prepared according to method B. m.p.
297–299°C (from ethanol), yield 51%. IR (KBr, cm-1):
123

1050
Med Chem Res (2011) 20:1042–1053
cm-1): 3364 (NH), 3060 (CH aromatic), 1600 (NH bend-
3-(5-Phenyl-1,3,4-thiadiazol-2-ylamino)-1,
1
1-dioxobenzo[d]isothiazole (6c)
ing). H-NMR (200 MHz, DMSO-d6: d, ppm): 6.88–8.67
(14H, m, aromatic H), 10.02 (2H, br s, NHs). MS: m/z (%)
367 (M ? 3, 72), 300(100). Anal. Calcd. for C22H16N6
(364.40): C, 72.51; H, 4.43; N, 23.06. Found: C, 72.40; H,
4.57; N, 23.61.
This compound was prepared according to method B. m.p.
229–231°C (from DMF), yield 76%. IR (KBr, cm-1): 3276
(NH), 3086 (CH aromatic), 1631 (NH bending), 1331,
1136 (SO2). 1H-NMR (200 MHz, DMSO-d6: d, ppm):
7.41–7.77 (10H, m, aromatic H and NH). MS: m/z (%) 342
(M?, 1.84), 60 (100). Anal. Calcd. for C15H10N4O2S2
(342.40): C, 52.62; H, 2.94; N, 16.36. Found: C, 52.76; H,
2.92; N, 16.06.
N,N0-Bis-1,1-dioxobenzo[d]isothiazol-3-ylbenzene-1,
4-diamine (8b)
This compound was prepared according to method B but
using 10 mmol of 3b and 5 mmol of p-phenylenediamine.
m.p. 188–190°C (from ethanol), yield 82%. IR (KBr,
cm-1): 3335 (NH), 3050 (CH aromatic), 1622 (NH bend-
ing), 1300, 1142 (SO2). 1H-NMR (200 MHz, DMSO-d6: d,
ppm): 6.47–8.79 (12H, m, aromatic H), 10.16 (2H, br s,
NHs). MS: m/z (%) 415 (M ? 1, 64), 71(100). Anal. Calcd.
for C20H14N4O4S2 (438.49): C, 54.78; H, 3.22; N, 12.78.
Found: C, 54.33; H, 3.15; N, 12.24.
3-(5-(4-Chlorophenyl)-1,3,4-thiadiazol-2-ylamino)-1,
1-dioxobenzo[d]isothiazole (6d)
This compound was prepared according to method B. m.p.
213–215°C (from DMF), yield 77%. IR (KBr, cm-1): 3272
(NH), 3084 (CH aromatic), 1631 (NH bending), 1333,
1136 (SO2). 1H-NMR (200 MHz, CDCl3: d, ppm):
7.40–8.00 (8H, m, aromatic H), 8.30(1H, s, NH). MS: m/z
(%) 379 (M??3, 18), 57 (100). Anal. Calcd. for
C15H9ClN4O2S2 (376.85): C, 47.81; H, 2.41; N, 14.87.
Found: C, 47.89; H, 2.69; N, 14.99.
N,N0-Bis-quinazolin-4-ylethylene-1,2-diamine (9a)
This compound was prepared according to method A but
using 10 mmol of 3a and 5 mmol of 1,2-ethylenediamine.
m.p. 207–208°C (from ethanol), yield 68%. IR (KBr,
cm-1): 3285 (NH), 3060 (CH aromatic), 2922–2852 (CH
aliphatic), 1619 (NH bending). 1H-NMR (200 MHz,
DMSO-d6: d, ppm): 3.06 (4H, s, CH2CH2), 6.60–8.77
(10H, m, aromatic H), 12.2 (2H, br s, NHs). MS: m/z (%)
314(M-2, 4.03), 174(100). Anal. Calcd. for C18H16N6
(316.35): C, 68.34; H, 5.10; N, 26.56. Found: C, 68.49; H,
5.44; N, 26.23.
N,N0-Bis-quinazolin-4-ylbenzene-1,3-diamine (7a)
This compound was prepared according to method B but
using 10 mmol of 3a and 5 mmol of m-phenylenediamine.
m.p. 183–185°C (from ethanol), yield 56%. IR (KBr,
cm-1): 3342 (NH), 3059 (CH aromatic), 1610 (NH bend-
1
ing). H-NMR (200 MHz, DMSO-d6: d, ppm): 6.62–8.74
(14H, m, aromatic H), 10.20 (2H, br s, NHs). MS: m/z (%)
364(M?, 57.5), 84 (100). Anal. Calcd. for C22H16N6
(364.40): C, 72.51; H, 4.43; N, 23.06. Found: C, 72.40; H,
3.73; N, 22.74.
N,N0-Bis-1,1-dioxobenzo[d]isothiazol-3-ylethylene-1,
2-diamine (9b)
N,N0-Bis-1,1-dioxobenzo[d]isothiazol-3-ylbenzene-1,
3-diamine (7b)
This compound was prepared by fusion of 1,2-ethylenedi-
amine (5 mmol, 0.30 g, 0.33 ml) and 3b (10 mmol; 2.01 g)
at 120° for 5 h. The reaction mixture was dissolved in
water, neutralized with sodium carbonate solution and
extracted with chloroform (3 9 20 ml). The aqueous layer
was evaporated under reduced pressure. The oily residue
left was cooled and then centrifuged. The supernatant oil
was decanted and dried in an oven under reduced pressure
to give compound 9b. Oil, yield 88%. IR (KBr, cm-1):
3302 (NH), 3072 (CH aromatic), 2952–2860 (CH ali-
This compound was prepared according to method B but
using 10 mmol of 3b and 5 mmol of m-phenylenediamine.
m.p. [350°C (from ethanol), yield 48%. IR (KBr, cm-1):
3351 (NH), 3060 (CH aromatic), 1623 (NH bending),
1300, 1159 (SO2). 1H-NMR (200 MHz, DMSO-d6: d,
ppm): 7.81–8.25 (12H, m, aromatic H), 10.31 (2H, br s,
NHs). Anal. Calcd. for C20H14N4O4S2 (438.49): C, 54.78;
H, 3.22; N, 12.78. Found: C, 54.99; H, 3.60; N, 13.12.
1
phatic), 1622 (NH bending), 1305, 1158 (SO2). H-NMR
N,N0-Bis-quinazolin-4-ylbenzene-1,4-diamine (8a)
(200 MHz, D2O: d, ppm): 3.40 (4H, s, CH2CH2), 7.72–
8.20 (8H, m, aromatic H). MS: m/z (%) 391(M ? 1, 3.16),
76(100). Anal. Calcd. for C16H14N4O4S2 (390.44): C,
49.22; H, 3.61; N, 14.35. Found: C, 49.49; H, 3.59; N,
14.99.
This compound was prepared according to method B but
using 10 mmol of 3a and 5 mmol of p-phenylenediamine.
m.p. 303–305°C (from ethanol), yield 72%. IR (KBr,
123

Med Chem Res (2011) 20:1042–1053
1051
In vitro antitumor activity measurement
Conclusion
Cells were plated in 96-multiwell plate (104 cells/well) for
24 h before treatment with the compounds to allow
attachment of cell to the wall of the plate. Different
concentrations of the compound under test (0, 1, 2.5, 5,
and 10 lg/ml) were added to the cell monolayer. Tripli-
cate wells were prepared for each individual dose.
Monolayer cells were then incubated with the compounds
for 48 h at 37°C and in atmosphere of 5% CO2. After this
time, cells were fixed, washed, and stained with Sulfo-
rhodamie B stain. Excess stain was washed with acetic
acid and attached stain was recovered with Tris EDTA
buffer. The color intensity was measured in an ELISA
reader. Finally, the relation between surviving fraction
and drug concentration was plotted to get the survival
curve of the tumor cell line after the specific compound
(Skehan et al., 1990).
Different substituted quinazoline and benzo[d]isothiazole
derivatives 2a–d, 4a–d, 5a–d, 6a–d, 7a,b, 8a,b, and 9a,b
were synthesized and their structures were established by
spectral (IR, 1H-NMR, and MS) as well as elemental
microanalytical methods. All compounds were screened for
their antitumor activity against human mammary carci-
noma cell line (MCF7) and they were found to possess
significant antitumor activity.
In general, the quinazoline derivatives were more active
than their benzo[d]isothiazole bioisosteres. Also, the
substituted amino derivatives 4–6a–d were more active
than the N-substituted ones 2a–d. Within the substituted
amino derivatives, the sulfamoylphenylhydrazino com-
pounds 5a–d were the most active. The bis compounds
with the 1,4-diaminophenyl spacer group 8a,b were more
active than the other derivatives; compound 8a being the
most active one (IC50 = 1.64 nmol).
In conclusion, the bis quinazoline derivative 8a has
succeeded in providing antitumor activity comparable to
the lead compounds III and IV exhibiting IC50 values of
1.08 and 1.98 nmol, respectively (Abouzid and Shouman,
2008). The other quinazoline derivatives have also exhib-
ited promising activities that may be subjected for future
structure optimization.
Docking study
All molecular modeling calculations and docking studies
were performed using ‘‘Molecular Operating Environment
(MOE) version 2008.10 release of Chemical Computing
Group’s’’. The program operated under ‘‘Windows XP’’
operating system installed on an Intel Pentium IV PC with
a 2.8 MHz processor and 512 RAM.
Docking study into the ATP binding domain of the
active site of EGFR-TK crystal structure could support the
postulation that our active compounds may act on the same
enzyme target as does the reference ligand, lapatinib.
The target compounds were built using the MOE builder
interface and subjected to energy minimization using the
included MOPAC. The produced model was subjected to
Systematic Conformational Search where all items were set
as default with RMS gradient of 0.01 kcal/mol and RMS
Acknowledgments The authors wish to offer their deep gratitude to
National Cancer Institute, Cairo University, Egypt, for carrying out
the antitumor screening, and for Zain H. Mohammed, teaching
assistant, Medicinal Chemistry department, Faculty of Pharmacy,
Assiut University, Egypt, for performing the docking study.
˚
distance of 0.1 A.
The X-ray crystallographic structure of the Tyrosine
Kinase Domain from Epidermal Growth Factor Receptor
(EGFR TK) complexed with lapatinib was obtained from
the Protein Data Bank; code ‘‘1XKK’’. The enzyme was
prepared for docking studies as follows:
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