Search for new pharmacophores for antimalarial activity. Part II: Synthesis and antimalarial activity of new 6-ureido-4-anilinoquinazolines

Article abstract of DOI:10.1016/j.bmc.2008.11.005

Synthesis of new 6-ureido-4-anilinoquinazolines have been accomplished and their in vitro antimalarial activity against chloroquine-sensitive P. falciparum have been examined. Out of 64 compounds evaluated, the IC₅₀ of 16 compounds which have d

Full text of DOI:10.1016/j.bmc.2008.11.005

Bioorganic & Medicinal Chemistry 17 (2009) 222–234
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Search for new pharmacophores for antimalarial activity. Part II:
Synthesis and antimalarial activity of new 6-ureido-4-anilinoquinazolines
S. Madapa a, Z. Tusi a, A. Mishra a, K. Srivastava b, S. K. Pandey b, R. Tripathi b, S. K. Puri b, S. Batra a,
*
a Medicinal and Process Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
b Parasitology Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of new 6-ureido-4-anilinoquinazolines have been accomplished and their in vitro antimalarial
Received 23 September 2008
Revised 4 November 2008
Accepted 4 November 2008
Available online 8 November 2008
activity against chloroquine-sensitive P. falciparum have been examined. Out of 64 compounds evaluated,
the IC50 of 16 compounds which have displayed MIC of 0.25 lg/mL were also recorded. One of the com-
pounds (24g) had IC50 value of 2.27 ng/mL which was equipotent to the standard drug chloroquine used
in the bioassay. The in vivo evaluation of a few compounds among the series led to discovery of one ana-
log (30g) displaying 40% curative activity (28 days) against mdr P. yoeilli nigeriensis at an oral dose of
100 mg/kg ꢀ 4days.
Keywords:
Quinazoline
Antimalarial
Urea
Ó 2008 Elsevier Ltd. All rights reserved.
In vitro
In vivo
P. falciparum
1. Introduction
results prompted us to present and discuss the details of the study
in this paper.
Quinazoline is an important scaffold due to variety of pharma-
cological properties associated with the derivatives bearing this
heterocycle.1 Especially their importance in the cancer chemother-
apy is unparallel.2 One of the prominent antimalarial the febrifu-
gine also belongs to quinazoline class of compounds.3 In our
efforts to discover new chemical pharmacophores which may be
responsible for the antimalarial activity, we have described our
studies on the synthesis and evaluation of 6-ureido-2-methyl-4-
quinolinamides as antimalarials.4 Notably the urea subunit was
discovered to be responsible for the antimalarial effect in these
compounds which was in line with the observation of Restelli
et al.5 Driven by the success of discovering prominent activity in
the ureido-derivatives it was desired to incorporate this pharmaco-
phore in another pharmacologically privileged core so as to explore
its potential further for antimalarial effect. As a result it was
decided to undertake the synthesis and antimalarial evaluation of
6-ureido-4-anilinoquinazolines. During this study we discovered
that several compounds display promising in vitro antimalarial
activity against CQ-sensitive P. falciparum. The in vivo screening
of a few compounds against mdr P. yoeilli nigeriensis led to identi-
fication of one of the analogs displaying curative activity. These
2. Results and discussion
The synthesis of compounds investigated in the present study is
outlined in Scheme 1. The required 6-nitro-4-anilino quinazoline
(1–10) were generated following the reported procedure wherein
the 5-nitoanthranonitrile was treated with dimethylformamide
dimethyl acetal to produce an intermediate which reacted with
anilines to furnish 1–10.6 The nitro group of 1–10 was reduced
to amine either via hydrogenation in the presence of 10% Pd-C in
a Parr assembly or with SnCl2ꢁ2H2O to yield products 11–20 in
good yields. Treatment of amine 11–20 with the aryl isocyanates
in THF at room temperature gave the required ureides (21–30) in
good to excellent yields.
2.1. In vitro antimalarial activity
In total sixty four compounds were investigated during the
present study. Results of antimalarial evaluation of the compounds
against CQ-sensitive P. falciparum are displayed in Table 1. It may
be noted that none of the compounds from 11 to 20 displayed
any antimalarial effect indicating that the observed activity was
due to the presence of urea sub-unit.
In order to generate a meaningful SAR, changes were introduced
in the two aryl rings A and B which were part of the 4-anilino and
* Corresponding author. Tel.: +91 522 2621411 18x4368; fax: +91 522 2623405.
E-mail addresses: batra_san@yahoo.co.uk, s_batra@cdri.res.in (S. Batra).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.11.005

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
223
N
N
N
O
R1
i
ii
N
N
N
H2N
N
H
N
H
O2N
HN
HN
HN
R
R
R
21a-e
22a-g
11-20
1-10
23a-e
a R1=4-Br
b R1=4-Cl
c R1=3-CN
1,11,21 R=H
2,12,22 R=3-F
3,13,23 R=3-Cl
4,14,24 R=3-CF3
5,15,25 R=3-OMe
6,16,26 R=4-F
24a-g
25a-e,h-i
26a-e
d R1=3-Cl,4-Me
e R1=3,4-(Cl)2
f R1=3,5-(Cl)2
g R1=4-Cl,3-CF3
h R1=3-COMe
i R1=4-COMe
27a-e
28a-e,h-i
29a-e,h-i
30a-i
7,17,27 R=4-Cl
8,18,28 R=4-OMe
9,19,29 R=4-Me
10,20,30R=3,4-(OMe)2
Scheme 1. Reagents and conditions: (i) 10% Pd-C, H2, 40 psi, rt, 2 h or SnCl2ꢁ2H2O, MeOH, reflux, 4 h; (ii) R1C6H4NCO, THF, rt, 5 min–6 h.
the urea sub-units, respectively. Five functional groups in ring B
namely 4-Br, 4-Cl, 3-CN, 3-Cl-4-Me and 3,4-Cl2 were common to
all prototypes. For 22,24,28–30 a few more analogs were prepared.
Amongst the analogs of 21 wherein the anilino phenyl ring A did
not carry any substitution, compound 21a bearing 4-bromo-group
on the B-ring of the aryl urea sub-unit was found to be the most
Next in the study the position of the substitution was changed
from 3 to 4 in the phenyl ring (A-ring) of the aniline unit. The
placement of fluorine at 4-position resulted in compounds 26a–e.
Though compound 26c having 3-cyano group on the aryl of the
urea group was found to be insoluble and could not be screened.
Relatively these compounds were less active than the compounds
of series 22 which had 3-F group in A-ring. Two compounds 26b
and 26d comprising of 4-Cl and 3-Cl-4-Me groups, respectively,
active analog with MIC of 0.25
3-cyano group on the B-ring had MIC of 0.5
(4-Cl) and 21d (3-Cl-4-Me) were equipotent with MIC of 1.0
mL. Compound 21e bearing 3,4-Cl2 substitution in the B-ring had
the MIC of 10.0 g/mL. The IC50 of the most active analog 21a
l
g/mL. Compound 21c containing
g/mL whereas 21b
g/
l
l
showed MIC of 0.5
lg/mL each whereas others (26a and 26e) had
MIC of 10 g/mL. Changing the fluoro to chloro substitution at 4-
l
l
position in A-ring led to compounds 27a–e. Here too the 3-cyano
analog 27c was found to be insoluble and was not evaluated.
Although these compounds have slightly better profile than com-
pounds of series 26, they showed similar pattern to that of com-
pounds of series 23 bearing 3-Cl in A-ring. Compounds 27b and
27e with 4-Cl and 3,4-Cl2 substitutions, respectively, had MIC of
was calculated to be 173.2 ng/mL while the SI was found to be
132.5. Introduction of 3-F group on the A-ring afforded compounds
belonging to series 22 which except for 22a, generally displayed
higher MIC values indicating increased antimalarial effect. Com-
pounds 22d and 22e incorporating 3-Cl-4-Me and 3,4-Cl2 substitu-
tions, respectively, in B-ring had the MIC value of 0.25
l
g/mL
0.5
lg/mL whereas 27a and 27d displayed MIC value of 1.0
lg/mL.
which were 4 and 40 times better than the corresponding com-
pounds in 21. Amongst them on the basis of the IC50 values, 22e
(22.5 ng/mL) was approximately 5 times more potent than 22d
(147.0 ng/mL). Even the SI value of 221.5 for 22e was better than
Following, a new series 28a–e,h–i containing 4-methoxy group
at 4-position of the aryl ring of the aniline moiety was evaluated.
Amongst them 28b and 28d with 4-Cl and 3-Cl-4-Me were the most
active with MIC value of 0.25
lg/mL, whereas all other compounds
76.6 of 22d. Compounds 22a–c with MIC of 0.5
lg/mL was equipo-
had MIC value of 1.0 g/mL or above. Fortunately, this group of com-
l
tent. Better activity profile of 22e led us to examine the activity of
another analog incorporating dichloro substitution of 3,5-position
of B-ring. Unfortunately, this compound 22f had MIC value of more
pounds was relatively more active than compounds of series 25.
Examination of the IC50 values revealed compound 28d (50 ng/mL)
to be twice more active than 28b (94 ng/mL), but the SI for 28b
(435.1) was better than 28 d (114.9). Increasing the hydrophobicity
by the introduction of a methyl group in place of the methoxy group
at 4-position led to compounds (29a–e,h–i) with lower activity pro-
file. Only one compound 29d bearing the 3-Cl-4-Me substitution on
than 10
compound 22g bearing 4-Cl-3-CF3 was found to possess MIC of
0.5 g/mL. Replacing the 3-F group at 3-position of the A-ring with
lg/mL indicating loss of activity. On the contrary a new
l
3-Cl resulted in the compounds belonging to the series 23. Unfor-
tunately the compounds 23a–e had higher MIC values as compared
to the corresponding analogs belonging to 22. Amongst this series,
23c and 23e incorporating 3-CN and 3,4-Cl2 groups, respectively,
the aryl ring of the urea sub-unit displayed the MIC of 0.5
lg/mL
while all other analogs in the series had activity of 1.0 g/mL or high-
l
er. In another variation 3,4-dimethoxy group was introduced in
A-ring to produce compounds 30a–i. Interestingly all compounds
in this series possessing disubstitution in B-ring showed pro-
nounced antimalarial effect. Compounds 30d–g bearing 3-Cl-4-
Me, 3,4-Cl2, 3,5-Cl2, and 4-Cl-3-CF3 groups displayed an MIC of
were the best with MIC values of 0.5 lg/mL.
In the next step of the study CF3 group was introduced at 3-po-
sition of A-ring to produce another set of compounds 24. Fortu-
nately this alteration led to compounds with better antimalarial
effect. Compounds 24b, 24e and 24g bearing 4-Cl group in the
0.25
lg/mL whereas 30a–c comprising of 4-Br, 4-Cl, and 3-CN sub-
B-ring which displayed MIC of 0.25
lg/mL were the best among
stitution on the B-ring showed MIC value of 0.5 lg/mL. However
this set of compounds. However IC50 value of 24g (2.3 ng/mL) with
SI of 1194 indicated it to be better than 24e (13.0 ng/mL) and 24b
(67.4 ng/mL). This implied that 24g was equipotent to the standard
CQ. The MIC value of other analogs among the series ranged from 1
30h and i were observed to relatively less potent. An IC50 evaluation
of compounds 30d–g indicated compound 30g to be the most active
with IC50 value of 18.2 and SI of 345.8. On the other hand the IC50 val-
ues calculated for 30d–f were 22.3, 80.7, and 83.2 with correspond-
ing SI of 449.0, 74.5, and 36.1.
On the basis of SAR of the compounds studied herein it could be
concluded that disubstitutions on both the phenyl rings results in
compounds with better antimalarial effect. Compounds bearing
4-Cl substitution on B-ring scores over other derivatives in terms
of bioactivity.
to 10
in general led to loss of antimalarial effect. Except for compound
25b which displayed an MIC of 0.25 g/mL all other compounds
lg/mL. Replacement of the CF3 with OMe in A-ring, however,
l
had higher MIC values. This implied that analogs comprising of
disubstitutions on the aryl ring of the urea sub-unit with at least
chloro at 4-position were more relevant for antimalarial activity.

224
S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
Table 1
Results of the in vitro activity against 3D7 P. falciparum and in vivo antimalarial activity against mdr P.yoelii nigeriensis in swiss mice
Compound
R
R1
MIC (l
g/mL)
IC50 (ng/mL)
Selectivity index
In vivo (% mean parasitaemia
SD on day 4)
In vivo (% mean parasitaemia
SD on day 7)
21a
21b
H
H
4-Br
4-Cl
0.25
1
173.2
—
132.5
—
—
—
—
—
21c
21d
21e
22a
22b
22c
22d
22e
H
H
H
3-F
3-F
3-F
3-F
3-F
3-CN
0.5
1
10
—
—
—
—
—
—
147.0
24.5
—
—
—
—
—
—
76.6
221.5
—
—
—
—
—
—
—
—
3-Cl-4-Me
3,4-Cl2
4-Br
4-Cl
3-CN
3-Cl-4-Me
3,4-Cl2
3,5-Cl2
4-Cl-3-CF3
4-Br
0.5
0.5
0.5
0.25
0.25
>10
0.5
1
0.0 0.0
46.4 11.2
—
—
0.03 0.04
Died
—
—
22f
22g
23a
3-F
3-F
3-Cl
—
—
—
—
—
—
22.0 4.30
—
14.5 2.12
—
23b
23c
23d
23e
24a
24b
24c
24d
24e
24f
24g
25a
25b
25c
25d
25e
3-Cl
3-Cl
3-Cl
3-Cl
4-Cl
3-CN
3-Cl-4-Me
3,4-Cl2
4-Br
>10
0.5
10
0.5
2.0
0.25
1
10
0.25
10
0.25
2
0.25
10
0.5
2
10
—
—
—
—
—
67.4
—
—
13.0
—
2.3
—
158.5
—
—
—
—
—
—
—
—
—
—
—
—
35.9
—
—
69.0
—
1194.0
—
378.9
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Died
—
—
—
3-CF3
3-CF3
3-CF3
3-CF3
3-CF3
3-CF3
3-CF3
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
4-F
50.4 6.80
—
—
—
—
—
10.0 5.03
—
—
4-Cl
3-CN
3-Cl-4-Me
3,4-Cl2
3,5-Cl2
4-Cl-3-CF3
4-Br
—
—
30.5 6.36
—
—
—
—
—
—
—
4-Cl
3-CN
3-Cl-4-Me
3,4-Cl2
3-COMe
4-COMe
4-Br
—
—
—
—
25h
25i
26a
26b
>10
10
0.5
—
—
4-F
4-Cl
1.18 0.77*
9.38 4.81
26c
26d
26e
27a
4-F
4-F
4-F
4-Cl
3-CN
Insoluble
0.5
10
—
—
—
—
—
—
—
—
—
—
3-Cl-4-Me
3,4-Cl2
4-Br
2.8 1.8*
4.06 1.49
—
—
—
—
1
27b
27c
27d
27e
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
3-CN
3-Cl-4-Me
3,4-Cl2
4-Br
0.5
Insoluble
1
0.5
1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
28a
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
3,4-(OMe)2
—
—
—
—
28b
28c
28d
28e
28h
28i
29a
29b
29c
29d
29e
29h
29i
30a
30b
30c
4-Cl
3-CN
0.25
2
0.25
2
10
2.0
1
1
10
0.5
1
2
94.0
—
50.0
—
—
—
—
77.1
—
—
—
435.1
—
114.9
—
—
—
—
126.3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
3-Cl-4-Me
3,4-Cl2
3-COMe
4-COMe
4-Br
4-Cl
3-CN
—
—
3-Cl-4-Me
3,4-Cl2
3-COMe
4-COMe
4-Br
3.38 1.5*
10.82 5.30
—
—
—
26.5 1.0
—
23.2 6.4
—
14.0 0.0
10.75 1.06
0.49 0.28
—
—
—
—
—
—
—
—
—
—
—
—
2
0.5
0.5
0.5
0.25
0.25
0.25
0.25
10
26.3 12.4
—
13.9 5.7
—
41 6.08
23.7 12.9
0.0 0.0
—
—
—
4-Cl
3-CN
—
—
30d
30e
30f
30g
30h
30i
3-Cl-4-Me
3,4-Cl2
3,4-Cl2
4-Cl-3-CF3
3-COMe
4-COMe
0.125
22.3
80.7
83.2
18.2
—
449.0
74.5
36.1
345.8
—
—
—
Died
10
2.0
—
—
—
—
Chloroquine
Control (MDR P .yoelii
nigeriensis)
Control (CQ-resistant
P .yoelii N-67)
—
—
—
55.7 4.64
—
—
8.88 4.27
16.12 3.73
*
Screened against CQ-resistant P .yoelii N67.

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
225
2.2. In vivo antimalarial activity
1H, ArH), 9.70 (d, 1H, J = 1.7 Hz, ArH), 10.15 (s, 1H, NH); 13C NMR
(DMSO-d6, 50 MHz) d = 114.7, 121.1, 123.2, 124.8, 126.8, 128.8,
129.7, 138.7, 144.7, 153.4, 158.0, 159.1; mass (ES+) m/z = 267.1
(M++1). Anal. Calcd for C14H10N4O2 C, 63.15; H, 3.79; N, 12.02.
Found C, 63.01; H, 3.51; N, 12.33.
Several of the analogs which displayed MIC of 0.5 lg/mL or below
were investigated for antimalarial activity in the in vivo assay either
against mdr P. yoellii nigeriensis or CQ-resistantN67 P. yoelli at an oral
dose of 100 mg/kg ꢀ 4 days. The two best compounds among this
series were 22b and 30g as they displayed complete suppression
of parasitemia on day 4 and 99% suppression on day 7. However fur-
ther monitoring indicated that animals which received 22b showed
significant amount of parasitemiaon day 10 onwards. In contrast the
group of 5 animals which have received compound 30g displayed
promising results. The mean levels of parasitemia on day 14 were
observed to be 0.49 0.28 whereas on day 21 it was observed to
be 13.0 15.3. Fortunately out of the group, 2 animals which sur-
vived till day 28 were found to be completely cured. All other com-
pounds which were investigated for their in vivo efficacy did not
display any promising activity. Even compound24g whichwas equi-
potent to the standard CQ in terms of IC50 and had high SI failed to
translate the effect in the in vivo system.
4.1.1.2. N-(3-Fluorophenyl)-6-nitroquinazolin-4-amine (2). 73%
as a light yellow solid, mp 227–229 °C; mmax (KBr) 3272 (NH)
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 6.99 (dt, 1H, J1 = 2.1 Hz,
;
J2 = 8.4 Hz, ArH), 7.44 (q, 1H, J = 7.0 Hz, ArH), 7.67 (d, 1H,
J = 8.1 Hz, ArH), 7.86–7.95 (m, 2H, ArH), 8.54 (dd, 1H, J1 = 2.3 Hz,
J2 = 9.2 Hz, ArH), 8.76 (s, 1H, NH), 9.63 (d, 2H, J = 1.8 Hz, ArH);
13C NMR (DMSO-d6, 50 MHz) d = 114.7, 118.4, 118.5, 121.1, 126.9,
129.9, 130.3, 130.4, 144.9, 153.3, 157.7, 158.9, 159.9, 164.6; mass
(ES+) m/z = 285.3 (M++1). Anal. Calcd for C14H9FN4O2 C, 59.16; H,
3.19; N, 19.71. Found C, 58.96; H, 3.34; N, 20.03.
4.1.1.3. N-(3-Chlorophenyl)-6-nitroquinazolin-4-amine (3). 96%
1
as a yellow solid, mp > 250 °C; mmax (KBr) 3295 (NH) cmꢂ1; H NMR
(DMSO-d6, 300 MHz) d = 7.21–7.24 (m, 1H, ArH), 7.44 (t, 1H,
J = 8.1 Hz, ArH), 7.83 (d, 1H, J = 8.0 Hz, ArH), 7.94 (d, 1H, J = 9.2 Hz,
ArH), 8.06 (s, 1H, ArH), 8.55 (dd, 1H, J1 = 2.4 Hz, J2 = 9.1 Hz, ArH),
8.77 (s, 1H, ArH), 9.64 (d, 1H, J = 2.1 Hz, ArH), 10.47 (s, 1H, NH); 13C
NMR (DMSO-d6, 50 MHz) d = 114.7, 121.1, 124.6, 127.0, 128.5,
128.8, 129.9, 137.8, 144.9, 153.3, 157.8, 158.9, 172.4; mass (ES+) m/
z = 301.2 (M++1), 303.2 (M++3). Anal. Calcd for C14H9ClN4O2 C,
55.92; H, 3.02; N, 18.63. Found C, 56.22; H, 3.28; N, 18.50.
3. Conclusions
In summary, we have disclosed the antimalarial efficacy of an-
other series of urea derivatives. Significantly though compounds
displayed better in vitro effect, like quinoline derivatives reported
earlier, no correlation could be drawn between their in vitro and
the in vivo effect. Nevertheless the potential of compound 30g to
cure the animals reflects the potential of the urea derivatives. It
would be interesting to study the effect of thiourea and guanidino
pharmacophore instead of urea due to their better compatibility
with the biological systems. Further work in this direction is
underway and the results would be reported shortly.
4.1.1.4. 6-Nitro-N-[3-(trifluoromethyl)phenyl]quinazolin-4-amine
(4). 67% as a yellow solid, mp 203–205 °C;
mmax (KBr) 3397 (NH)
cmꢂ1 1H NMR (DMSO-d6, 200 MHz) d = 7.27 (s, 1H, ArH), 7.48–
;
7.63 (m, 2H, ArH), 8.03 (d, 2H, J = 8.9 Hz, ArH), 8.17 (s, 1H, NH),
8.55 (dd, 1H, J1 = 1.7 Hz, J2 = 9.1 Hz, ArH), 8.86 (s, 1H, ArH), 9.05
(s, 1H, ArH); mass (ES+) m/z = 335.1 (M++1). Anal. Calcd for
C15H9F3N4O2 C, 53.90; H, 2.71; N, 16.76. Found C, 54.21; H, 2.99;
N, 16.58.
4. Experimental
4.1. General
4.1.1.5. N-(3-Methoxyphenyl)-6-nitroquinazolin-4-amine
Melting points are uncorrected and were determined in capil-
lary tubes on an apparatus containing silicon oil. IR spectra were
recorded using a Perkin Elmer’s Spectrum RX I FTIR spectropho-
tometer. 1H NMR and 13C NMR spectra were recorded either on a
Bruker DPX-200 FT or Bruker Avance DRX-300 spectrometer, using
TMS as an internal standard (chemical shifts in d). The ESMS and
FABMS were recorded on MICROMASS Quadro-II LCMS and JEOL
SX/102/DA 6000 system, respectively. Elemental analyses were
performed on a Carlo Erba’s 108 or an Elementar’s Vario EL III
microanalyzer.
(5). 71% as a yellow solid, mp 216-218 °C;
mmax (KBr) 3021 (NH)
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 3.77 (s, 3H, CH3), 6.73 (d,
;
1H, J = 7.3 Hz, ArH), 7.28 (t, 1H, J = 8.1 Hz, ArH), 7.44 (d, 2H,
J = 12.2 Hz, ArH), 7.72–7.83 (m, 1H, ArH), 8.44 (d, 1H, J = 7.2 Hz,
ArH), 8.64–8.68 (m, 1H, ArH), 9.53 (s, 1H, ArH), 10.25 (s, 1H,
NH); 13C NMR (DMSO-d6, 75 MHz) d = 55.5, 109.0, 110.1, 114.7,
115.3, 121.1, 126.8, 129.6, 129.8, 140.0, 144.8, 149.4, 153.3,
159.7, 160.6; mass (ES+) m/z = 297.2 (M++1). Anal. Calcd for
C15H12N4O3 C, 60.81; H, 4.08; N, 18.91. Found C, 61.13; H, 4.02;
N, 19.20.
4.1.1. General procedure for the preparation of 6-nitro-4-
arylamino>quinazoline (1–10)
4.1.1.6. N-(4-Fluorophenyl)-6-nitroquinazolin-4-amine (6). 88%
as a light yellow solid, mp > 250 °C; mmax (KBr) 3369 (NH) cmꢂ1 1H
;
A mixture of N0-(2-cyano-4-nitrophenyl)-N,N-dimethylformam-
ide (13.7 mmol, 3.0 g) and appropriate aniline (15.1 mmol) in
AcOH was heated at reflux for 1–8 h. On completion, the reaction
was cooled to ambient temperature. The separated solid was fil-
tered and washed with ether to obtain the compounds 2–3, 10.
Some of the reaction mixtures did not give the solid products. In
such cases excess AcOH was evaporated from reaction mixtures
to obtain the residue which upon trituration with the mixture of
hexanes and EtOAc afforded desired compounds 1, 4–9.
NMR (DMSO-d6, 300 MHz) d = 7.28 (t, 2H, J = 8.8 Hz, ArH), 7.81–7.86
(m, 2H, ArH), 7.93 (d, 1H, J = 8.8 Hz, ArH), 8.56 (dd, 1H, J1 = 2.3 Hz,
J2 = 9.2 Hz, ArH), 8.69 (s, 1H, ArH), 9.63 (d, 1H, J = 8.8 Hz, ArH),
10.48 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 114.7, 115.5,
115.8, 121.2, 125.4, 127.1, 129.9, 135.1, 144.9, 153.5, 158.1, 159.3;
mass (ES+) m/z = 285.3 (M++1). Anal. Calcd for C14H9FN4O2 C, 59.16;
H, 3.19; N, 19.71. Found C, 59.27; H, 3.51; N, 19.95.
4.1.1.7. N-(4-Chlorophenyl)-6-nitroquinazolin-4-amine (7). 87%
1
as a yellow solid, mp > 250 °C; mmax (KBr) 3302 (NH) cmꢂ1; H NMR
4.1.1.1. 6-Nitro-N-phenylquinazolin-4-amine (1). 98% as
yellow solid, mp 242–243 °C; mmax (KBr) 3449 (NH) cmꢂ1
NMR (DMSO-d6, 300 MHz) d = 7.21 (t, 1H, J = 7.3 Hz, ArH), 7.39–
7.46 (m, 2H, ArH), 7.82 (d, 2H, J = 7.9 Hz, ArH), 7.92 (d, 1H,
J = 9.1 Hz, ArH), 8.52 (dd, 1H, J1 = 1.8 Hz, J2 = 9.1 Hz, ArH), 8.76 (s,
a
(DMSO-d6, 300 MHz) d = 7.10 (td, 1H, J1 = 0.6 Hz, J2 = 7.9 Hz, ArH),
7.27 (dd, 1H, J1 = 2.3 Hz, J2 = 8.8 Hz, ArH), 7.34-7.41 (m, 2H, ArH),
7.55 (d, 1H, J = 8.8 Hz, ArH), 7.83 (dd, 1H, J1 = 1.1 Hz, J2 = 8.2 Hz,
ArH), 8.11 (t, 1H, J = 1.9 Hz, ArH), 8.39 (s, 1H, ArH), 9.60 (s, 1H, NH);
13C NMR (DMSO-d6, 50 MHz) d = 101.8, 117.4, 120.6, 121.6, 123.1,
;
1H

226
S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
124.7, 129.1, 130.7, 133.4, 142.3, 142.8, 148.3, 150.1, 156.6; mass
(ES+) m/z = 301.1 (M++1), 303.1 (M++3). Anal. Calcd for C14H9ClN4O2
C, 55.92; H, 3.02; N, 18.63. Found C, 55.97; H, 3.34; N, 18.64.
ArH); 13C NMR (DMSO-d6, 50 MHz) d = 101.3, 117.0, 117.5, 124.3,
128.6, 130.1, 130.3, 142.0, 142.2, 147.9, 149.7, 156.2, 160.0, 164.8;
mass (ES+) m/z = 255.4 (M++1). Anal. Calcd for C14H11FN4 C, 66.13;
H, 4.36; N, 22.04. Found C, 65.82; H, 4.69; N, 22.18.
4.1.1.8. N-(4-Methoxyphenyl)-6-nitroquinazolin-4-amine
(8). 75% as a yellow solid, mp 202–204 °C;
mmax (KBr) 3415 (NH)
4.1.2.3. N4-[3-(Trifluoromethyl)phenyl]quinazoline-4,6-diamine
(14). 73% as a yellow solid, mp > 250 °C; mmax (KBr) 3300 (NH),
cmꢂ1; 1H NMR (DMSO-d6, 300 MHz) d = 3.85 (s, 3H, CH3), 6.95–7.00
(m, 2H, ArH), 7.56–7.62 (m, 2H, ArH), 7.98 (d, 2H, J = 9.0 Hz, ArH),
8.52 (dd, 1H, J1 = 2.4 Hz, J2 = 9.2 Hz, ArH), 8.77 (s, 1H, ArH), 8.94 (d,
1H, J = 2.3 Hz, ArH); 13C NMR (DMSO-d6, 75 MHz) d = 54.4, 112.9,
113.4, 119.9, 123.8, 125.5, 128.4, 130.3, 143.4, 152.2, 155.5,
157.0, 157.9, 171.2; mass (ES+) m/z = 297.2 (M++1). Anal. Calcd
for C15H12N4O3 C, 60.81; H, 4.08; N, 18.91. Found C, 60.94; H,
4.39; N, 19.32.
3412 (NH2) cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 5.70 (s, 2H,
;
NH2), 7.29–7.41 (m, 3H, ArH), 7.55–7.61 (m, 2H, ArH), 8.25 (d,
1H, J = 7.5 Hz, ArH), 8.41 (d, 2H, J = 17.2 Hz, ArH), 9.66 (s, 1H,
NH); 13C NMR (DMSO-d6, 200 MHz) d = 101.3, 117.2, 117.7,
119.2, 123.0, 124.4, 125.2, 126.6, 129.4, 129.9, 141.4, 143.2,
147.9, 150.0, 156.2; mass (ES+) m/z = 305.4 (M++1). Anal. Calcd
for C15H11F3N4 C, 59.21; H, 3.64; N, 18.41. Found C, 59.52; H,
3.71; N, 18.56.
4.1.1.9. N-(4-Methylphenyl)-6-nitroquinazolin-4-amine (9). 75%
as a yellow solid, mp 163–165 °C; mmax (KBr) 3418 (NH) cmꢂ1
;
1H
4.1.2.4. N4-(3-Methoxyphenyl)quinazoline-4,6-diamine (15). 71%
as a yellow solid, mp 216–218 °C; mmax (KBr) 3352 (NH and NH2)
NMR (CDCl3, 300 MHz) d = 2.40 (s, 3H, CH3), 7.27 (d, 2H, J = 8.0,
ArH), 7.61 (d, 2H, J = 8.4 Hz, ArH), 7.89 (s, 1H, NH), 8.02 (d, 1H,
J = 9.2 Hz, ArH), 8.57 (dd, 1H, J1 = 2.4 Hz, J2 = 9.2 Hz, ArH), 8.85 (s,
1H, ArH), 8.96 (d, 1H, J = 2.3 Hz, ArH); 13C NMR (DMSO-d6, 75 MHz)
d = 19.8, 113.5, 120.0, 122.1, 125.6, 128.1, 128.5, 132.9, 134.9, 143.5,
152.2, 156.9, 157.9; mass (ES+) m/z = 281.2 (M++1). Anal. Calcd for
C15H12N4O2 C, 64.28; H, 4.32; N, 19.99. Found C, 64.14; H, 4.40; N,
19.91.
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 3.77 (s, 3H, CH3), 5.58 (br s,
;
2H, NH2), 6.64–6.66 (m, 1H, ArH), 7.23–7.28 (m, 2H, ArH), 7.39 (s,
1H, ArH), 7.50–7.59 (m, 3H, ArH), 8.36 (s, 1H, ArH), 9.30 (s, 1H, NH);
mass (ES+) m/z = 267.2 (M++1). Anal. Calcd for C15H14N4O C, 67.65;
H, 5.30; N, 21.04. Found C, 67.83; H, 5.51; N, 21.10.
4.1.2.5. N4-(4-Fluorophenyl)quinazoline-4,6-diamine (16). 92%
as a light yellow solid, mp 169–171 °C; mmax (KBr) 3333 (NH and
4.1.1.10. N-(3,4-Dimethoxyphenyl)-6-nitroquinazolin-4-amine
(10). 69% as a red solid, mp 195–198 °C; mmax (KBr) 3409 (NH)
NH2) cmꢂ1 1H NMR (DMSO-d6, 200 MHz) d = 5.55 (br s, 2H, NH2),
;
7.11–7.28 (m, 2H, ArH), 7.35 (d, 1H, J = 1.8 Hz, ArH), 7.52 (d, 1H,
J = 8.8 Hz, ArH), 7.80–7.87 (m, 2H, ArH), 8.24 (s, 1H, ArH), 8.32 (s,
1H, ArH), 9.47 (s, 1H, NH); mass (ES+) m/z = 255.3 (M++1). Anal.
Calcd for C14H11FN4 C, 66.13; H, 4.36; N, 22.04. Found C, 66.41; H,
4.54; N, 22.03.
cmꢂ1
;
1H NMR (DMSO-d6, 300 MHz) d = 3.78 (s, 6H, 2ꢀ OCH3),
7.00 (d, 1H, J = 8.5 Hz, ArH), 7.38–7.42 (m, 2H, ArH), 7.90 (d, 1H,
J = 9.2 Hz, ArH), 8.53 (dd, 1H, J1 = 2.3 Hz, J2 = 9.1 Hz, ArH), 8.66 (s,
1H, ArH), 9.62 (d, 1H, J = 2.1 Hz, ArH), 10.32 (s, 1H, NH); 13C NMR
(DMSO-d6, 50 MHz) d = 55.9, 56.1, 108.4, 112.0, 114.7, 115.6,
121.0, 126.8, 129.7, 131.9, 144.7, 146.4, 148.8, 153.4, 158.1,
159.0; mass (ES+) m/z = 327.1 (M++1). Anal. Calcd for C16H14N4O4
C, 58.89; H, 4.32; N, 17.17. Found C, 58.67; H, 4.59; N, 17.08.
4.1.2.6. N4-(4-Methoxyphenyl)quinazoline-4,6-diamine (18). 81%
as a light yellow solid, mp 125–128 °C; mmax (KBr) 3332 (NH and
NH2) cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 3.75 (s, 3H, CH3), 5.55
;
(br s, 2H, NH2), 6.93 (d, 2H, J = 9.0 Hz, ArH), 7.20 (dd, 1H, J1 = 2.2 Hz,
J2 = 8.8 Hz, ArH), 7.32 (d, 1H, J = 2.2 Hz, ArH), 7.48 (d, 1H, J = 8.8 Hz,
ArH), 7.68 (d, 2H, J = 9.0 Hz, ArH), 8.24 (s, 1H, ArH), 9.23 (s, 1H, NH);
13C NMR (DMSO-d6, 50 MHz) d = 55.6, 101.6, 113.9, 116.9, 123.8,
124.2, 128.8, 133.1, 142.6, 147.5, 150.4, 155.7, 156.1; mass (ES+) m/
z = 267.2 (M++1). Anal. Calcd for C15H14N4O C, 67.65; H, 5.30; N,
21.04. Found C, 67.46; H, 5.34; N, 20.87.
4.1.2. General procedure for the preparation of compounds
11–12, 14–16, 18–20
To a methanolic solution of appropriate compound from 1 to 2,
4 to 6, 8 to 10 (3.0 mmol), 10% Pd-C (0.125 g) was added under
nitrogen atmosphere. The atmosphere of the vessel was replaced
by hydrogen gas and the reaction was hydrogenated on the Parr
assembly at 40 psi at room temperature for 1 h. Thereafter, the cat-
alyst was filtered over a celite bed and the filtrate was evaporated
to yield a solid residue. The residue was recrystallized from MeOH
to afford the pure compounds11–12, 14–16, 18–20 as yellow solids
in good yields.
4.1.2.7. N4-(4-Methylphenyl)quinazoline-4,6-diamine (19). 89%
as a light yellow solid, mp 181–183 °C; mmax (KBr) 3337 (NH
;
and NH2) cmꢂ1 1H NMR (CD3OD, 300 MHz) d = 2.37 (s, 3H,
CH3), 7.22 (d, 2H, J = 8.2 Hz, ArH), 7.29–7.33 (m, 2H, ArH), 7.54–
7.58 (m, 2H, ArH), 8.25 (s, 1H, ArH); 13C NMR (CD3OD, 75 MHz)
d = 19.0, 101.1, 115.5, 122.6, 123.6, 124.7, 128.3, 134.0, 134.9,
137.8, 147.4, 148.2, 156.8; mass (ES+) m/z = 251.3 (M++1). Anal.
Calcd for C15H14N4 C, 71.98; H, 5.64; N, 22.38. Found C, 71.91;
H, 5.59; N, 22.21.
4.1.2.1. N4-Phenylquinazoline-4,6-diamine (11). 84% as a yel-
low solid, mp 197–199 °C; mmax (KBr) 3297 (NH), 3363 (NH2)
cmꢂ1 1H NMR (DMSO-d6, 300 MHz,) d = 5.58 (br s, 2H, NH2), 7.06
;
(t, 1H, J = 7.4 Hz, ArH), 7.23 (dd, 1H, J1 = 2.3 Hz, J2 = 8.6 Hz, ArH),
7.32 (s, 1H, ArH), 7.35–7.37 (m, 2H, ArH), 7.52 (d, 1H, J = 8.8 Hz,
ArH), 7.84 (d, 2H, J = 7.8 Hz, ArH), 8.32 (s, 1H, ArH), 9.37 (s, 1H,
NH); 13C NMR (DMSO-d6, 50 MHz) d = 101.5, 117.0, 122.2, 123.3,
124.0, 128.7, 128.8, 140.2, 142.6, 147.7, 150.1, 156.5; mass (ES+)
m/z = 237.3 (M++1). Anal. Calcd for C14H12N4 C, 71.17; H, 5.12; N,
23.71. Found C, 70.85; H, 5.33; N, 23.96.
4.1.2.8. N4-(3,4-Dimethoxyphenyl)quinazoline-4,6-diamine
(20). 79% as a light yellow solid, mp 198–200 °C; mmax (KBr)
3334 (NH), 3499 (NH2) cmꢂ1
;
1H NMR (DMSO-d6, 300 MHz)
d = 3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 5.51 (s, 2H, NH2), 6.94
(d, 1H, J = 8.7 Hz, ArH), 7.22 (dd, 1H, J1 = 2.2 Hz, J2 = 8.9 Hz, ArH),
7.34 (d, 1H, J = 2.1 Hz, ArH), 7.43 (dd, 1H, J1 = 2.4 Hz, J2 = 8.7 Hz,
ArH), 7.48–7.52 (m, 2H, ArH), 8.28 (s, 1H, ArH), 9.18 (s, 1H, NH);
13C NMR (DMSO-d6, 50 MHz) d = 56.0, 56.2, 101.5, 107.7, 112.3,
114.6, 116.9, 123.8, 128.9, 133.6, 142.7, 145.3, 147.5, 148.8,
150.4, 156.5; mass (ES+) m/z = 297.2 (M++1). Anal. Calcd for
C16H16N4O2 C, 64.85; H, 5.44; N, 18.91. Found C, 64.93; H, 5.19;
N, 19.25.
4.1.2.2. N4-(3-Fluorophenyl)quinazoline-4,6-diamine (12). 75%
as a yellow solid, mp 122–124 °C; mmax (KBr) 3437 (NH and NH2)
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 6.88 (dt, 1H, J1 = 2.2 Hz,
;
J2 = 8.4 Hz, ArH), 7.28 (dd, 1H, J1 = 2.2 Hz, J2 = 8.9 Hz, ArH), 7.34–
7.42 (m, 3H, ArH and NH), 7.56 (d, 1H, J = 8.8 Hz, ArH), 7.68 (d,
1H, J = 8.2 Hz, ArH), 7.92 (d, 1H, J = 12.1 Hz, ArH), 8.41 (s, 1H,

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
227
4.1.3. General procedure for the preparation of compounds 13
and 17
151.3, 151.5, 156.0; mass (ES+) m/z = 390.1 (M++1), 392.1
(M++3). Anal. Calcd for C21H16ClN5O C, 64.70; H, 4.14; N, 17.96.
Found C, 64.41; H, 5.34; N, 18.19.
A solution of N-(chlorophenyl)-6-nitroquinazolin-4-amine (3, 7)
(5.86 mmol) and anhydrous SnCl2ꢁ2H2O (29.32 mmol, 5.56 g) in
MeOH (20 mL) was heated at reflux for 30 min under nitrogen atmo-
sphere. Thereafter excessive MeOH was evaporated and the residue
was dissolved in EtOAc (100 mL) and basified with aqueous NaHCO3
solution. The resulting mixture was filtered through a celite bed fol-
lowed by separation of organic layer and water layer was extracted
with EtOAc (2ꢀ 20 mL), these organic fractions were combined,
dried over anhydrous Na2SO4 and concentrated under reduced pres-
sure to obtain the desired N4-chlorophenylquinazoline-4, 6-diamine
(13, 17). The crude products were recrystallized from MeOH.
4.1.4.3. N-(4-Anilinoquinazolin-6-yl)-N0-(3-cyanophenyl)urea
(21c). 98% as a white solid, mp 230–232 °C; Rt = 17.85 min;
mmax (KBr) 1706 (CO), 2220 (CN), 3344 (NH) cmꢂ1 1H NMR
;
(DMSO-d6, 300 MHz) d = 7.11 (t, 1H, J = 7.4 Hz, ArH), 7.35–7.54
(m, 4H, ArH), 7.70–7.90 (m, 5H, ArH), 8.04–8.05 (m, 1H, ArH),
8.49 (d, 2H, J = 4.0 Hz, ArH), 9.15 (s, 1H, NH), 9.28 (s, 1H, NH),
9.74 (s, 1H, NH); mass (ES+) m/z = 381.2 (M++1). Anal. Calcd for
C22H16N6O C, 69.46; H, 4.24; N, 22.09. Found C, 69.23; H, 4.51;
N, 22.37.
4.1.4.4. N-(4-Anilinoquinazolin-6-yl)-N0-(3-chloro-4-methyl-
4.1.3.1. N4-(3-Chlorophenyl)quinazoline-4,6-diamine (13). 90%
as a light yellow solid, mp 180–182 °C; mmax (KBr) 3384 (NH and
NH2) cmꢂ1; 1H NMR (DMSO-d6, 300 MHz) d = 5.63 (s, 2H, NH2), 7.08
(dd, 1H, J1 = 1.2 Hz, J2 = 7.9 Hz, ArH), 7.26 (dd, 1H, J1 = 1.9 Hz,
J2 = 8.8 Hz, ArH), 7.32–7.38 (m, 2H, ArH), 7.54 (d, 1H, J = 8.9 Hz,
ArH), 7.80 (d, 1H, J = 8.9 Hz, ArH), 8.09 (s, 1H, ArH), 8.36 (s, 1H, ArH),
9.48 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 101.3, 117.1,
120.2, 121.2, 122.8, 124.3, 129.1, 130.4, 133.2, 141.9, 143.0, 147.9,
150.0, 156.2; mass (ES+) m/z = 271.3(M++1), 273.3 (M++3). Anal. Calcd
for C14H11ClN4 C, 62.11; H, 4.10; N, 20.70. Found C, 62.29; H, 4.18; N,
20.53.
phenyl)urea (21d). 76% as
a
white solid, mp > 250 °C;
Rt = 21.86 min; mmax (KBr) 1705 (CO), 3442 (NH) cmꢂ1
;
1H NMR
(DMSO-d6, 300 MHz) d = 2.26 (s, 3H, CH3), 7.11 (t, 1H, J = 7.2
Hz, ArH), 7.24–7.27 (m, 2H, ArH), 7.37 (t, 2H, J = 7.6 Hz, ArH),
7.72–7.87 (m, 5H, ArH), 8.48 (s, 2H, ArH), 8.99 (s, 2H, 2ꢀ NH),
9.73 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 17.5, 109.2,
114.3, 115.8, 117.0, 121.1, 122.2, 125.2, 127.0, 129.9, 131.9,
136.0, 137.4, 138.1, 144.6, 151.2, 151.5, 156.0; mass (ES+) m/
z = 404.2 (M++1), 406.1 (M++3). Anal. Calcd for C22H18ClN5O C,
65.43; H, 4.49; N, 17.34. Found C, 65.19; H, 4.25; N, 17.61.
4.1.4.5. N-(4-Anilinoquinazolin-6-yl)-N0-(3,4-dichlorophenyl)-
4.1.3.2. N4-(4-Chlorophenyl)quinazoline-4,6-diamine (17). 88%
urea (21e). 90% as
a
light green solid, mp > 250 °C;
as a yellow solid, mp 237–239 °C;
mmax (KBr) 3295 (NH), 3425 (NH2)
Rt = 21.42 min; mmax (KBr) 1662 (CO), 3426 (NH) cmꢂ1
;
1H NMR
cmꢂ1 1H NMR (DMSO-d6, 200 MHz) d = 7.15 (t, 1H, J = 7.1 Hz, ArH),
;
(DMSO-d6, 300 MHz) d = 7.13 (t, 1H, J = 7.3 Hz, ArH), 7.39–7.42
(m, 3H, ArH), 7.55 (d, 1H, J = 8.8 Hz, ArH), 7.74–7.82 (m, 3H,
ArH), 7.88 (dd, 1H, J1 = 1.9 Hz, J2 = 9.0 Hz, ArH), 7.97 (d, 1H,
J = 2.3 Hz, ArH), 8.50–8.53 (m, 2H, ArH), 9.31 (s, 1H, NH), 9.49
(s, 1H, NH), 9.86 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz)
d = 111.0, 115.8, 118.7, 119.6, 123.2, 123.6, 124.3, 127.1, 127.7,
128.8, 131.0, 131.4, 137.9, 139.5, 140.3, 144.8, 152.7, 152.9,
157.9; mass (ES+) m/z = 424.2 (M++1), 426.1 (M++3). Anal. Calcd
for C21H15Cl2N5O C, 59.45; H, 3.56; N, 16.51. Found C, 59.32; H,
3.72; N, 16.42.
7.27–7.44 (m, 3H, ArH), 7.57 (d, 1H, J = 8.8 Hz, ArH), 7.75 (d, 1H,
J = 8.3 Hz, ArH), 7.85 (d, 1H, J = 8.7 Hz, ArH), 7.73–7.87 (m, 2H, ArH),
8.44 (d, 1H, J = 6.1 Hz, ArH), 10.00 (s, 1H, NH); mass (ES+) m/z = 271.3
(M++1), 273.2 (M++1). Anal. Calcd for C14H11ClN4 C, 62.11; H, 4.10; N,
20.70. Found C, 62.35; H, 4.03; N, 20.58.
4.1.4. General procedure for the preparation of compounds
169–173a–j, 174–175d,f,j,176–177g–i
A mixture of appropriate amine from 168a to j (1.06 mmol) and
aryl isocyanate (1.16 mmol) in anhydrous THF (10 mL) was stirred
at room temperature for 5 min–6 h. Thereafter the reaction mix-
ture was slurried and purified by column chromatography over sil-
ica gel or alumina using hexanes/EtOAc (30–10:70–90, v/v) as the
eluent to yield the desired compounds 169–173a–j, 174–
175d,f,j,176–177g–i.
4.1.4.6. N-(6-Amino-2-methylquinolin-4-yl)-2-furamide
(11). 87% as a light yellow silod, mp 195–197 °C;
mmax (KBr)
1665 (CO), 3327 (NH and NH2) cmꢂ1 1H NMR (DMSO-d6,
;
300 MHz) d = 2.82 (s, 3H, CH3), 6.70 (q, 1H, J = 1.7 Hz, ArH), 7.43
(d, 1H, J = 3.6 Hz, ArH), 7.73 (d, 1H, J = 1.1 Hz, ArH), 8.18 (d, 1H,
J = 9.2 Hz, ArH), 8.49–8.53 (m, 2H, ArH), 8.88–8.91 (m, 2H, ArH
and NH); mass (ES+) m/z = 268.2 (M++1). Anal. Calcd for
C15H13N3O2 C, 67.40; H, 4.90; N, 15.72. Found C, 67.04; H, 4.96;
N, 15.65.
4.1.4.1. N-(4-Anilinoquinazolin-6-yl)-N0-(4-bromophenyl)urea
(21a). 76% as a white solid, mp > 250 °C; Rt = 21.30 min; mmax
(KBr) 1658 (CO), 3429 (NH) cmꢂ1 1H NMR (DMSO-d6, 300 MHz)
;
d = 7.12 (t, 1H, J = 7.2 Hz, ArH), 7.39 (t, 2H, J = 8.1 Hz, ArH), 7.47–
7.52 (m, 4H, ArH), 7.74–7.91 (m, 4H, ArH), 8.48–8.49 (m, 2H,
ArH), 9.00 (s, 1H, NH), 9.05 (s, 1H, NH), 9.76 (s, 1H, NH); 13C
NMR (DMSO-d6, 50 MHz) d = 116.2, 118.7, 119.1, 121.2, 125.9,
128.1, 128.7, 129.1, 131.1, 132.1, 134.0, 137.2, 142.9, 143.8,
144.6, 145.0, 151.6, 158.0, 158.2, 158.5, 162.9; mass (ES+) m/
z = 434.2 (M++1), 436.1 (M++3). Anal. Calcd for C21H16BrN5O C,
58.08; H, 3.71; N, 16.13. Found C, 58.21; H, 3.49; N, 16.07.
4.1.4.7. N-(4-Bromophenyl)-N0-[4-(3-fluoroanilino)quinazolin-
6-yl]urea (22a). 91% as a white solid, mp > 250 °C; mmax (KBr)
1655 (CO), 3284 (NH) cmꢂ1
;
1H NMR (DMSO-d6, 300 MHz)
d = 7.14 (d, 1H, J = 7.6 Hz, ArH), 7.36–7.48 (m, 5H, ArH), 7.74–7.91
(m, 3H, ArH), 8.06 (s, 1H, ArH), 8.53 (d, 2H, J = 7.6 Hz, ArH), 9.56
(s, 1H, NH), 9.68 (s, 1H, NH), 9.91 (s, 1H, NH); 13C NMR (DMSO-
d6, 75 MHz) d = 108.6, 112.0, 114.4, 118.7, 119.1, 120.1, 121.6,
125.2, 127.2, 128.7, 130.3, 131.4, 136.5, 138.0, 140.0, 144.6,
151.2, 151.4, 155.8; mass (ES+) m/z = 452.2 (M++1). Anal. Calcd
for C21H15BrFN5O C, 55.77; H, 3.34; N, 15.48. Found C, 55.68; H,
3.53; N, 15.31.
4.1.4.2. N-(4-Anilinoquinazolin-6-yl)-N0-(4-chlorophenyl)urea
(21b). 84% as a white solid, mp 250–251 °C; Rt = 20.13 min; mmax
(KBr) 1657 (CO), 3295 (NH) cmꢂ1 1H NMR (DMSO-d6, 300 MHz)
;
d = 7.11 (t, 1H, J = 7.4 Hz, ArH), 7.33–7.40 (m, 4H, ArH), 7.54 (d,
2H, J = 8.8 Hz, ArH), 7.72–7.90 (m, 4H, ArH), 8.47 (d, 2H,
J = 3.7 Hz, ArH), 9.02 (s, 1H, NH), 9.08 (s, 1H, NH), 9.74 (s, 1H,
NH); 13C NMR (DMSO-d6, 75 MHz) d = 109.3, 114.3, 118.6, 121.1,
122.2, 124.3, 125.2, 127.1, 127.4, 136.0, 137.3, 138.1, 144.6,
4.1.4.8. N-(4-Chlorophenyl)-N0-[4-(3-fluoroanilino)quinazolin-
6-yl]urea (22b). 78% as
Rt = 17.96 min; mmax (KBr) 1703 (CO), 3296 (NH) cmꢂ1
(DMSO-d6, 300 MHz) d = 6.92 (dt, 1H, J1 = 2.0 Hz, J2 = 8.4 Hz, ArH),
a
brown solid, mp 228–230 °C;
;
1H NMR

228
S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
7.33–7.45 (m, 3H, ArH), 7.57 (d, 2H, J = 8.8 Hz, ArH), 7.68 (d, 1H,
J = 8.2 Hz, ArH), 7.74–7.79 (m, 1H, ArH), 7.88–7.93 (m, 2H, ArH),
8.51 (s, 1H, ArH), 8.56 (s, 1H, ArH), 9.43 (s, 1H, NH), 9.45 (s, 1H,
NH), 9.84 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz) d = 108.7,
109.2, 110.5, 116.1, 118.0, 120.2, 124.1, 125.8, 127.0, 128.6,
128.8, 129.0, 130.1, 138.2, 138.9, 141.7, 146.3, 152.8, 157.4,
160.1, 164.7; mass (ES+) m/z = 408.2 (M++1). Anal. Calcd for
C21H15ClFN5O C, 61.85; H, 3.71; N, 17.17. Found C, 61.81; H,
3.94; N, 17.36.
4.1.4.13. N-(3,5-Dichlorophenyl)-N0-[4-(3-fluoroanilino)quinaz-
olin-6-yl]urea (22f). 65% as brown solid, mp > 250 °C;
Rt = 21.51 min; mmax (KBr) 1708 (CO), 3351 (NH) cmꢂ1 1H NMR
a
;
(DMSO-d6, 300 MHz) d = 6.94 (t, 1H, J = 7.4 Hz, ArH), 7.19 (s, 1H,
NH), 7.38–7.45 (m, 1H, J = 7.4 Hz, ArH), 7.60–7.68 (m, 4H, ArH),
7.77–7.90 (m, 3H, ArH), 8.56 (s, 1H, ArH), 8.59 (s, 1H, ArH), 9.25
(s, 1H, NH), 9.34 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz)
d = 109.0, 109.5, 110.4, 111.2, 115.9, 116.8, 118.2, 121.4, 127.3,
128.3, 130.1, 130.3, 134.5, 137.7, 141.5, 142.5, 145.7, 152.7,
157.5, 159.9, 164.7; mass (ES+) m/z = 442.2 (M++1), 444.1 (M++3).
Anal. Calcd for C21H14Cl2FN5O C, 57.03; H, 3.19; N, 15.83. Found
C, 59.86; H, 3.23; N, 15.46.
4.1.4.9. N-(6-Amino-2-methylquinolin-4-yl)-2-(4-ethylpiperazin-
1-yl)acetamide (22). 83% as an off white solid, mp 201–
202 °C; mmax (KBr) 1694 (CO), 3186 (NH2), 3399 (NH) cmꢂ1 1H
;
NMR (CDCl3, 300 MHz) d = 1.02 (t, 3H, J = 7.1 Hz, CH2CH3), 2.39
(q, 2H, J = 7.1 Hz, CH2CH3), 2.50 (s, 7H, CH3 and 2ꢀ CH2), 2.62
(s, 4H, 2ꢀ CH2), 3.25 (s, 2H, CH2), 5.55 (s, 2H, NH2), 6.75 (d,
1H, J = 1.7 Hz, ArH), 7.14 (dd, 1H, J1 = 1.9 Hz, J2 = 8.9 Hz, ArH),
7.62 (d, 1H, J = 8.9 Hz, ArH), 7.87 (s, 1H, ArH), 9.91 (s, 1H, NH);
13C NMR (DMSO-d6, 50 MHz) d = 12.5, 25.0, 51.8, 52.8, 53.3,
62.0, 98.4, 111.3, 120.6, 121.7, 130.2, 138.3, 142.6, 146.8,
153.3, 169.4; mass (ES+) m/z = 328.1 (M++1). Anal. Calcd for
C18H25N5O C, 66.03; H, 7.70; N, 21.39. Found C, 66.31; H, 7.53;
N, 21.47.
4.1.4.14. N-[4-Chloro-3-(trifluoromethyl)phenyl]-N0-[4-(3-flu-
oroanilino)quinazolin-6-yl]urea (22g). 65% as a brown solid,
mp 138–140 °C; mmax (KBr) 1710 (CO), 3331 (NH) cmꢂ1 1H NMR
;
(DMSO-d6, 300 MHz) d = 6.92 (dt, 1H, J1 = 2.1 Hz, J2 = 8.4 Hz, ArH),
7.40 (q, 1H, J = 8.1 Hz, ArH), 7.62–7.71 (m, 3H, ArH), 7.78 (d, 1H,
J = 8.9 Hz, ArH), 7.86–7.90 (m, 2H, ArH), 8.18 (d, 1H, J = 2.0 Hz,
ArH), 8.52 (d, 1H, J = 1.5 Hz, ArH), 8.57 (s, 1H, ArH), 9.13 (s, 1H,
NH), 9.35 (s, 1H, NH), 9.87 (s, 1H, NH); 13C NMR (DMSO-d6,
50 MHz) d = 108.8, 109.8, 111.2, 116.0, 117.3, 118.1, 122.9, 123.5,
126.8, 127.2, 128.9, 130.3, 132.4, 137.5, 139.6, 141.8, 146.5,
152.9, 153.1, 157.4, 160.0, 164.8; mass (ES+) m/z = 476.2 (M++1),
478.1 (M++3). Anal. Calcd for C22H14ClF4N5O C, 55.53; H, 2.97; N,
14.72. Found C, 55.91; H, 3.02; N, 14.71.
4.1.4.10. N-(3-Cyanophenyl)-N0-[4-(3-fluoroanilino)quinazolin-
6-yl]urea (22c). 72% as
Rt = 15.52 min; mmax (KBr) 1702 (CO), 2231 (CN), 3318 (NH)
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 6.95 (dt, 1H, J1 = 2.0 Hz,
a brown solid, mp 233–234 °C;
;
4.1.4.15. N-(4-Bromophenyl)-N0-[4-(3-chloroanilino)quinazolin-
J2 = 8.4 Hz, ArH), 7.38–7.55 (m, 3H, ArH), 7.65–7.94 (m, 6H, ArH),
8.05 (s, 1H, ArH), 8.55 (s, 1H, ArH), 8.60 (s, 1H, NH), 9.27 (s, 1H,
NH), 9.38 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz) d = 111.0,
112.0, 115.9, 118.3, 119.2, 121.2, 123.3, 125.9, 127.3, 128.1,
130.1, 130.3, 130.6, 137.9, 140.9, 141.4, 141.6, 145.2, 152.9,
157.6, 159.9, 164.7; mass (ES+) m/z = 399.1 (M++1). Anal. Calcd
for C22H15FN6O C, 66.33; H, 3.80; N, 21.09. Found C, 59.98; H,
4.01; N, 21.18.
6-yl]urea (23a). 97% as
a
white solid, mp 250–251 °C;
Rt = 22.09 min; mmax (KBr) 1655 (CO), 3284 (NH) cmꢂ1
;
1H NMR
(DMSO-d6, 300 MHz) d = 7.14 (d, 1H, J = 7.6 Hz, ArH), 7.36–7.48
(m, 5H, ArH), 7.74–7.91 (m, 3H, ArH), 8.06 (s, 1H, ArH), 8.53 (d,
2H, J = 7.6 Hz, ArH), 9.56 (s, 1H, NH), 9.68 (s, 1H, NH), 9.91 (s, 1H,
NH); 13C NMR (DMSO-d6, 75 MHz) d = 108.6, 112.0, 114.4, 118.7,
119.1, 120.1, 121.6, 125.2, 127.2, 128.7, 130.3, 131.4, 136.5, 138.0,
140.0, 144.6, 151.2, 151.4, 155.8; mass (ES+) m/z = 468.2 (M++1),
470.1 (M++3). Anal. Calcd for C21H15BrClN5O C, 53.81; H, 3.23; N,
14.94. Found C, 54.08; H, 3.76; N, 15.31.
4.1.4.11. N-(3-Chloro-4-methylphenyl)-N0-[4-(3-fluoroanilino)-
quinazolin-6-yl]urea (22d). 74% as an off white solid, mp
221–222 °C; Rt = 20.50 min; mmax (KBr) 1704 (CO), 3331 (NH)
4.1.4.16. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-(4-chloro-
phenyl)urea (23b). 96% as an off white solid, mp > 250 °C;
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 2.27 (s, 3H, CH3), 6.93
;
(dt, 1H, J1 = 2.1 Hz, J2 = 8.3 Hz, ArH), 7.22–7.28 (m, 2H, ArH),
7.41 (m, 1H, ArH), 7.67 (d, 1H, J = 8.1 Hz, ArH), 7.76–7.79 (m,
2H, ArH), 7.87–7.92 (m, 2H, ArH), 8.53 (s, 1H, ArH), 8.57 (s,
1H, ArH), 9.03 (s, 1H, NH), 9.07 (s, 1H, NH), 9.93 (s, 1H, NH);
13C NMR (DMSO-d6, 50 MHz) d = 22.7, 112.5, 112.8, 113.4,
113.7, 114.3, 119.6, 121.0, 121.6, 122.2, 130.6, 132.3, 132.4,
133.7, 133.8, 135.1, 137.1, 141.5, 142.7, 156.5, 161.0, 167.5;
mass (ES+) m/z = 422.2 (M++1), 424.1 (M++3). Anal. Calcd for
C22H17ClFN5O C, 62.64; H, 4.06; N, 16.60; Found C, 62.79; H,
3.98; N, 16.27.
mmax (KBr) 1703 (CO), 3501 (NH) cmꢂ1 1H NMR (DMSO-d6,
;
300 MHz) d = 7.16 (dd, 1H, J1 = 1.3 Hz, J2 = 7.9 Hz, ArH), 7.34–
7.43 (m, 3H, ArH), 7.55 (dd, 2H, J1 = 2.0 Hz, J2 = 7.0 Hz, ArH),
7.76–7.90 (m, 3H, ArH), 8.07 (t, 1H, J = 1.9 Hz, ArH), 8.51 (d,
1H, J = 1.8 Hz, ArH), 8.56 (s, 1H, ArH), 9.04 (s, 1H, NH), 9.06
(s, 1H, NH), 9.87 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz)
d = 110.7, 116.0, 120.3, 120.7, 121.8, 123.3, 126.0, 127.0,
128.9, 129.0, 130.3, 133.1, 137.9, 138.9, 141.5, 146.3, 152.9,
157.4; mass (ES+) m/z = 424.3 (M++1), 426.3 (M++3). Anal. Calcd
for C21H15Cl2N5O C, 59.45; H, 3.56; N, 16.51. Found C, 59.79; H,
3.89; N, 16.70.
4.1.4.12. N-(3,4-Dichlorophenyl)-N0-[4-(3-fluoroanilino)quinaz-
olin-6-yl]urea (22e). 72% as a yellow solid, mp 233–234 °C;
4.1.4.17. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-(3-cyano-
phenyl)urea (23c). 91% as a light yellow solid, mp 239–240 °C;
Rt = 20.35 min; mmax (KBr) 1690 (CO), 2226 (CN), 3334 (NH)
Rt = 22.25 min; mmax (KBr) 1703 (CO), 3326 (NH) cmꢂ1 1H NMR
;
(DMSO-d6, 300 MHz) d = 6.92 (t, 1H, J = 7.4 Hz, ArH), 7.36–7.44
(m, 3H, ArH), 7.53 (d, 1H, J = 8.7 Hz, ArH), 7.66 (d, 1H, J = 7.7 Hz,
ArH), 7.77 (d, 1H, J = 8.9 Hz, ArH), 7.86–7.95 (m, 3H, ArH and
NH), 8.52 (s, 1H, ArH), 8.57 (s, 1H, ArH), 9.13 (s, 1H, NH), 9.23 (s,
1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 107.8, 108.1, 108.8,
109.1, 109.9, 114.8, 116.9, 117.6, 118.6, 122.5, 126.0, 127.4,
128.9, 129.7, 130.3, 136.6, 139.0, 144.7, 156.3, 159.6, 162.8; mass
(ES+) m/z = 442.2 (M++1), 444.1 (M++3). Anal. Calcd for
C21H14Cl2FN5O C, 57.03; H, 3.19; N, 15.83. Found C, 57.13; H,
3.35; N, 16.02.
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 7.15 (dd, 1H, J1 = 1.4 Hz,
;
J2 = 7.9 Hz, ArH), 7.37–7.54 (m, 3H, ArH), 7.71–7.89 (m, 4H, ArH),
8.04–8.07 (m, 2H, ArH), 8.52–8.56 (m, 2H, ArH), 9.15 (s, 1H, NH),
9.24 (s, 1H, NH), 9.86 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d = 109.1, 110.4, 114.1, 117.6, 119.3, 119.9, 121.0, 121.4, 122.5,
124.1, 125.3, 125.8, 128.8, 129.0, 131.4, 136.8, 139.2, 139.3,
150.4, 151.4, 156.4; mass (ES+) m/z = 415.4 (M++1), 417.5 (M++3).
Anal. Calcd for C22H15ClN6O C, 63.69; H, 3.64; N, 20.26. Found C,
63.52; H, 3.79; N, 20.42.

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
229
4.1.4.18. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-(3,4-dichlo-
rophenyl)urea (23e). 95% as an off white solid, mp > 250 °C;
z = 472.1 (M++1), 474.1 (M++3). Anal. Calcd for C23H17ClF3N5O C,
58.54; H, 3.63; N, 14.84. Found C, 58.37; H, 3.79; N, 14.53.
Rt = 21.12 min; mmax (KBr) 1708 (CO), 3334 (NH) cmꢂ1 1H NMR
;
(DMSO-d6, 300 MHz) d = 7.15 (dd, 1H, J1 = 1.3 Hz, J2 = 8.0 Hz,
ArH), 7.35–7.43 (m, 2H, ArH), 7.54 (d, 1H, J = 8.8 Hz, ArH), 7.76–
7.87 (m, 3H, ArH), 7.95 (d, 1H, J = 2.4 Hz, ArH), 8.05 (s, 1H, ArH),
8.52–8.56 (m, 2H, ArH), 9.13 (s, 1H, NH), 9.23 (s, 1H, NH), 9.87 (s,
1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 109.3, 114.3, 117.2,
118.2, 119.2, 120.2, 121.7, 122.1, 125.5, 127.2, 128.7, 129.3,
129.8, 131.4, 136.0, 138.5, 139.8, 144.6, 151.1, 151.3, 155.8; mass
(ES+) m/z = 458.2 (M++1), 460.1 (M++3). Anal. Calcd for
C21H14Cl3N5O C, 54.89; H, 3.08; N, 15.27. Found C, 54.72; H, 3.15;
N, 15.42.
4.1.4.23. N-(3,4-Dichlorophenyl)-N 0-{4-[3-(trifluoromethyl)ani-
lino]quinazolin-6-yl}urea (24e). 87% as
a
white solid,
mp > 250 °C; mmax (KBr) 1699 (CO), 3324 (NH) cmꢂ1
;
1H NMR
(DMSO-d6, 300 MHz) d = 7.16 (t, 1H, J = 1.6 Hz, ArH), 7.43 (d, 1H,
J = 7.6 Hz, ArH), 7.58–7.63 (m, 3H, ArH), 7.77–7.86 (m, 2H, ArH),
8.20 (d, 1H, J = 8.2 Hz, ArH), 8.28 (s, 1H, ArH), 8.57 (s, 2H, ArH),
9.19 (s, 1H, ArH), 9.25 (s, 1H, NH), 9.97 (s, 1H, NH); 13C NMR
(DMSO-d6, 75 MHz) d = 109.9, 114.7, 115.7, 116.0, 117.4, 118.7,
120.3, 121.6, 124.9, 125.8, 126.1, 127.8, 128.2, 128.7, 133.3,
136.4, 139.5, 141.3, 145.4, 151.5, 151.8, 156.3; mass (ES+) m/
z = 492.1 (M++1), 494.0 (M++3). Anal. Calcd for C22H14Cl2F3N5O C,
53.68; H, 2.87; N, 14.23. Found C, 53.44; H, 3.14; N, 14.07.
4.1.4.19. N-(4-Bromophenyl)-N0-{4-[3-(trifluoromethyl)anilino]-
quinazolin-6-yl}urea (24a). 89% as a white solid, mp 245–
4.1.4.24. N-(3,5-Dichlorophenyl)-N 0-{4-[3-(trifluoromethyl)ani-
247 °C; mmax (KBr) 1707 (CO), 3454 (NH) cmꢂ1 1H NMR (DMSO-
;
lino]quinazolin-6-yl}urea (24f). 83% as
mp > 250 °C; Rt = 20.90 min; mmax (KBr) 1708 (CO), 3338 (NH)
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 7.14 (d, 1H, J = 1.5 Hz,
a
white solid,
d6, 300 MHz) d = 7.44–7.56 (m, 3H, ArH), 7.63 (t, 1H, J = 7.9 Hz,
ArH), 7.72–7.89 (m, 3H, ArH), 8.06 (s, 1H, ArH), 8.22 (d, 1H,
J = 8.2 Hz, ArH), 8.31 (d, 1H, J = 6.3 Hz, ArH), 8.58 (s, 2H, ArH), 9.20
(s, 1H, NH), 9.26 (s, 1H, NH), 10.01 (s, 1H, NH); 13C NMR (DMSO-
d6, 300 MHz) d = 109.2, 110.1, 113.2, 113.7, 113.9, 117.3, 119.4,
121.5, 122.9, 123.1, 124.0, 125.1, 126.8, 128.7, 134.0, 135.5, 138.9,
144.3, 151.0, 154.5, 155.8, 159.3; mass (ES+) m/z = 502.1 (M++1),
504.1 (M++3). Anal. Calcd for C22H15BrF3N5O C, 52.61; H, 3.01; N,
13.94. Found C, 52.56; H, 2.89; N, 13.72.
;
ArH), 7.42 (d, 1H, J = 7.6 Hz, ArH), 7.57–7.62 (m, 3H, ArH), 7.75
(d, 1H, J = 8.9 Hz, ArH), 7.84 (dd, 1H, J1 = 1.7 Hz, J2 = 9.0 Hz, ArH),
8.19 (d, 1H, J = 8.0 Hz, ArH), 8.28 (s, 1H, ArH), 8.29 (s, 1H, NH),
8.55–8.57 (m, 2H, ArH), 9.70 (br s, 2H, 2ꢀ NH); mass (ES+) m/
z = 492.1 (M++1), 494.1 (M++3). Anal. Calcd for C22H14Cl2F3N5O C,
53.68; H, 2.87; N, 14.23. Found C, 53.51; H, 2.88; N, 14.54.
4.1.4.25. N-[4-Chloro-3-(trifluoromethyl)phenyl]-N0-{4-[3-tri-
fluoromethyl)anilino]quinazolin-6-yl}urea (24g). 78% as an
off white solid, mp > 250 °C; mmax (KBr) 1699 (CO), 3324 (NH)
4.1.4.20. N-(4-Chlorophenyl)-N0-{4-[3-(trifluoromethyl)anilino]-
quinazolin-6-yl}urea (24b). 68% as a brown solid, mp 246–
248 °C; mmax (KBr) 1705 (CO), 3319 (NH) cmꢂ1
;
1H NMR
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 7.42 (d, 1H, J = 7.7 Hz,
;
(DMSO-d6, 300 MHz) d = 7.30–7.36 (m, 2H, ArH), 7.42–7.44 (m,
1H, ArH), 7.49–7.64 (m, 3H, ArH), 7.79 (d, 1H, J = 8.9 Hz, ArH),
7.86–7.90 (m, 1H, ArH), 8.23 (d, 1H, J = 8.2 Hz, ArH), 8.30 (s,
1H, ArH), 8.55–8.58 (m, 2H, ArH), 9.04 (s, 2H, 2ꢀ NH), 9.99 (s,
1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 109.7, 115.1, 117.3,
117.5, 119.4, 119.5, 125.1, 125.2, 126.2, 128.0, 128.1, 128.5,
129.0, 131.2, 137.1, 138.0, 139.9, 145.5, 151.9, 152.0, 156.6; mass
(ES+) m/z = 458.1 (M++1), 460.1 (M++3). Anal. Calcd for
C22H15ClF3N5O C, 57.71; H, 3.30; N, 15.30. Found C, 57.42; H,
3.38; N, 15.61.
ArH), 7.57–7.70 (m, 3H, ArH), 7.77–7.88 (m, 2H, ArH), 8.17–
8.21 (m, 2H, ArH), 8.28 (s, 1H, ArH), 8.57 (s, 2H, ArH), 9.15 (s,
1H, NH), 9.36 (s, 1H, NH), 9.98 (s, 1H, NH); 13C NMR (DMSO-d6,
75 MHz) d = 109.9, 114.8, 116.0, 117.3, 121.6, 122.4, 124.9,
125.8, 126.1, 127.8, 128.2, 128.6, 128.7, 131.2, 136.4, 138.4,
139.5, 145.4, 151.7, 151.8, 156.3; mass (ES+) m/z = 526.1
(M++1), 528.1 (M++3). Anal. Calcd for C23H14ClF6N5O C, 52.53;
H, 2.68; N, 13.32. Found C, 52.73; H, 2.89; N, 13.17.
0
4.1.4.26. N-(4-Bromophenyl)-N -[4-(3-methoxyanilino)quinazo-
lin-6-yl]urea (25a). 91% as a white solid, mp 230–231 °C; mmax
4.1.4.21. N-(3-Cyanophenyl)-N0-{4-[3-(trifluoromethyl)anilino]-
quinazolin-6-yl}urea (24c). 89% as a white solid, mp 245–
(KBr) 1655 (CO), 3296 (NH) cmꢂ1 1H NMR (DMSO-d6, 300 MHz)
;
d = 3.76 (s, 3H, OCH3), 6.69 (dd, 1H, J1 = 2.1 Hz, J2 = 8.1 Hz, ArH),
7.27 (t, 1H, J = 8.2 Hz, ArH), 7.44–7.50 (m, 6H, ArH), 7.74 (d, 1H,
J = 8.9 Hz, ArH), 7.87 (dd, 1H, J1 = 1.9 Hz, J2 = 9.0 Hz, ArH), 8.46 (d,
1H, J = 1.8 Hz, ArH), 8.50 (s, 1H, ArH), 9.00 (s, 1H, NH), 9.04 (s, 1H,
NH), 9.69 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz) d = 55.4, 108.5,
109.1, 110.8, 113.8, 114.9, 116.0, 120.7, 126.9, 128.7, 129.5, 131.9,
137.8, 139.5, 141.0, 146.2, 153.0, 153.1, 157.6, 159.7; mass (ES+)
m/z = 464.1 (M++1), 466.1 (M++3). Anal. Calcd for C22H18BrN5O2 C,
56.91; H, 3.91; N, 15.08. Found C, 56.83; H, 4.23; N, 15.36.
247 °C; mmax (KBr) 1707 (CO), 2244 (CN), 3454 (NH) cmꢂ1 1H
;
NMR (DMSO-d6, 300 MHz) d = 7.44–7.56 (m, 3H, ArH), 7.63 (t,
1H, J = 8.0 Hz, ArH), 7.72–7.89 (m, 3H, ArH), 8.06 (s, 1H, ArH),
8.22 (d, 1H, J = 8.2 Hz, ArH), 8.31 (d, 1H, J = 6.3 Hz, ArH), 8.58
(s, 2H, ArH), 9.20 (s, 1H, NH), 9.26 (s, 1H, NH), 10.01 (s, 1H,
NH); 13C NMR (DMSO-d6, 300 MHz) d = 109.2, 110.1, 113.2,
113.7, 113.9, 117.3, 119.4, 121.5, 122.9, 123.1, 124.0, 125.1,
126.8, 128.7, 134.0, 135.5, 138.9, 144.3, 151.0, 154.5, 155.8,
159.3; mass (ES+) m/z = 449.3 (M++1). Anal. Calcd for
C23H15F3N6O C, 61.61; H, 3.37; N, 18.74. Found C, 61.34; H,
3.39; N, 18.92.
4.1.4.27. N-(4-Chlorophenyl)-N0-[4-(3-methoxyanilino)quinazo-
lin-6-yl]urea (25b). 88% as an off white solid, mp 222–224 °C,
;
mmax (KBr) 1655 (CO), 3291 (NH) cmꢂ1 1H NMR (DMSO-d6,
4.1.4.22. N-(3-Chloro-4-methylphenyl)-N0-{4-[3-(trifluoromethyl)-
300 MHz) d = 3.77 (s, 3H, OCH3), 6.69 (dd, 1H, J1 = 1.9 Hz,
J2 = 8.0 Hz, ArH), 7.24–7.36 (m, 3H, ArH), 7.44–7.55 (m, 4H, ArH),
7.74 (d, 1H, J = 8.9 Hz, ArH), 7.88 (dd, 1H, J1 = 1.9 Hz, J2 = 9.0 Hz,
ArH), 8.46 (d, 1H, J = 1.6 Hz, ArH), 8.51 (s, 1H, ArH), 8.99 (s, 1H,
NH), 9.04 (s, 1H, NH), 9.69 (s, 1H, NH); 13C NMR (DMSO-d6,
50 MHz) d = 55.4, 108.5, 109.1, 110.9, 114.9, 116.0, 120.3, 126.0,
126.9, 128.8, 129.0, 129.5, 137.7, 138.9, 141.0, 146.3, 153.0,
153.1, 157.6, 159.7; mass (ES+) m/z = 420.1 (M++1), 422.0 (M++3).
Anal. Calcd for C22H18ClN5O2 C, 62.93; H, 4.32; N, 16.68. Found C,
63.20; H, 4.23; N, 17.01.
anilino]quinazolin-6-yl}urea (24d). 71% as
a
white solid,
;
mp > 250 °C; mmax (KBr) 1705 (CO), 3326 (NH) cmꢂ1
1H NMR
(DMSO-d6, 300 MHz) d = 2.27 (s, 3H, CH3), 7.25 (s, 2H, ArH), 7.44 (d,
1H, J = 7.6 Hz, ArH), 7.86 (t, 1H, J = 7.9 Hz, ArH), 7.77–7.88 (m, 3H,
ArH), 8.22 (d, 1H, J = 8.2 Hz, ArH), 8.30 (d, 1H, J = 1.6 Hz, ArH), 8.57
(s, 2H, ArH), 8.98 (s, 1H, NH), 9.04 (s, 1H, NH), 9.98 (s, 1H, NH); 13C
NMR (DMSO-d6, 75 MHz) d = 18.0, 109.4, 114.8, 116.3, 117.5, 118.7,
124.8, 125.3, 125.9, 126.3, 127.6, 127.7, 127.9, 128.7, 130.4, 132.3,
136.8, 137.9, 139.6, 145.2, 149.2, 151.7, 156.3; mass (ES+) m/

230
S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
4.1.4.28. N-(3-Cyanophenyl)-N 0-[4-(3-methoxyanilino)quinazo-
lin-6-yl]urea (25c). 97% as an off white solid, mp 243–244 °C;
m
(DMSO-d6, 300 MHz) d = 3.78 (s, 3H, OCH3), 6.70 (dd, 1H,
J1 = 2.0 Hz, J2 = 8.0 Hz, ArH), 7.29 (t, 1H, J = 8.2 Hz, ArH), 7.45–
7.55 (m, 4H, ArH), 7.72–7.78 (m, 2H, ArH), 7.89 (dd, 1H,
J1 = 2.0 Hz, J2 = 9.0 Hz, ArH), 8.06 (s, 1H, ArH), 8.50 (d, 1H,
1H, J = 8.1 Hz, ArH), 7.52 (d, 1H, J = 2.0 Hz, ArH), 7.65 (d, 2H,
J = 8.7 Hz, ArH), 7.77 (d, 1H, J = 8.9 Hz, ArH), 7.88–7.95 (m, 3H,
ArH), 8.51–8.53 (m, 2H, ArH), 9.10 (s, 1H, NH), 9.34 (s, 1H, NH),
9.73 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 26.8, 55.5,
108.6, 109.2, 111.2, 115.0, 116.1, 117.7, 127.0, 128.9, 129.6,
130.2, 131.1, 137.6, 141.1, 144.7, 146.5, 152.8, 153.3, 157.7,
159.8, 196.8; mass (ES+) m/z = 428.2 (M++1). Anal. Calcd for
C24H21N5O3 C, 67.44; H, 4.95; N, 16.38. Found C, 67.69; H, 5.03;
N, 16.41.
max (KBr) 1696 (CO), 2227 (CN), 3353 (NH) cmꢂ1 1H NMR
;
J = 1.9 Hz, ArH), 8.53 (s, 1H, ArH), 9.14 (s, 1H, NH), 9.26 (s, 1H,
13 C NMR (DMSO-d
NH), 9.71 (s, 1H, NH);
6, 75 MHz) d = 54.2, 107.3,
108.0, 110.1, 110.9, 113.8, 114.8, 118.0, 120.2, 122.2, 124.7,
125.8, 127.6, 128.3, 129.4, 136.3, 139.7, 139.8, 145.3, 151.8,
152.1, 156.5, 158.6; mass (ES+) m/z = 411.2 (M++1). Anal. Calcd
for C23H18N6O2 C, 67.31; H, 4.42; N, 20.48. Found C, 67.57; H,
4.66; N, 20.69.
4.1.4.33. N-(4-Bromophenyl)-N0-[4-(4-fluoroanilino)quinazo-
lin-6-yl]urea (26a). 85% as a white solid, mp > 250 °C; mmax
(KBr) 1706 (CO), 3328 (NH) cmꢂ1
;
1H NMR (DMSO-d6,
300 MHz) d = 7.23 (t, 2H, J = 8.8 Hz, ArH), 7.49 (s, 4H, ArH),
7.73–7.88 (m, 4H, ArH), 8.47 (s, 2H, ArH), 9.01 (s, 1H, NH), 9.05
(s, 1H, NH), 9.80 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz)
d = 110.8, 113.9, 115.1, 115.6, 115.9, 120.7, 124.8, 124.9, 126.9,
128.8, 131.9, 136.0, 137.7, 139.4, 146.2, 152.9, 153.2, 156.4,
157.7, 161.1; mass (ES+) m/z = 452.2 (M++1), 454.1 (M++3). Anal.
Calcd for C21H15BrFN5O C, 55.77; H, 3.34; N, 17.67. Found C,
55.53; H, 3.62; N, 17.36.
4.1.4.29. N-(3-Chloro-4-methylphenyl)-N0-[4-(3-methoxyanili-
no)quinazolin-6-yl]urea (25d). 90% as a light yellow solid,
mp > 250 °C; mmax (KBr) 1703 (CO), 3427 (NH) cmꢂ1 1H NMR
;
(DMSO-d6, 300 MHz) d = 2.27 (s, 3H, CH3), 3.78 (s, 3H, OCH3),
6.70 (dd, 1H, J1 = 2.0 Hz, J2 = 8.1 Hz, ArH), 7.22–7.31 (m, 3H,
ArH), 7.45–7.53 (m, 2H, ArH), 7.74–7.78 (m, 2H, ArH), 7.87 (dd,
1H, J1 = 2.1 Hz, J2 = 9.0 Hz, ArH), 8.49 (d, 1H, J = 2.1 Hz, ArH),
8.52 (s, 1H, ArH), 9.00 (s, 1H, NH), 9.01 (s, 1H, NH), 9.70 (s, 1H,
NH); 13C NMR (DMSO-d6, 75 MHz) d = 18.0, 54.2, 107.3, 107.9,
109.7, 113.8, 114.9, 116.3, 117.5, 125.7, 127.6, 128.2, 130.4,
132.4, 136.5, 137.9, 139.8, 145.1, 151.7, 151.9, 156.4, 158.5; mass
(ES+) m/z = 434.2 (M++1), 436.1 (M++3). Anal. Calcd for
C23H20ClN5O2 C, 63.67; H, 4.65; N, 16.14. Found C, 63.44; H,
4.63; N, 16.29.
4.1.4.34. N-(4-Chlorophenyl)-N0-[4-(4-fluoroanilino)quinazo-
lin-6-yl]urea (26b). 81% as a yellow solid, mp 274–276 °C;
mmax (KBr) 1594 (CO), 3425 (NH) cmꢂ1 1H NMR (DMSO-d6,
;
200 MHz) d = 7.17–7.26 (m, 2H, ArH), 7.34 (d, 2H, J = 8.7 Hz,
ArH), 7.53 (d, 2H, J = 8.7 Hz, ArH), 7.71–7.88 (m, 4H, ArH), 8.47
(s, 2H, ArH), 9.00 (s, 1H, NH), 9.03 (s, 1H, NH), 9.89 (s, 1H, NH);
13C NMR (DMSO-d6, 50 MHz) d = 110.8, 115.1, 115.6, 115.8,
120.3, 124.9, 125.1, 126.1, 127.0, 128.2, 129.0, 135.9, 137.9,
138.9, 145.4, 152.9, 156.5, 157.8, 161.3; mass (FAB+) m/z = 408
(M++1). Anal. Calcd for C21H15ClFN5O C, 61.85; H, 3.71; N,
17.17. Found C, 62.07; H, 3.72; N, 17.42.
4.1.4.30. N-(3,4-Dichlorophenyl)-N0-[4-(3-methoxyanilino)qui-
nazolin-6-yl]urea (25e). 93% as a yellow solid, mp > 250 °C;
mmax (KBr) 1711 (CO), 3394 (NH) cmꢂ1 1H NMR (DMSO-d6,
;
300 MHz) d = 3.78 (s, 3H, OCH3), 6.69–6.72 (m, 1H, ArH), 7.29 (t,
1H, J = 8.2 Hz, ArH), 7.38 (dd, 1H, J1 = 2.4 Hz, J2 = 8.8 Hz, ArH),
7.45–7.48 (m, 1H, ArH), 7.51–7.56 (m, 2H, ArH), 7.76 (d, 1H,
J = 8.9 Hz, ArH), 7.87 (dd, 1H, J1 = 2.1 Hz, J2 = 9.0 Hz, ArH), 7.97
(d, 1H, J = 2.4 Hz, ArH), 8.51 (d, 1H, J = 2.0 Hz, ArH), 8.53 (s, 1H,
ArH), 9.11 (s, 1H, NH), 9.22 (s, 1H, NH), 9.71 (s, 1H, NH); 13C
NMR (DMSO-d6, 75 MHz) d = 54.2, 107.3, 107.9, 110.1, 113.8,
114.8, 117.6, 118.7, 122.5, 125.8, 127.6, 128.2, 129.8, 130.3,
136.2, 139.0, 139.8, 145.3, 151.6, 152.1, 156.4, 158.5; mass (ES+)
m/z = 454.1 (M++1), 456.2 (M++3). Anal. Calcd for C22H17ClN5O2
C, 58.16; H, 3.77; N, 15.42. Found C, 57.94; H, 4.96; N, 15.65.
4.1.4.35. N-(3-Cyanophenyl)-N 0-[4-(4-fluoroanilino)quinazolin-
6-yl]urea (26c). 81% as
Rt = 22.50 min; mmax (KBr) 1708 (CO), 2234 (CN), 3365 (NH)
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 7.22 (t, 2H, J = 8.9 Hz,
a white solid, mp 215–217 °C;
;
ArH), 7.44–7.55 (m, 2H, ArH), 7.71–7.88 (m, 5H, ArH), 8.05 (s, 1H,
ArH), 8.47–8.50 (m, 2H, ArH), 9.14 (s, 1H, NH), 9.25 (s, 1H, NH),
9.80 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz) d = 109.2, 110.1,
113.2, 113.7, 117.3, 119.4, 121.5, 122.9, 123.1, 124.0, 125.1,
126.8, 128.7, 134.0, 135.5, 138.9, 144.3, 151.0, 151.3, 154.5,
155.8, 159.3; mass (ES+) m/z = 399.2 (M++1). Anal. Calcd for
C22H15FN6O C, 66.33; H, 3.80; N, 21.09. Found C, 66.57; H, 3.89;
N, 21.02.
4.1.4.31. N-(3-Acetylphenyl)-N 0-[4-(3-methoxyanilino)quinazo-
lin-6-yl]urea (25h). 91% as a light yellow solid, mp 238–239 °C;
4.1.4.36. N-(3-Chloro-4-methylphenyl)-N0-[4-(4-fluoroanilino)-
mmax (KBr) 1703 (CO), 3427 (NH) cmꢂ1
;
1H NMR (DMSO-d6,
quinazolin-6-yl]urea (26d). 72% as
a
yellow solid, mp
278–280 °C; mmax (KBr) 1655 (CO), 3304 (NH) cmꢂ1
;
1H NMR
300 MHz) d = 2.57 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 6.69 (dd, 1H,
J1 = 1.9 Hz, J2 = 8.1 Hz, ArH), 7.27 (t, 1H, J = 8.2 Hz, ArH), 7.44–
7.51 (m, 3H, ArH), 7.61 (d, 1H, J = 7.7 Hz, ArH), 7.73 (t, 2H,
J = 9.2 Hz, ArH), 7.89 (dd, 1H, J1 = 1.9 Hz, J2 = 9.0 Hz, ArH), 8.14 (s,
1H, ArH), 8.47–8.51 (m, 2H, ArH), 9.00 (s, 1H, NH), 9.13 (s, 1H,
NH), 9.71 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 27.2, 55.5,
108.6, 109.2, 111.0, 115.0, 116.1, 117.9, 122.7, 123.4, 127.0,
128.9, 129.6, 129.7, 137.8, 137.9, 140.5, 141.1, 146.4, 153.1,
157.7, 159.8, 198.2; mass (ES+) m/z = 428.2 (M++1). Anal. Calcd
for C24H21N5O3 C, 67.44; H, 4.95; N, 16.38. Found C, 67.70; H,
4.72; N, 16.53.
(DMSO-d6, 200 MHz) d = 2.29 (s, 3 H, CH3), 7.21–7.30 (m, 4H,
ArH), 7.75–7.86 (m, 5H, ArH), 8.50–8.52 (m, 2H, ArH), 9.01 (s,
1H, NH), 9.03 (s, 1H, NH), 9.89 (s, 1H, NH); 13C NMR (DMSO-d6,
50 MHz) d = 19.2, 110.7, 115.1, 115.6, 115.8, 117.5, 118.7, 125.0,
125.1, 127.0, 128.3, 128.9, 131.6, 133.5, 135.9, 137.8, 139.0,
145.5, 152.9, 157.8, 161.3; mass (FAB+) m/z = 422 (M++1). Anal.
Calcd for C22H17ClFN5O C, 62.64; H, 4.06; N, 16.60. Found C,
62.41; H, 3.85; N, 16.53.
4.1.4.37. N-(3,4-Dichlorophenyl)-N0-[4-(4-fluoroanilino)quinaz-
olin-6-yl]urea (26e). 81% as an off white solid, mp > 250 °C;
4.1.4.32. N-(4-Acetylphenyl)-N 0-[4-(3-methoxyanilino)quinazo-
lin-6-yl]urea (25i). 90% as an off white solid, mp 243–244 °C;
mmax (KBr) 1706 (CO), 3345 (NH) cmꢂ1 1H NMR (DMSO-d6,
;
300 MHz) d = 7.22 (t, 2H, J = 8.1 Hz, ArH), 7.38 (d, 1H, J = 7.7 Hz,
ArH), 7.55 (d, 1H, J = 8.3 Hz, ArH), 7.74–7.83 (m, 4H, ArH), 7.97 (s,
1H, ArH), 8.49 (d, 1H, J = 7.4 Hz, ArH), 9.11 (s, 1H, NH), 9.22 (s,
1H, NH), 9.80 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz) d = 111.1,
mmax (KBr) 1720 (CO), 3351 (NH) cmꢂ1
;
1H NMR (DMSO-d6,
300 MHz) d = 2.53 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 6.70 (dd, 1H,
J1 = 2.0 Hz, J2 = 8.0 Hz, ArH), 7.29 (t, 1H, J = 8.1 Hz, ArH), 7.47 (d,

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
231
115.1, 115.5, 115.8, 118.8, 119.8, 123.7, 124.8, 125.0, 126.9, 128.8,
130.9, 131.5, 136.0, 137.4, 140.2, 146.3, 152.8, 153.3, 156.4, 157.7,
161.2; mass (ES+) m/z = 442.2 (M++1), 444.1 (M++3). Anal. Calcd for
C21H14Cl2FN5O C, 57.03; H, 3.19; N, 15.83. Found C, 66.85; H, 4.13;
N, 15.52.
Calcd for C21H14Cl3N5O C, 54.98; H, 3.08; N, 15.27. Found C,
54.62; H, 3.39; N, 15.53.
0
4.1.4.43. N-(4-Bromophenyl)-N -[4-(4-methoxyanilino)quinazo-
lin-6-yl]urea (28a). 82% as a white solid, mp 237–238 °C;
Rt = 24.69 min; mmax (KBr) 1658 (CO), 3290 (NH) cmꢂ1 1H NMR
;
4.1.4.38. N-(4-Bromophenyl)-N0-[4-(4-chloroanilino)quinazolin-
6-yl]urea (27a). 82% as a brown solid, mp > 250 °C; mmax (KBr)
(DMSO-d6, 300 MHz) d = 3.76 (s, 3H, OCH3), 6.95 (d, 2H,
J = 9.0 Hz, ArH), 7.44–7.51 (m, 4H, ArH), 7.64–7.72 (m, 3H, ArH),
7.85 (dd, 1H, J1 = 1.9 Hz, J2 = 9.0 Hz, ArH), 8.41–8.43 (m, 2H, ArH),
8.94 (s, 1H, NH), 9.02 (s, 1H, NH), 9.64 (s, 1H, NH); 13C NMR
(DMSO-d6, 75 MHz) d = 54.7, 110.1, 113.0, 113.1, 115.0, 119.8,
124.0, 125.9, 127.9, 131.1, 131.7, 136.7, 138.6, 145.3, 152.1,
152.6, 155.2, 157.0; mass (ES+) m/z = 464.2 (M++1), 466.2 (M++3).
Anal. Calcd for C22H18BrN5O2 C, 56.91; H, 3.91; N, 15.08. Found C,
56.65; H, 4.13; N, 15.37.
1707 (CO), 3302 (NH) cmꢂ1
;
1H NMR (DMSO-d6, 300 MHz)
d = 7.41–7.48 (m, 6H, ArH), 7.75 (d, 1H, J = 9.0 Hz, ArH), 7.85–7.90
(m, 3H, ArH), 8.48–8.50 (m, 2H, ArH), 9.01 (s, 1H, NH), 9.05 (s, 1H,
NH), 9.83 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 109.1,
112.2, 114.3, 119.0, 122.4, 125.3, 125.7, 126.9, 127.2, 130.3, 136.1,
137.2, 137.7, 144.6, 151.0, 151.2, 151.3, 155.8; mass (ES+) m/
z = 468.2 (M++1), 470.0 (M++3). Anal. Calcd for C21H15BrClN5O C,
53.81; H, 3.23; N, 14.94. Found C, 53.49; H, 3.51; N, 15.27.
4.1.4.44. N-(4-Chlorophenyl)-N0-[4-(4-methoxyanilino)quinazo-
lin-6-yl]urea (28b). 69% as a white solid, mp 244–246 °C;
4.1.4.39. N-[4-(4-Chloroanilino)quinazolin-6-yl]-N0-(4-chloro-
Rt = 20.53 min; mmax (KBr) 1704 (CO), 3325 (NH) cmꢂ1 1H NMR
;
phenyl)urea (27b). 87% as
a
yellow solid, mp > 250 °C;
(DMSO-d6, 300 MHz) d = 3.78 (s, 3H, OCH3), 6.97 (d, 2H,
J = 8.8 Hz, ArH), 7.35 (d, 2H, J = 8.7 Hz, ArH), 7.55 (d, 2H,
J = 8.7 Hz, ArH), 7.66–7.73 (m, 3H, ArH), 7.87 (d, 1H, J = 8.8 Hz,
ArH), 8.43 (d, 2H, J = 1.4 Hz, ArH), 8.94 (s, 1H, NH), 9.03 (s, 1H,
NH), 9.63 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz) d = 55.6,
110.9, 114.0, 115.9, 120.2, 124.8, 125.8, 126.7, 128.6, 129.0,
132.6, 137.7, 139.1, 146.1, 153.0, 153.3, 156.1, 157.8; mass
(ES+) m/z = 420.2 (M++1), 422.1 (M++3). Anal. Calcd for
C22H18ClN5O2 C, 62.93; H, 4.32; N, 16.68. Found C, 63.20; H,
4.23; N, 17.01.
Rt = 22.02 min; mmax (KBr) 1706 (CO), 3332 (NH) cmꢂ1
;
1H NMR
(DMSO-d6, 300 MHz) d = 7.34 (d, 2H, J = 8.8 Hz, ArH), 7.42 (d,
2H, J = 8.9 Hz, ArH), 7.53 (d, 2H, J = 8.9 Hz, ArH), 7.75 (d, 1H,
J = 8.9 Hz, ArH), 7.85–7.90 (m, 3H, ArH), 8.48–8.51 (m, 2H,
ArH), 9.00 (s, 1H, NH), 9.04 (s, 1H, NH), 9.83 (s, 1H, NH); 13C
NMR (DMSO-d6, 75 MHz) d = 109.1, 114.3, 118.6, 122.4, 124.3,
125.3, 125.7, 126.9, 127.2, 127.4, 136.2, 137.2, 144.6, 151.2,
151.3, 155.8; mass (ES+) m/z = 424.2 (M++1), 426.2 (M++3). Anal.
Calcd for C21H15Cl2N5O C, 59.45; H, 3.56; N, 16.51. Found C,
59.76; H, 3.91; N, 16.85.
4.1.4.45. N-(3-Cyanophenyl)-N 0-[4-(4-methoxyanilino)quinazo-
lin-6-yl]urea (28c). 73% as a light yellow solid, mp 215–216 °C;
4.1.4.40. N-[4-(4-Chloroanilino)quinazolin-6-yl]-N0-(3-cyano-
phenyl)urea (27c). 80% as a white solid, mp 223–224 °C; mmax
(KBr) 1708 (CO), 2221 (CN), 3320 (NH) cmꢂ1; 1H NMR (DMSO-d6,
300 MHz) d = 7.41–7.54 (m, 4H, ArH), 7.70–7.78 (m, 2H, ArH),
7.85–7.89 (m, 3H, ArH), 8.04 (s, 1H, ArH), 8.51 (s, 2H, ArH),
9.14 (s, 1H, NH), 9.24 (s, 1H, NH), 9.83 (s, 1H, NH); 13C NMR
(DMSO-d6, 50 MHz) d = 111.0, 112.0, 115.9, 119.2, 121.3, 123.4,
124.2, 125.9, 127.1, 127.4, 128.6, 128.9, 130.6, 137.6, 138.8,
140.8, 146.4, 152.9, 153.1, 157.5; mass (ES+) m/z = 415.1
(M++1), 417.1 (M++3). Anal. Calcd for C22H15ClN6O C, 63.69; H,
3.64; N, 20.26. Found C, 63.45; H, 3.87; N, 20.02.
Rt = 21.11 min; mmax (KBr) 1711 (CO), 2229 (CN), 3338 (NH) cmꢂ1
;
1H NMR (DMSO-d6, 300 MHz) d = 3.76 (s, 3H, OCH3), 6.96 (d, 2H,
J = 9.0 Hz, ArH), 7.43–7.54 (m, 2H, ArH), 7.64–7.73 (m, 4H, ArH),
7.85 (dd, 1H, J1 = 1.9 Hz, J2 = 9.0 Hz, ArH), 8.04 (s, 1H, ArH), 8.42–
8.46 (m, 2H, ArH), 9.07 (s, 1H, NH), 9.22 (s, 1H, NH), 9.64 (s, 1H,
NH); 13C NMR (DMSO-d6, 75 MHz) d = 54.7, 110.4, 111.2, 113.1,
115.0, 118.4, 120.5, 122.5, 124.0, 125.0, 126.0, 127.9, 129.8,
131.7, 136.4, 140.1, 145.4, 152.1, 152.7, 155.3, 157.0; mass (ES+)
m/z = 411.1 (M++1). Anal. Calcd for C23H18N6O2 C, 67.31; H, 4.42;
N, 20.48. Found C, 67.45; H, 4.48; N, 20.79.
4.1.4.41. N-[4-(4-Chloroanilino)quinazolin-6-yl]-N0-(3-chloro-
4.1.4.46. N-(3-Chloro-4-methylphenyl)-N0-[4-(4-methoxyanilino)-
quinazolin-6-yl]urea (28d). 85% as a yellow solid, mp > 250 °C;
4-methylphenyl)urea (27d). 86% as
mp > 250 °C; Rt = 22.50 min; mmax (KBr) 1701 (CO), 3399 (NH)
cmꢂ1 1H NMR (DMSO-d6, 300 MHz) d = 2.27 (s, 3H, CH3), 7.22–
a
yellow solid,
mmax (KBr) 1700 (CO), 3321 (NH) cmꢂ1
;
1H NMR (DMSO-d6,
;
300 MHz) d = 2.27 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 6.97 (d, 2H,
J = 8.8 Hz, ArH), 7.25–7.28 (m, 2H, ArH), 7.65-7.86 (m, 5H, ArH),
8.44 (d, 2H, J = 9.7 Hz, ArH), 8.94 (s, 1H, NH), 8.96 (s, 1H, NH), 9.64
(s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 18.0, 54.4, 109.7,
112.8, 114.6, 116.2, 117.4, 123.7, 124.1, 125.5, 127.5, 127.6, 130.4,
131.4, 132.4, 136.3, 137.9, 144.9, 151.7, 152.2, 154.9; mass (ES+) m/
z = 434.2 (M++1), 436.1 (M++3). Anal. Calcd for C23H20ClN5O2 C,
63.67; H, 4.65; N, 16.14. Found C, 64.01; H, 4.23; N, 16.37.
7.29 (m, 2H, ArH), 7.44 (d, 2H, J = 8.8 Hz, ArH), 7.76 (d, 2H,
J = 8.6 Hz, ArH), 7.85–7.91 (m, 3H, ArH), 8.50–8.52 (m, 2H,
ArH), 8.99 (s, 1H, NH), 9.02 (s, 1H, NH), 9.82 (s, 1H, NH); 13C
NMR (DMSO-d6, 50 MHz) d = 19.2, 110.6, 115.9, 117.5, 118.7,
124.2, 127.0, 127.5, 128.6, 128.8, 128.9, 131.6, 133.5, 137.8,
138.8, 139.0, 146.2, 152.9, 153.0, 157.5; mass (ES+) m/z = 438.2
(M++1), 440.1 (M++3). Anal. Calcd for C22H17Cl2N5O C, 60.29; H,
3.91; N, 15.98. Found C, 59.93; H, 3.86; N, 16.37.
4.1.4.47. N-(3,4-Dichlorophenyl)-N0-[4-(4-methoxyanilino)qui-
nazolin-6-yl]urea (28e). 82% as a yellow solid, mp 245–246 °C;
4.1.4.42. N-[4-(4-Chloroanilino)quinazolin-6-yl]-N0-(3,4-dichlo-
Rt = 23.67 min; mmax (KBr) 1706 (CO), 3450 (NH) cmꢂ1 1H NMR
;
rophenyl)urea (27e). 86% as
a
yellow solid, mp > 250 °C;
Rt = 22.95 min; mmax (KBr) 1705 (CO), 3332 (NH) cmꢂ1
;
1H NMR
(DMSO-d6, 300 MHz) d = 3.76 (s, 3H, CH3), 6.95 (d, 2H, J = 8.9 Hz,
ArH), 7.36 (dd, 1H, J1 = 2.4 Hz, J2 = 8.8 Hz, ArH), 7.53 (d, 1 H,
J = 8.8 Hz, ArH), 7.63–7.72 (m, 3H, ArH), 7.83 (dd, 1H, J1 = 1.7 Hz,
J2 = 8.9 Hz, ArH), 7.96 (d, 1H, J = 2.4 Hz, ArH), 8.41–8.46 (m, 2H,
ArH), 9.04 (s, 1H, NH), 9.19 (s, 1H, NH), 9.64 (s, 1H, NH); 13C
NMR (DMSO-d6, 75 MHz) d = 54.4, 110.1, 112.8, 114.7, 117.6,
118.6, 122.5, 123.7, 125.6, 127.5, 129.8, 130.3, 131.4, 136.1,
139.1, 145.1, 151.7, 152.3, 154.9, 156.7; mass (ES+) m/z = 454.2
(DMSO-d6, 300 MHz) d = 7.38–7.44 (m, 3H, ArH), 7.54 (d, 1H,
J = 8.8 Hz, ArH), 7.76 (d, 1H, J = 8.9 Hz, ArH), 7.83–7.89 (m, 3H,
ArH), 7.95 (d, 1H, J = 2.4 Hz, ArH), 8.51 (s, 2H, ArH), 9.11 (s, 1H,
NH), 9.22 (s, 1H, NH), 9.83 (s, 1H, NH); 13C NMR (DMSO-d6,
75 MHz) d = 109.4, 114.3, 117.2, 118.2, 122.1, 122.5, 125.4, 125.7,
126.9, 127.2, 129.3, 129.8, 135.9, 137.1, 138.5, 144.7, 151.1,
151.4, 155.8; mass (ES+) m/z = 458.2 (M++1), 460.2 (M++3). Anal.

232
S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
(M++1), 456.1 (M++3). Anal. Calcd for C22H17Cl2N5O2 C, 58.16; H,
3.77; N, 15.42. Found C, 58.32; H, 3.71; N, 15.19.
z = 395.1 (M++1). Anal. Calcd for C23H18N6O C, 70.04; H, 4.60; N,
21.31. Found C, 70.21; H, 4.69; N, 21.18.
4.1.4.48. N-(3-Acetylphenyl)-N 0-[4-(4-methoxyanilino)quinazo-
lin-6-yl]urea (28h). 85% as a yellow solid, mp 221–223 °C;
4.1.4.53. N-(3-Chloro-4-methylphenyl)-N0-[4-(4-toluidino)qui-
nazolin-6-yl]urea (29d). 94% as an off white solid, mp > 250 °C;
Rt = 24.96 min; mmax (KBr) 1685 (CO), 3345 (NH) cmꢂ1
;
1H NMR
Rt = 19.98 min; mmax (KBr) 1705 (CO), 3332 (NH) cmꢂ1 1H NMR
;
(DMSO-d6, 300 MHz) d = 2.57 (s, 3H, COCH3), 3.76 (s, 3H, OCH3),
6.95 (d, 2H, J = 8.9 Hz, ArH), 7.45 (t, 1H, J = 7.9 Hz, ArH), 7.59–
7.73 (m, 5H, ArH), 7.86 (dd, 1H, J1 = 1.6 Hz, J2 = 8.9 Hz, ArH), 8.14
(s, 1H, ArH), 8.41–8.46 (m, 2H, ArH), 8.95 (s, 1H, NH), 9.12 (s, 1H,
NH), 9.66 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 26.3, 54.7,
110.1, 113.1, 115.0, 116.9, 121.7, 122.4, 124.0, 125.9, 127.8,
128.7, 131.7, 136.7, 136.9, 137.0, 145.2, 152.2, 152.5, 155.3,
157.0, 197.3, mass (ES+) m/z = 428.2 (M++1). Anal. Calcd for
C24H21N5O3 C, 67.44; H, 4.95; N, 16.38. Found C, 67.57; H, 5.05;
N, 16.25.
(DMSO-d6, 200 MHz) d = 2.31 (s, 3H, CH3), 2.35 (s, 3H, CH3), 7.21–
7.33 (m, 4H, ArH), 7.70–7.91 (m, 5H, ArH), 8.49 (s, 2H, ArH), 9.01
(s, 2H, NH), 9.71 (s, 1H, NH); mass (FAB+) m/z = 418 (M++1). Anal.
Calcd for C23H20ClN5O C, 66.10; H, 4.82; N, 16.76. Found C, 66.36;
H, 5.03; N, 16.95.
4.1.4.54. N-(3,4-Dichlorophenyl)-N0-[4-(4-toluidino)quinazolin-
6-yl]urea (29e). 74% as
a
light green solid, mp > 250 °C;
Rt = 20.89 min; mmax (KBr) 1707 (CO), 3349 (NH) cmꢂ1
;
1H NMR
(DMSO-d6, 300 MHz) d = 2.31 (s, 3H, CH3), 7.19 (d, 2H, J = 8.2
Hz, ArH), 7.38 (dd, 1H, J1 = 2.3 Hz, J2 = 8.8 Hz, ArH), 7.55 (d,
1H, J = 8.8 Hz, ArH), 7.67–7.75 (m, 3H, ArH), 7.85 (dd, 1H,
J1 = 1.7 Hz, J2 = 9.0 Hz, ArH), 7.97 (d, 1H, J = 2.2 Hz, ArH), 8.48
(d, 2H, J = 8.1 Hz, ArH), 9.09 (s, 1H, NH), 9.23 (s, 1H, NH), 9.69
(s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 19.7, 110.1, 114.7,
117.6, 118.6, 121.8, 122.5, 125.7, 127.6, 128.0, 129.8, 130.3;
131.8, 135.9, 136.1, 139.0, 145.2, 151.6, 152.2, 156.5; mass
(ES+) m/z = 438.2 (M++1), 440.1 (M++3). Anal. Calcd for
C22H17Cl2N5O C, 60.29; H, 3.91; N, 15.98. Found C, 60.32; H,
4.01; N, 16.03.
4.1.4.49. N-(4-Acetylphenyl)-N 0-[4-(4-methoxyanilino)quinazo-
lin-6-yl]urea (28i). 81% as a light yellow solid, mp 233–235 °C;
Rt = 24.48 min; mmax (KBr) 1678 (CO), 3297 (NH) cmꢂ1 1H NMR
;
(DMSO-d6, 300 MHz) d = 2.52 (s, 3H, COCH3), 3.76 (s, 3H, OCH3),
6.94–6.97 (d, 2H, J = 7.0 Hz, ArH), 7.62–7.74 (m, 5H, ArH), 7.84–
7.94 (m, 3H, ArH), 8.42–8.46 (m, 2H, ArH), 9.04 (s, 1H, NH), 9.31
(s, 1H, NH), 9.67 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d = 25.9, 54.7, 110.3, 113.1, 115.0, 116.8, 124.0, 125.9, 127.9,
129.2, 130.1, 131.7, 136.4, 143.8, 145.4, 151.8, 152.6, 155.3,
157.0, 195.9; mass (ES+) m/z = 428.2 (M++1). Anal. Calcd for
C24H21N5O3 C, 67.44; H, 4.95; N, 16.38. Found C, 67.57; H, 5.05;
N, 16.25.
4.1.4.55. N-(3-Acetylphenyl)-N0-[4-(4-toluidino)quinazolin-6-yl]-
urea (29h). 78% as an off white solid, mp 235–237 °C;
Rt = 20.84 min; mmax (KBr) 1685 (CO), 3275 (NH) cmꢂ1 1H NMR
;
4.1.4.50. N-(4-Bromophenyl)-N0-[4-(4-toluidino)quinazolin-6-yl]-
urea (29a). 85% as a white solid, mp > 250 °C; Rt = 20.48 min; mmax
(DMSO-d6, 300 MHz) d = 2.30 (s, 3H, CH3), 2.56 (s, 3H, COCH3),
7.18 (d, 2H, J = 8.2 Hz, ArH), 7.45 (t, 1H, J = 7.8 Hz, ArH), 7.59–7.74
(m, 5H, ArH), 7.87 (dd, 1H, J1 = 1.7 Hz, J2 = 8.9 Hz, ArH), 8.14 (s, 1H,
ArH), 8.45–8.48 (m, 2H, ArH), 8.98 (s, 1H, NH), 9.13 (s, 1H, NH),
9.70 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 20.1, 26.3,
110.2, 115.1, 117.0, 121.8, 122.2, 122.5, 126.0, 127.8, 128.4, 128.8,
132.2, 136.3, 136.8, 137.0, 139.6, 145.2, 152.2, 152.4, 156.9, 197.4;
mass (ES+) m/z = 412.2 (M++1). Anal. Calcd for C24H21N5O2 C,
70.06; H, 5.14; N, 17.02. Found C, 69.85; H, 5.33; N, 17.24.
(KBr) 1655 (CO), 3304 (NH) cmꢂ1 1H NMR (DMSO-d6, 300 MHz)
;
d = 2.31 (s, 3H, CH3), 7.19 (d, 2H, J = 8.3 Hz, ArH), 7.46–7.52 (m, 4H,
ArH), 7.67–7.75 (m, 3H, ArH), 7.87 (dd, 1H, J1 = 2.0 Hz, J2 = 9.0 Hz,
ArH), 8.46 (s, 2H, ArH), 8.99 (s, 1H, NH), 9.07 (s, 1H, NH), 9.70 (s,
1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 19.7, 109.8, 112.6, 114.8,
119.4, 121.7, 125.6, 127.5, 128.0, 130.8; 131.7, 136.0, 136.4, 138.2,
145.0, 151.7, 152.1, 156.5; mass (ES+) m/z = 448.2 (M++1), 450.2
(M++3). Anal. Calcd for C22H18BrN5O C, 58.94; H, 4.05; N, 15.62. Found
C, 58.82; H, 4.21; N, 15.68.
4.1.4.56. N-(4-Acetylphenyl)-N0-[4-(4-toluidino)quinazolin-6-yl]-
urea (29i). 75% as a white solid, mp > 250 °C; Rt = 21.45 min;
4.1.4.51. N-(4-Chlorophenyl)-N0-[4-(4-toluidino)quinazolin-6-
;
mmax (KBr) 1679 (CO), 3329 (NH) cmꢂ1 1H NMR (DMSO-d6,
yl]urea (29b). 69% as
a
light yellow solid, mp > 250 °C;
Rt = 20.41 min; mmax (KBr) 1655 (CO), 3295 (NH) cmꢂ1
;
1H
300 MHz) d = 2.30 (s, 3H, CH3), 2.52 (s, 3H, COCH3), 7.18 (d, 2H,
J = 8.3 Hz, ArH), 7.62–7.75 (m, 5H, ArH), 7.86–7.94 (m, 3H, ArH),
8.46–8.48 (m, 2H, ArH), 9.06 (s, 1H, NH), 9.32 (s, 1H, NH), 9.71
(s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) d = 20.1, 25.9, 110.4,
115.1, 116.8, 122.1, 126.0, 127.9, 128.4, 129.2, 130.1, 132.2,
136.3, 136.5, 143.7, 145.4, 151.8, 152.5, 156.9, 195.8; mass (ES+)
m/z = 412.2 (M++1). Anal. Calcd for C24H21N5O2 C, 70.06; H, 5.14;
N, 17.02. Found C, 69.93; H, 5.02; N, 17.31.
NMR (DMSO-d6, 300 MHz) d = 2.31 (s, 3H, CH3), 7.19 (d, 2H,
J = 7.9 Hz, ArH), 7.35 (d, 2H, J = 8.5 Hz, ArH), 7.55 (d, 2H,
J = 8.6 Hz, ArH), 7.68–7.75 (m, 3H, ArH), 7.88 (d, 1H,
J = 8.7 Hz, ArH), 8.46 (s, 2H, ArH), 8.94 (s, 1H, NH), 9.02 (s,
1H, NH), 9.65 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz)
d = 20.9, 111.0, 116.0, 120.2, 122.9, 126.0, 126.8, 128.7, 129.0,
129.2, 132.9, 137.2, 137.6, 139.0, 146.2, 152.9, 153.3, 157.7;
mass (ES+) m/z = 404.2 (M++1), 406.1 (M++3). Anal. Calcd for
C22H18ClN5O C, 65.43; H, 4.49; N, 17.34. Found C, 65.07; H,
4.72; N, 17.42.
4.1.4.57. N-(4-Bromophenyl)-N0-[4-(3,4-dimethoxyanilino)qui-
nazolin-6-yl]urea (30a). 79% as
a
yellow solid, mp 246–
248 °C; mmax (KBr) 1705 (CO), 3317 (NH) cmꢂ1
;
1H NMR
4.1.4.52. N-(3-Cyanophenyl)-N0-[4-(4-toluidino)quinazolin-6-yl]-
(DMSO-d6, 300 MHz) d = 3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3),
6.96 (d, 1H, J = 8.7 Hz, ArH), 7.36–7.47 (m, 6H, ArH), 7.71 (d,
1H, J = 8.9 Hz, ArH), 7.84 (d, 1H, J = 8.8 Hz, ArH), 8.44 (s, 2H,
ArH), 8.93 (s, 1H, NH), 9.01 (s, 1H, NH), 9.58 (s, 1H, NH); 13C
NMR (DMSO-d6, 50 MHz) d = 55.9, 56.1, 108.3, 111.0, 112.1,
112.1, 113.8, 115.3, 115.9, 120.7, 126.8, 128.7, 131.9, 133.1,
137.5, 139.4, 145.7, 146.2, 148.8, 152.9, 153.4, 157.8; mass
(ES+) m/z = 494.2 (M++1), 496.1 (M++3). Anal. Calcd for
C23H20BrN5O3 C, 55.88; H, 4.08; N, 14.17. Found C, 55.61; H,
3.86; N, 14.15.
urea (29c). 83% as
a light green solid, mp 233–235 °C;
Rt = 17.97 min; mmax (KBr) 1703 (CO), 2232 (CN), 3352 (NH) cmꢂ1
;
1H NMR (DMSO-d6, 300 MHz) d = 2.31 (s, 3H, CH3), 7.19 (d, 2H,
J = 8.3 Hz, ArH), 7.44–7.55 (m, 2H, ArH), 7.67–7.76 (m, 4H, ArH),
7.87 (dd, 1H, J1 = 2.1 Hz, J2 = 9.0 Hz, ArH), 8.06 (s, 1H, ArH), 8.47–
8.49 (m, 2H, ArH), 9.12 (s, 1H, NH), 9.26 (s, 1H, NH), 9.70 (s, 1H,
NH); 13C NMR (DMSO-d6, 75 MHz) d = 19.7, 110.1, 110.8, 114.7,
118.0, 120.1, 121.8, 122.2, 124.7, 125.7, 127.5, 128.0, 129.4, 131.8,
135.9, 136.2, 139.7, 145.1, 151.7, 152.2, 156.5; mass (ES+) m/

S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
233
4.1.4.58. N-(4-Chlorophenyl)-N0-[4-(3,4-dimethoxyanilino)qui-
nazolin-6-yl]urea (30b). 76% as a yellow solid, mp 233–235 °C;
4.1.4.63. N-[4-Chloro-3-(trifluoromethyl)phenyl]-N0-[4-(3,4-
dimethoxyanilino)quinazolin-6-yl]urea (30g). 71% as a yel-
mmax (KBr) 1705 (CO), 3338 (NH) cmꢂ1
;
1H NMR (DMSO-d6,
low solid, mp 240–242 °C; mmax (KBr) 1709 (CO), 3340 (NH)
300 MHz) d = 3.78 (s, 6H, 2ꢀ OCH3), 6.97 (d, 1H, J = 8.5 Hz, ArH),
7.34–7.45 (m, 4H, ArH), 7.55 (d, 2H, J = 8.4 Hz, ArH), 7.72 (d, 1H,
J = 8.8 Hz, ArH), 7.86 (d, 1H, J = 8.7 Hz, ArH), 8.45 (s, 2H, ArH),
8.96 (s, 1H, NH), 9.04 (s, 1H, NH), 9.60 (s, 1H, NH); 13C NMR
(DMSO-d6, 50 MHz) d = 55.9, 56.1, 108.3, 111.0, 112.2, 115.3,
115.9, 120.2, 125.9, 126.7, 128.7, 129.0, 133.1, 137.6, 140.0,
145.7, 146.2, 148.8, 153.0, 153.4, 157.7; mass (ES+) m/z = 450.2
(M++1), 452.2 (M++3). Anal. Calcd for C23H20ClN5O3 C, 61.40; H,
4.48; N, 15.57. Found C, 61.17; H, 4.63; N, 15.31.
cmꢂ1
;
1H NMR (DMSO-d6, 300 MHz) d = 3.76 (s, 6H, 2ꢀ OCH3),
6.96 (d, 1H, J = 8.4 Hz, ArH), 7.34–7.41 (m, 2H, ArH), 7.61–7.73
(m, 3H, ArH), 7.81–7.84 (m, 1H, ArH), 8.18 (s, 1H, ArH), 8.46
(d, 2H, J = 7.4 Hz, ArH), 9.08 (s, 1H, NH), 9.36 (s, 1H, NH), 9.60
(s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz) d = 55.9, 56.1, 108.4,
111.5, 112.2, 115.4, 115.9, 117.3, 122.9, 123.6, 127.0, 128.8,
132.4, 133.0, 137.2, 139.7, 145.8, 146.4, 148.8, 152.9, 153.5,
157.8; mass (ES+) m/z = 518.2 (M++1), 520.1 (M++3). Anal. Calcd
for C24H19ClF3N5O3 C, 55.66; H, 3.70; N, 13.52. Found C, 55.37;
H, 3.78; N, 13.81.
4.1.4.59. N-(3-Cyanophenyl)-N0-[4-(3,4-dimethoxyanilino)qui-
nazolin-6-yl]urea (30c). 77% as a brown solid, mp 185–187 °C;
4.1.4.64. N-(3-Acetylphenyl)-N0-[4-(3,4-dimethoxyanilino)qui-
nazolin-6-yl]urea (30h). 67% as a yellow solid, mp 181–183 °C;
m
max (KBr) 1707 (CO), 2233 (CN), 3323 (NH) cmꢂ1; 1H NMR (DMSO-
d6, 300 MHz) d = 3.76 (s, 6H, 2ꢀ OCH3), 6.96 (d, 1H, J = 8.5 Hz, ArH),
7.35–7.51 (m, 4H, ArH), 7.72 (d, 2H, J = 8.5 Hz, ArH), 7.83 (d, 1H,
J = 8.0 Hz, ArH), 8.04 (s, 1H, ArH), 8.44 (s, 1H, ArH), 8.46 (s, 1H,
ArH), 9.12 (s, 1H, NH), 9.26 (s, 1H, NH), 9.59 (s, 1H, NH); 13C NMR
(DMSO-d6, 50 MHz) d = 55.9, 56.1, 108.3, 111.3, 112.0, 112.2,
115.3, 115.9, 119.2, 121.3, 123.4, 125.8, 126.9, 128.7, 130.6,
133.0, 137.3, 140.9, 145.7, 146.3, 148.8, 153.0, 153.4, 157.8; mass
(ES+) m/z = 441.2 (M++1). Anal. Calcd for C24H20N6O3 C, 65.45; H,
4.58; N, 19.08. Found C, 65.21; H, 4.39; N, 18.84.
mmax (KBr) 1707 (CO), 3323 (NH) cmꢂ1 1H NMR (DMSO-d6,
,
300 MHz) d = 2.58 (s, 3H, CH3), 3.78 (s, 6H, 2ꢀ OCH3), 6.97 (d,
1H, J = 6.9 Hz, ArH), 7.40–7.44 (m, 3H, ArH), 7.61–7.86 (m, 4H,
ArH), 8.15 (s, 1H, ArH), 8.46 (s, 2H, ArH), 8.98 (s, 1H, NH), 9.13 (s,
1H, NH), 9.62 (s, 1H, NH); mass (ES+) m/z = 458.2 (M++1). Anal.
Calcd for C25H23N5O4 C, 65.63; H, 5.07; N, 15.31. Found C, 65.66;
H, 5.38; N, 15.54.
4.1.4.65. N-(3-Acetylphenyl)-N0-[4-(3,4-dimethoxyanilino)qui-
nazolin-6-yl]urea (30i). 71% as a yellow solid, mp 165–167 °C;
4.1.4.60. N-(3-Chloro-4-methylphenyl)-N0-[4-(3,4-dimethoxy-
anilino)quinazolin-6-yl]urea (30d). 70% as a yellow solid, mp
mmax (KBr) 1701 (CO), 3315 (NH) cmꢂ1 1H NMR (DMSO-d6,
,
300 MHz) d = 2.59 (s, 3H, CH3), 3.78 (s, 6H, 2ꢀ OCH3), 6.97 (d,
1H, J = 8.5 Hz, ArH), 7.34–7.45 (m, 4H, ArH), 7.55 (d, 2H,
J = 8.4 Hz, ArH), 7.72 (d, 1H, J = 8.8 Hz, ArH), 7.86 (d, 1H,
J = 8.7 Hz, ArH), 8.45 (s, 2H, ArH), 8.96 (s, 1H, NH), 9.04 (s, 1H,
NH), 9.60 (s, 1H, NH); mass (ES+) m/z = 458.2 (M++1). Anal. Calcd
for C25H23N5O4 C, 65.63; H, 5.07; N, 15.31. Found C, 65.66; H,
5.38; N, 15.54.
235–236 °C; mmax (KBr) 1705 (CO), 3319 (NH) cmꢂ1 1H NMR
;
(DMSO-d6, 300 MHz) d = 2.27 (s, 3H, CH3), 3.77 (s, 6H, 2ꢀ
OCH3), 6.97 (d, 1H, J = 8.6 Hz, ArH), 7.25 (s, 2H, ArH), 7.37–7.42
(m, 2H, ArH), 7.71–7.85 (m, 3H, ArH), 8.45 (d, 1H, J = 4.1 Hz,
ArH), 9.03 (s, 2H, 2ꢀ NH), 9.60 (s, 1H, NH); 13C NMR (DMSO-d6,
50 MHz) d = 19.2, 55.9, 56.1, 108.3, 110.9, 112.1, 115.3, 115.9,
117.4, 118.7, 126.7, 128.7, 128.8, 131.6, 133.1, 133.5, 137.6,
139.2, 145.7, 146.1, 148.8, 153.0, 153.3, 157.8; mass (ES+) m/
z = 464.2 (M++1), 466.1 (M++3). Anal. Calcd for C24H22ClN5O3 C,
62.14; H, 4.78; N, 15.10. Found C, 62.21; H, 4.67; N, 14.98.
4.2. Materials and methods
4.2.1. In vitro antimalarial assay
The in vitro antimalarial activity of the compounds was
assessed against CQ-sensitive 3D7 strain of P. falciparum and com-
pared with that of chloroquine. The schizontocidal activities (MIC)
as well as 50% inhibitory concentration (IC50) were obtained fol-
lowing techniques of Rickman’s et al. and Smilkstein et al.,
respectively.7,8 In brief the parasites were maintained in vitro in
RPNI medium (Srivastava and Puri)9 supplemented with genta-
4.1.4.61. N-(3,4-Dichlorophenyl)-N0-[4-(3,4-dimethoxyanilino)-
quinazolin-6-yl]urea (30e). 77% as a yellow solid, mp > 250 °C;
mmax (KBr) 1707 (CO), 3365 (NH) cmꢂ1
;
1H NMR (DMSO-d6,
300 MHz) d = 3.78 (s, 6H, 2ꢀ OCH3), 6.97 (d, 1H, J = 8.7 Hz, ArH),
7.37–7.43 (m, 3H, ArH), 7.55 (d, 1H, J = 8.8 Hz, ArH), 7.73 (d, 1H,
J = 8.9 Hz, ArH), 7.83 (d, 1H, J = 8.8 Hz, ArH), 7.97 (d, 1H, J = 1.8
Hz, ArH), 8.47 (d, 1H, J = 5.8 Hz, ArH), 9.06 (s, 1H, NH), 9.20 (s,
1H, NH), 9.59 (s, 1H, NH); 13C NMR (DMSO-d6, 50 MHz) d = 55.9,
56.1, 108.3, 111.3, 112.1, 115.3, 115.9, 118.8, 119.8, 123.7, 126.9,
128.7, 131.0, 131.5, 133.0, 137.3, 140.2, 145.7, 146.3, 148.8,
152.8, 153.5, 157.8; mass (ES+) m/z = 484.2 (M++1), 486.1
(M++3). Anal. Calcd for C23H19Cl2N5O3 C, 57.04; H, 3.95; N, 14.46.
Found C, 56.79; H, 3.65; N, 14.17.
mycin at 40 lg/mL; (Sigma), Fungizone at 0.25 lg/mL; (GIBCO)
and 10% fetal bovine serum (pH 7.2), at 37 °C in a CO2 incubator.
The compounds were dissolved in DMSO at 5 mg/mL and
required dilutions were made in a template plate with RPMI
medium. 20
in the test plate and two wells receiving 20
as untreated control. For evaluation of schizontocidal activity
parasite culture was synchronized using 5% -sorbitol to obtain
ring stages only and 180 L of 3% cell suspension containing 1%
l
L from each dilution was transferred, in duplicate,
lL of vehicle were kept
D
4.1.4.62. N-(3,5-Dichlorophenyl)-N0-[4-(3,4-dimethoxyanilino)-
l
quinazolin-6-yl]urea (30f). 73% as
a
white solid, mp
parasitized cells was added to each well containing test
compounds.10 The plates were incubated at 37 °C in CO2 incubator
for more than 40 h. after which thin smears were prepared from
each well on grease-free glass slides. These were fixed in methanol,
stained with Giemsa’s stain and examined under light microscope,
100ꢀ oil immersion. The minimum inhibitory concentration (MIC)
of test compound was designated as the minimum concentration
required producing 100% inhibition of schizont maturation.
250–251 °C; mmax (KBr) 1716 (CO), 3312 (NH) cmꢂ1
;
1H NMR
(DMSO-d6, 300 MHz) d = 3.78 (s, 6H, 2ꢀ OCH3), 6.97 (d, 1H,
J = 8.7 Hz, ArH), 7.19 (s, 1H, NH), 7.37–7.43 (m, 2H, ArH), 7.54 (d,
1H, J = 1.3 Hz, ArH), 7.61 (d, 2H, J = 1.0 Hz, ArH), 7.73 (d, 1H,
J = 8.9 Hz, ArH), 7.82 (d, 1H, J = 8.9 Hz, ArH), 8.46 (s, 1H, ArH),
8.49 (s, 1H, ArH), 9.23 (br s, 2H, 2ꢀ NH); 13C NMR (DMSO-d6,
50 MHz) d = 55.9, 56.1, 108.3, 111.5, 112.1, 115.4, 115.8, 116.8,
117.1, 121.4, 126.9, 128.7, 133.0, 134.5, 137.1, 142.2, 142.6,
145.7, 146.4, 148.8, 152.8, 153.5, 157.8; mass (ES+) m/z = 484.2
(M++1), 486.1 (M++3). Anal. Calcd for C23H19Cl2N5O3 C, 57.04; H,
3.95; N, 14.46. Found C, 57.24; H, 3.91; N, 14.38.
Percent inhibition of maturation ¼ CS ꢂ TS ꢀ 100=CS
CS—no. of schizonts in untreated culture; TS—no. of schizonts in
treated culture.

234
S. Madapa et al. / Bioorg. Med. Chem. 17 (2009) 222–234
For evaluation of IC50 of the compounds, SYBR Green I-based
Acknowledgments
fluorescence (MSF) assay was used. For the assays, fresh dilutions
of all compounds in screening medium were prepared and 50 lL
Three authors (S.M., A.M., S.K.P.) acknowledge the financial sup-
port from CSIR, New Delhi and ICMR, New Delhi in the form of fel-
lowships. This work was supported by the DST grant to Z.T. under
WOS program.
of highest starting concentration (10–500 ng/mL) was dispensed
in duplicate wells in row ‘B’ of 96-well tissue culture plate. The
highest starting concentration for chloroquine was 25 ng/mL. Sub-
sequently two fold serial dilutions were prepared up to row ‘H’ (se-
ven concentrations) and finally 50 lL of 2.5% parasitized cell
References and notes
suspension containing 0.5% parasitaemia was added to each well
except 4 wells in row ‘A’ received non-infected cell suspension.
These wells containing non infected erythrocytes in the absence
of compound served as negative control, while parasitized erythro-
cytes in the presence of CQ served as positive control. After incu-
This is CDRI communication number 7626
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BMG Labtechnologies). The IC50 was determined using Logit
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4.3. Cytotoxicity assay
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line (C1008; Monkey kidney fibroblast) following the method of
Mosmann with certain modifications.11 The cells were incubated
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Selectivity Index (SI): It was calculated as
SI ¼ CC50=IC50
:
4.3.1. In vivo antimalarial assay
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