Search for new pharmacophores for antimalarial activity. Part III: Synthesis and bioevaluation of new 6-thioureido-4-anilinoquinazolines

Article abstract of DOI:10.1016/j.ejmech.2009.06.001

Syntheses and in vitro antimalarial evaluation of 42 new thioureidoquinazolines have been carried out. Several analogs showed promising antimalarial effect in the in vitro investigation against chloroquine-sensitive 3D7 strain of Plasmodium falciparum whe

Full text of DOI:10.1016/j.ejmech.2009.06.001

European Journal of Medicinal Chemistry 44 (2009) 4404–4412
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Search for new pharmacophores for antimalarial activity. Part III: Synthesis
and bioevaluation of new 6-thioureido-4-anilinoquinazolinesq
,
A. Mishra a, K. Srivastava 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:
Syntheses and in vitro antimalarial evaluation of 42 new thioureidoquinazolines have been carried out.
Several analogs showed promising antimalarial effect in the in vitro investigation against chloroquine-
sensitive 3D7 strain of Plasmodium falciparum whereas one of the compounds shows 50% curative effect
in the mouse model at an oral dose of 100 mg/kg ꢀ 4 days against multidrug resistant Plasmodium yoelii
nigeriensis.
Received 18 March 2009
Received in revised form
2 June 2009
Accepted 3 June 2009
Available online 12 June 2009
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Quinazoline
Antimalarial
Thiourea
In vitro
In vivo
Plasmodium falciparum
1. Introduction
these studies we considered worthwhile to supplement the ureido
group in 4-anilinoquinazolines with a thioureido moiety and
The widespread presence of chloroquine (CQ)-resistant Plasmo-
dium falciparum strains has severely affected global malaria eradi-
cation program. The paucity of new affordable drugs has not only
complicated the clinical management of malaria in endemic areas,
but has also resulted in increase in the mortality rate. This situation
underscores the need for urgent discovery of new antimalarial
agents. In this context it becomes essential to carry out exploratory
studies for finding new pharmacophores which associate with
antimalarial activity. Installing these pharmacophores in scaffolds
with proven biological property as anti-infectious agent could lead
to discovery of new antimalarial compound. In our research
program aimed at this objective, we have reported the potent
antimalarial effect of new quinazoline derivatives which were
afforded by placing a ureido group at 6-position of 4-anilinoquina-
zolines [1]. In a set of compounds belonging to this prototype, we
could identify an analog that displayed 40% curative activity at an
oral dose of 100 mg/kg ꢀ 4 days in mice model against multidrug
resistant (MDR) Plasmodium yoelii nigeriensis. In continuation of
investigate the antimalarial effect of the resulting compounds. Our
decision to evaluate thioureidoquinazolines for antimalarial activity
was influenced by several reports disclosing the antimalarial effect
of thiourea-based compounds via different mechanisms. For
example, Rastelli et al. [2] reported that the thiourea-unit of
compound I binds with the pfDHFR whereas Kasam et al. [3]
disclosed the plasmepsin inhibitory effect of thioureides repre-
sented by II (Fig. 1). It was also proposed that the thio-group
provides opportunity for nucleophilic addition of enzymes through
thiol formation resulting in antimalarial effect [4]. The antimalarial
efficacy of different thioureides (III–VI) has been demonstrated in
several other reports too, but in majority of them it is limited to the
in vitro examination [5,6]. We describe herein the synthesis and
bioevaluation of new series of 6-thioureido-4-anilinoquinazolines
as antimalarial agents.
2. Results and discussion
The preparation of the targeted compounds was straightforward
as outlined in Scheme 1. The starting quinazolinamines (1–6) were
obtained following the procedure recently reported by us [1].
Amines were treated with the commercially available iso-
thiocyanates to afford the desired compounds (7–12a–g) in good
q
CDRI communication number. 7714.
* Corresponding author. Tel.: þ91 522 2612411x18; fax: þ91 522 2623405.
E-mail address: s_batra@cdri.res.in (S. Batra).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.06.001

A. Mishra et al. / European Journal of Medicinal Chemistry 44 (2009) 4404–4412
4405
exhibited better antimalarial response with IC50 of 26.7, 21.0,
11.5 ng/mL whereas 8a and 8f having an unsubstituted phenyl or
4-bromophenyl substitution on thiourea displayed IC50 of 258.2
and 105.8 ng/mL, respectively. However, even this activity was
low as compared to the standard drug CQ. On the basis of the SI
for compounds of this series, 8d with SI of 1615 was ideal for the
in vivo examination. On replacing the OMe group at 3-position of
the phenyl ring of aniline with the Cl-group resulted in
compounds of series 9. However, this change led to significant
drop in antimalarial efficacy of the compounds. Except for
compounds 9d and 9f incorporating 3-Cl and 4-Br on the phenyl
O
O
O
S
HN
S
Me
N
NH2
R
HN
N
H
N
H
N
N
I
Me
II
S
S
HN
N
N
Ar
HN
N
H
N
H
R1
of thiourea group, all other derivatives displayed MIC of 10 mg/mL
IV
III
Cl
or more. Compounds 9d and 9f showed IC50 of 8.8 and 526.1 ng/
mL, respectively, whereas the SI was found to be 556.3 and 1.0.
This implied that among this set of compounds too, the 3-Cl
substitution on the phenyl ring of the arylthiourea showed better
antimalarial efficacy compared to other analogs in the series.
Next, replacing the 3-Cl with 3-CF3 in the 4-anilino moiety
produced compounds belonging to series 10. However, analogs of
this series did not show any marked improvement in the antima-
larial effect and here too except for 10f, all compounds displayed
Cl
N
H
H
N
N
S
R
S
HN
N
N
NHR
O
H
H3CO
X
X= C, N
VI
V
Cl
H3CO
N
Fig. 1. Structure of a few thiourea derivatives showing antimalarial activity.
MIC of 10 mg/mL. The IC50 value of 10f having 4-Br substitution in
phenyl ring of the thiourea was found to be 39.2 ng/mL. Previous
study with 6-ureido-4-anilinoquinazolines has indicated that
installing 3,4-(OMe)2 substitution on phenyl ring of the anilino
group furnished compounds displaying best in vitro antimalarial
effect. This invoked us to prepare compounds of series 11 in which
3,4-(OMe)2 substitution was placed in the aryl ring of the anilino
core. Unlike ureidoquinazolines, the compounds belonging to this
series showed moderate antimalarial effect only. Compounds 11c,
d and e bearing 3-CN, 3-Cl and 4-Cl groups, respectively, showed
yields as solids. The new compounds were characterized spectro-
scopically and analytically. Results of the in vitro antimalarial effi-
cacy against CQ-sensitive P. falciparum of the 42 compounds, which
were investigated during the present study, are displayed in Table 1.
The MIC of CQ that was used as standard in the bioassay was
0.12
mg/mL whereas the IC50 was found to be 2.0 ng/mL. Generally,
compounds having MIC of 2
mg/mL or less were evaluated for their
IC50 values. We introduced changes at both the phenyl rings
present in the molecule during the synthesis of compounds
included herein. In all six variations were made in the phenyl ring
of the anilino group which included H, 3-OMe, 3-Cl, 3-CF3, 3,4-
(OMe)2, 4-OMe while seven changes represented by H, 3-F, 3-CN, 3-
Cl, 4-Cl, 4-Br or 1-naphthyl were made in the phenyl group of the
thiourea subunit.
MIC of 10
mg/mL whereas other four analogs (11a, b, f and g)
exhibited antimalarial response at MIC value of 2
mg/mL. The IC50
values for 11a, b, f and g ranged between 207.2 and 682.8 ng/mL
whereas the SI values were 90.0, 63.7, 85.7 and 133.8, respectively.
From this result it was suspected that placing a substitution at the
4-position result in the loss of antimalarial effect. In order to check
this, finally we prepared the series 12 wherein the phenyl ring of
the aniline core carried methoxy group at 4-position. The resulting
set of compounds 12a–g was found to be the least active. Except for
12a,b and f containing an unsubstituted phenyl, 3-F-phenyl or 4-Br-
phenyl, respectively, in the arylthiourea part, all other compounds
In series 7, the phenyl ring of the anilino moiety was devoid of
any substitution. Amongst the compounds of this series, 7a,b,d,e
and g displayed antimalarial effect at MIC of 2
and 7f bearing 3-CN and 3-Br substitutions, respectively, on the
aryl ring of the thiourea subunit showed MIC of 10 g/mL or more.
Out of five compounds with MIC of 2 g/mL, the IC50 for 7b and 7d
mg/mL whereas 7c
m
m
displayed MIC of 10 mg/mL. In terms of IC50 12b and f had only
was examined. Compound 7b bearing the 3-F substitution showed
moderate activity with IC50 value of 792 ng/mL whereas 7d having
3-Cl group had comparable effect with IC50 value of 813 ng/mL.
Introduction of a methoxy group at 3-position in the phenyl ring
of the anilino part resulted in compounds belonging to series 8
which exhibited significant antimalarial activity. Except for
compounds 8e and 8g, all compounds displayed MIC of either 2 or
moderate activity with values of 53.2 ng/mL (SI ¼ 206.4) and
50.2 ng/mL (SI ¼ 114.9), respectively. In comparison 12a was even
less active with IC50 of 242.6 ng/mL (SI ¼ 80.4). These results made
it evident that having a substitution at 4-position of the phenyl ring
of the aniline-part could result in loss in antimalarial activity in
thioureidoquinazolines. The result of the in vitro study also reflec-
ted that 3-Cl- or 4-Br-phenyl in the arylthiourea entity were better
suited to show the antimalarial effect.
1 mg/mL leading to the determination of their IC50 values. Thio-
ureides 8b,c and d bearing 3-F, 3-CN and 3-Cl substitutions,
respectively, in the phenyl ring on the arylthiourea portion
Essentially to further investigate the utility of these
compounds as antimalarial agents it was decided to determine
R1
R1 Compd. no R1
a
b
c
d
e
f
Ph
1,7
H
HN
HN
N
3-F-C6H5
3-CN-C6H5
3-Cl-C6H5
4-Cl-C6H5
4-Br-C6H5
1-Naphthyl
R2NCS, DMF
6-20h
H
N
H
N
2,8
3-OMe
3-Cl
H2N
N
R2
N
3,9
4,10
5,11
6,12
S
3-CF3
3,4-(OMe)2
4-OMe
N
7-12a-g
1-6
g
Scheme 1.

4406
A. Mishra et al. / European Journal of Medicinal Chemistry 44 (2009) 4404–4412
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 no.
R1
R2
MIC (
m
g/mL)
IC50 (ng/mL)
Selectivity index
% Inhibition on day 4a
% Inhibition on day 7a
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
8g
9a
9b
H
H
H
H
H
H
H
Ph
2
2
>10
2
2
10
2
2
1
1
2
10
1
10
10
10
>10
2.0
10
2
10
2
10
2
10
10
2
10
2
2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3-F-C6H4
3-CN-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
1-Naphthyl
Ph
3-F-C6H4
3-CN-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
1-Naphthyl
Ph
3-F-C6H4
3-CN-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
1-Naphthyl
Ph
3-F-C6H4
3-CN-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
1-Naphthyl
Ph
3-F-C6H4
3-CN-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
1-Naphthyl
Ph
3-F-C6H4
3-CN-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
1-Naphthyl
792.2
–
813.2
–
–
–
258.2
26.7
21.0
11.5
–
105.8
–
–
70.3
–
29.0
–
–
–
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
38.7
510.7
453.0
1615.3
–
187.0
–
–
–
–
–
–
46.54
28.45
–
99.9
–
–
100.0
–
–
–
–
–
–
–
85.71
61.12
–
16.10
–
–
–
–
–
–
–
–
Died
–
–
–
–
–
–
–
–
–
–
–
–
–
9c
9d
9e
9f
–
8.8
–
526.1
–
991.7
–
443.0
–
556.3
–
1.0
–
69.0
–
5.5
–
77.19
–
–
–
–
–
–
–
–
9.78
–
–
–
–
–
–
–
–
3-Cl
3-Cl
9g
10a
10b
10c
10d
10e
10f
10g
11a
11b
11c
11d
11e
11f
11g
12a
12b
12c
12d
12e
12f
12g
3-CF3
3-CF3
3-CF3
3-CF3
3-CF3
3-CF3
3-CF3
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
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
–
–
39.2
–
303.0
385.3
–
67.1
–
90.0
63.7
–
10
10
10
2
2
2
–
–
–
–
682.8
207.2
242.6
53.2
–
85.7
133.8
80.4
206.4
–
–
–
–
–
–
–
–
2
>10
>10
>10
2
–
–
–
–
50.15
114.9
–
–
–
10
a
Screened against multidrug resistant P. yoelii nigeriensis[6].
the oral efficacy of a few derivatives in mouse model against MDR
P. yoelii nigeriensis. Hence the antimalarial effect of compounds
8d, f, 9b, d and 10f were investigated at a dose of 100 mg/kg ꢀ 4d
via oral route. The thioureide 8f showed 100% and 99.9%
suppression in parasitaemia in mice on day 4 and 7, respectively.
It was encouraging to note that 50% of the treated mice survived
on completion of the experiment on 28th day. Compared to this,
at identical dose compounds 9b and d could cause 85.7% and
77.2% reduction in the level of day 4 parasitaemia. By day 7,
although the suppression of parasitaemia in animals which were
administered 9b was around 61%, it decreased for animals treated
with 9d to 16% only. Further, for compound 8d which elicited
good antimalarial response in the in vitro assay could cause only
3. Conclusions
In summary we have disclosed the antimalarial investigation of
new thiourea analogs of 4-anilinoquinazolines. It was observed that
compounds display moderate antimalarial efficacy against the CQ-
sensitive 3D7 strain of P. falciparum. Out of a few analogs evaluated
for in vivo efficacy against MDR strain via oral route, one compound
was found to show 50% curative effect. These results provide
impetus for designing new compounds incorporating thiourea
moiety for the discovery of new antimalarials.
4. Experimental
46.5% suppression of parasitaemia on day
4
which further
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 RX I FTIR spectrophotometer. 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
decreased to 28.5% by day 7. Compound 10f caused only 9.8% of
suppression in day 4 level of parasitaemia and all the animals
died on day 7 reflecting its inactivity in the in vivo system. Except
for compound 8f, animals treated with different analogs died by
day 28 of the experiment. It is assumed that low level of solubility
of these compounds could be one of the reasons for their limited
efficacy in the in vivo system. However, the result of the in vivo
evaluation indicated that amongst the set of compounds
described herein there was no correlation between the in vitro
and in vivo antimalarial efficacy.
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. HPLC
was performed on Agilent 1100 having a DA detector (lmax ¼ 220
and 254 nm) using a gradient run of 10–100% MeCN containing

A. Mishra et al. / European Journal of Medicinal Chemistry 44 (2009) 4404–4412
4407
0.01% TFA in water over a period of 30 min in a RP-18e column
(250 mm ꢀ 4.6 mm) with particle size of 5 m.
(ESþ) m/z ¼ 406.1 (Mþ þ 1). Anal. Calcd for C21H16ClN5S (exact mass:
m
405.0815): C, 62.14; H, 3.97; N,17.25. Found: C, 62.42; H, 4.14; N,17.02.
4.1. General procedure for the preparation of 6-amino-4-
arylaminoquinazoline (1–6)
4.2.5. N-(4-Anilinoquinazolin-6-yl)-N0-(4-chlorophenyl)
thiourea (7e)
Yield: 47% (0.56 g from 0.70 g) as a brown solid, mp 167–169 ꢁC.
See Ref. [1]
nmax (KBr) 1216 (C]S), 3409 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
300 MHz)
d
¼ 7.12 (t, 1H, J ¼ 7.4 Hz, ArH), 7.36–7.41 (m, 4H, ArH),
4.2. General procedure for the preparation of compounds 7–12a–g
7.54 (d, 2H, J ¼ 8.8 Hz, ArH), 7.77 (d, 1H, J ¼ 8.8 Hz, ArH), 7.85 (d, 3H,
J ¼ 7.0 Hz, ArH), 8.50 (d, 1H, J ¼ 1.3 Hz, ArH), 8.57 (s, 1H, ArH), 9.76
(s, 1H, NH), 10.00 (s, 1H, NH), 10.10 (s, 1H, NH). 13C NMR (DMSO-d6,
A mixture of appropriate amine from 1–6 (1.0 equiv) and aryl iso-
thiocyanate (1.3 equiv) in anhydrous DMF (2.0 mL) was stirred at room
temperature for 6–20 h. Thereafter the reaction mixture was diluted
with 50 mL water and extracted with ethyl acetate (4 ꢀ 20 mL). The
combined organic layer was dried over anhydrous Na2SO4, concen-
trated and the residue thus obtained was purified through silica-gel
column chromatography using hexanes:EtOAc (30–10:70–90, v/v) as
eluent to yield the desired compounds 7–12a–g.
50 MHz)
d
¼ 116.1, 119.4, 123.2, 124.6, 126.3, 126.7, 128.8, 129.2,
129.4, 129.6, 132.8, 137.9, 139.2, 139.3, 140.1, 148.5, 155.0, 158.3,
181.5. Mass (ESþ) m/z ¼ 406.1 (Mþ þ 1). Anal. Calcd for C21H16ClN5S
(exact mass: 405.0815): C, 62.14; H, 3.97; N, 17.25. Found: C, 62.34;
H, 3.68; N, 17.12.
4.2.6. N-(4-Anilinoquinazolin-6-yl)-N0-(4-bromophenyl)
thiourea (7f)
4.2.1. N-(4-Anilinoquinazolin-6-yl)-N0-phenylthiourea (7a)
Yield: 44% (0.25 g from 0.30 g) as a yellow solid, mp 123–125 ꢁC.
Yield: 50% (0.55 g from 0.70 g) as a yellow solid, mp 142–143 ꢁC.
nmax (KBr) 1242 (C]S), 3454 (NH) cmꢂ1.1H NMR (DMSO-d6, 300 MHz)
nmax (KBr) 1216 (C]S), 3359 (NH) cmꢂ1
.
1H NMR (DMSO-d6,
d
¼ 7.12 (t,1H, J ¼ 7.3 Hz, ArH), 7.38 (t, 1H, J ¼ 7.7 Hz, ArH), 7.46–7.54 (m,
300 MHz)
d
¼ 7.13 (d, 2H, J ¼ 6.4 Hz, ArH), 7.34–7.50 (m, 6H, ArH),
4H, ArH), 7.69 (s, 1H, ArH), 7.75 (d, 1H, J ¼ 8.8 Hz, ArH), 7.84 (d, 3H,
J ¼ 8.0 Hz, ArH), 8.48(s,1H, ArH), 8.55 (s,1H, ArH), 9.74 (s,1H, NH), 9.97
7.73–7.83 (m, 4H, ArH), 8.48 (s, 1H, ArH), 8.55 (s, 1H, ArH), 9.75 (s,
1H, NH), 9.95 (s, 1H, NH), 9.99 (s, 1H, NH). 13C NMR (DMSO-d6,
(s, 1H, NH), 10.07 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 116.1,
75 MHz)
d
¼ 116.0, 119.3, 123.1, 124.5, 125.0, 125.6, 128.6, 129.3,
117.6, 118.7, 119.3, 123.2, 123.3, 124.6, 126.9, 129.3, 132.1, 132.8, 138.0,
139.8, 140.1, 141.3, 148.1, 154.9, 158.3, 181.4. Mass (ESþ) m/z ¼ 452.0
(Mþ þ 2). Anal. Calcd for C21H16BrN5S (exact mass: 449.0310): C, 56.01;
H, 3.58; N, 15.55. Found: C, 56.22; H, 3.67; N, 15.58.
132.8, 138.0, 140.1, 148.3, 154.8, 158.3, 181.3. Mass (ESþ) m/z ¼ 372.1
(Mþ þ 1). Anal. Calcd for C21H17N5S (exact mass: 371.1205): C,
67.90; H, 4.61; N, 18.85. Found: C, 68.05; H, 4.65; N, 18.73.
4.2.2. N-(4-Anilinoquinazolin-6-yl)-N0-(3-fluorophenyl)
thiourea (7b)
4.2.7. N-(4-Anilinoquinazolin-6-yl)-N0-(2-naphthyl)thiourea (7g)
Yield: 50% (0.63 g from 0.70 g) as a yellow solid, mp 140–142 ꢁC.
Yield: 48% (0.55 g from 0.70 g) as a yellow solid, mp 157–158 ꢁC.
nmax (KBr) 1254 (C]S), 3352 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
nmax (KBr) 1234 (C]S), 3409 (NH) cmꢂ1
.
1H NMR (DMSO-d6,
300 MHz)
d
¼ 7.11 (t,1H, J ¼ 7.3 Hz, ArH), 7.38 (t, 2H, J ¼ 7.8 Hz, ArH),
300 MHz)
d
¼ 6.96 (s, 1H, ArH), 7.12 (s, 1H, ArH), 7.29–7.38 (m, 4H,
7.51–7.61 (m, 4H, ArH), 7.74 (d, 1H, J ¼ 8.9 Hz, ArH), 7.83–7.90 (m,
3H, ArH), 7.95 (t, 1H, J ¼ 6.7 Hz, ArH), 8.04 (d, 1H, J ¼ 8.0 Hz, ArH),
8.48 (s, 1H, ArH), 8.54 (s, 1H, ArH), 8.56 (s, 1H, ArH), 9.76 (s, 1H, NH),
10.05 (s, 1H, NH), 10.19 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
ArH), 7.53 (d, 1H, J ¼ 9.5 Hz, ArH), 7.77–7.83 (m, 4H, ArH), 8.48 (s, 1H,
ArH), 8.55 (s, 1H, ArH), 9.74 (s, 1H, NH), 10.07 (s, 1H, NH), 10.13 (s, 1H,
NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 111.2, 111.5, 111.8, 112.0, 116.0,
119.3, 120.3, 123.1, 124.5, 128.8, 129.3, 130.7, 130.8, 132.7, 137.8, 140.0,
141.9, 142.1, 148.5, 154.9, 158.2, 161.0, 164.2, 181.2. Mass (ESþ) m/
z ¼ 390.1(Mþ þ 1). Anal.CalcdforC21H16FN5S(exactmass:389.1110):
C, 64.76; H, 4.14; N, 17.98. Found: C, 65.00; H, 4.32; N, 18.14.
d
¼ 115.9, 119.7, 123.1, 124.0, 124.5, 126.4, 126.5, 127.0, 127.1, 127.8,
128.5, 128.9, 129.3, 130.8, 133.2, 134.8, 135.8, 138.2, 140.1, 148.5,
154.8, 158.3, 182.8. Mass (ESþ) m/z ¼ 422.1 (Mþ þ 1). Anal. Calcd for
C25H19N5S (exact mass: 421.1361): C, 71.23; H, 4.54; N,16.61. Found:
C, 71.48; H, 4.88; N, 16.94.
4.2.3. N-(4-Anilinoquinazolin-6-yl)-N0-(3-cyanophenyl)
thiourea (7c)
4.2.8. N-[4-(3-Methoxyanilino)quinazolin-6-yl]-N0-
phenylthiourea (8a)
Yield: 55% (0.46 g from 0.50 g) as a brown solid, mp 118–120 ꢁC.
nmax (KBr) 1216 (C]S), 2215 (CN), 3436 (NH) cmꢂ1. 1H NMR (DMSO-
Yield: 75% (0.28 g from 0.25 g) as an off-white solid, mp 174–
d6, 300 MHz)
d
¼ 7.12 (t, 1H, J ¼ 7.3 Hz, ArH), 7.38 (t, 2H, J ¼ 7.8 Hz,
175 ꢁC. nmax (KBr) 1259 (C]S), 3417 (NH) cmꢂ1. 1H NMR (DMSO-d6,
ArH), 7.51–7.60 (m, 2H, ArH), 7.75–7.86 (m, 5H, ArH), 8.00 (s,1H, ArH),
300 MHz)
d
¼ 3.77 (s, 3H, OCH3), 6.70 (dd, 1H, J1 ¼8.2 Hz,
8.48 (d,1H, J ¼ 1.4 Hz, ArH), 8.55 (s,1H, ArH), 9.75 (s,1H, NH),10.10 (s,
J2 ¼ 2.1 Hz, ArH), 7.14 (t, 1H, J ¼ 7.3 Hz, ArH), 7.25–7.37 (m, 3H, ArH),
7.47–7.54 (m, 4H, ArH), 7.75 (d, 1H, J ¼ 8.9 Hz, ArH), 7.86 (dd, 1H,
J1 ¼8.9 Hz, J2 ¼1.9 Hz, ArH), 8.47 (d, 1H, J ¼ 1.6 Hz, ArH), 8.57 (s, 1H,
ArH), 9.69 (s, 1H, NH), 9.96 (s, 1H, NH), 9.99 (s, 1H, NH). 13C NMR
1H, NH), 10.25 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 112.0,
116.1, 119.5, 123.3, 124.7, 128.1, 128.9, 129.0, 129.4, 129.8, 130.6, 132.7,
137.6, 140.0, 141.3, 148.6, 155.0, 158.4, 181.6. Mass (ESþ) m/z ¼ 397.1
(Mþ þ 1). Anal. Calcd for C22H16N6S (exact mass: 396.1157): C, 66.65;
H, 4.07; N, 21.20. Found: C, 66.33; H, 3.84; N, 21.37.
(DMSO-d6, 75 MHz)
d
¼ 53.8, 98.3, 106.8, 107.7, 113.2, 114.0, 117.2,
122.5, 123.0, 123.6, 126.6, 127.3, 128.0, 130.8, 136.0, 138.0, 139.2,
146.3, 152.7, 156.2, 158.1, 179.3. Mass (ESþ) m/z ¼ 402.8 (Mþ þ 1).
Anal. Calcd for C22H19N5OS (exact mass: 401.1310): C, 65.81; H,
4.77; N, 17.44. Found: C, 66.04; H, 4.96; N, 17.23.
4.2.4. N-(4-Anilinoquinazolin-6-yl)-N0-(3-chlorophenyl)
thiourea (7d)
Yield: 50% (0.60 g from 0.70 g) as a yellow solid, mp 123–125 ꢁC.
nmax (KBr) 1252 (C]S), 3400 (NH) cmꢂ1
.
1H NMR (DMSO-d6,
4.2.9. N-(3-Fluorophenyl)-N0-[4-(3-methoxyanilino)quinazolin-6-
yl]thiourea (8b)
300 MHz)
d
¼ 7.10–7.21 (m, 2H, ArH), 7.36–7.41 (m, 4H, ArH), 7.69 (s,
1H, ArH), 7.75–7.85 (m, 4H, ArH), 8.49 (s, 1H, ArH), 8.56 (s, 1H, ArH),
Yield: 55% (0.26 g from 0.30 g) as a yellow solid, mp 178–179 ꢁC.
9.77 (s,1H, NH),10.05(s,1H, NH),10.19(s,1H, NH).13CNMR(DMSO-d6,
nmax (KBr) 1216 (C]S), 3430 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
75 MHz)
d
¼ 115.7, 119.0, 122.8, 123.0, 124.1, 124.2, 124.8, 128.5, 128.9,
300 MHz)
d
¼ 3.77 (s, 3H, OCH3), 6.70 (dd, 1H, J1 ¼8.0 Hz, J2 ¼ 1.9 Hz,
130.5, 132.3, 133.0, 137.3, 139.6, 141.4, 148.1, 154.6, 157.9, 181.0. Mass
ArH), 6.94–6.99 (m, 1H, ArH), 7.25–7.41 (m, 3H, ArH), 7.47–7.54 (m,

4408
A. Mishra et al. / European Journal of Medicinal Chemistry 44 (2009) 4404–4412
3H, ArH), 7.76 (d, 1H, J ¼ 8.8 Hz, ArH), 7.85 (dd, 1H, J1 ¼8.9 Hz,
J2 ¼1.6 Hz, ArH), 8.48 (d,1H, J ¼ 1.3 Hz, ArH), 8.58 (s,1H, ArH), 9.68 (s,
1H, NH), 10.06 (s, 1H, NH), 10.11 (s, 1H, NH). 13C NMR (DMSO-d6,
4.2.14. N-[4-(3-Methoxyanilino)quinazolin-6-yl]-N0-
(2-naphthyl)thiourea (8g)
Yield: 53% (0.27 g from 0.30 g) as an off-white solid, mp 159–
75 MHz)
d
¼ 55.8, 108.8, 109.7, 111.2, 111.5, 111.7, 112.0, 115.2, 116.0,
160 ꢁC. tR ¼ 15.32 min, nmax (KBr) 1216 (C]S), 3406 (NH) cmꢂ1 1
.
119.3, 120.3, 128.7, 130.0, 130.7, 130.8, 132.7, 137.8, 141.2, 141.9, 142.0,
148.5, 154.8, 158.2, 160.2, 161.0, 164.2, 181.3. Mass (ESþ) m/z ¼ 420.1
(Mþ þ 1). Anal. Calcd for C22H18FN5OS (exact mass: 419.1216): C,
62.99; H, 4.33; N, 16.70. Found: C, 62.68; H, 4.61; N, 16.94.
H NMR (DMSO-d6, 300 MHz)
d
¼ 3.78 (s, 3H, OCH3), 6.70 (dd, 1H,
J1 ¼8.2 Hz, J2 ¼ 2.1 Hz, ArH), 7.28 (t,1H, J ¼ 8.2 Hz, ArH), 7.49–7.59
(m, 6H, ArH), 7.74(d, 1H, J ¼ 8.9 Hz, ArH), 7.86–7.98 (m, 3H, ArH),
8.04 (d, 1H, J ¼ 8.0 Hz, ArH), 8.47 (d, 1H, J ¼ 1.4 Hz, ArH), 8.57 (s,
1H, ArH), 9.68 (s, 1H, NH), 9.93 (s, 1H, NH), 10.03 (s, 1H, NH). 13C
4.2.10. N-(3-Cyanophenyl)-N0-[4-(3-methoxyanilino)quinazolin-6-
yl] thiourea (8c)
NMR (DMSO-d6, 50 MHz)
d
¼ 55.4, 108.3, 109.2, 114.7, 115.5, 119.1,
123.6, 125.9, 126.1, 126.5, 126.6, 127.4, 128.1, 128.5, 129.6, 130.4,
132.8, 134.3, 135.3, 137.8, 140.8, 148.0, 154.3, 157.7, 159.7, 182.4.
Mass (ESþ) m/z ¼ 452.1 (Mþ þ 1). Anal. Calcd for C26H21N5OS
(exact mass: 451.1467): C, 69.16; H, 4.69; N,15.51. Found: C, 69.37;
H, 4.78; N, 15.34.
Yield: 75% (0.48 g from 0.40 g) as a yellow solid, mp 160–161 ꢁC.
nmax (KBr) 1244 (C]S), 2230 (CN), 3453 (NH) cmꢂ1.1H NMR (DMSO-
d6, 300 MHz)
d
¼ 3.77 (s, 3H, OCH3), 6.71 (dd, 1H, J1 ¼8.1 Hz,
J2 ¼ 2.0 Hz, ArH), 7.29 (t,1H, J ¼ 8.1 Hz, ArH), 7.46–7.61 (m, 4H, ArH),
7.76–7.88 (m, 3H, ArH), 8.01 (s,1H, ArH), 8.51 (s,1H, ArH), 8.61 (s,1H,
ArH), 9.80 (s, 1H, NH), 10.20 (s, 1H, NH), 10.33 (s, 1H, NH). 13C NMR
4.2.15. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-phenylthiourea
(9a)
(DMSO-d6, 75 MHz)
d
¼ 54.3, 107.4, 108.3, 110.3, 113.7, 114.4, 117.8,
126.3,126.9,127.3,128.1,128.5,129.0,131.3,136.1,139.5,139.6,146.3,
153.1, 156.7, 158.6, 179.9. Mass (ESþ) m/z ¼ 427.0 (Mþ þ 1). Anal.
Calcd for C23H18N6OS (exact mass: 426.1263): C, 64.77; H, 4.25; N,
19.70. Found: C, 64.95; H, 4.47; N, 19.54.
Yield: 55% (0.37 g from 0.45 g) as a yellow solid, mp 167–168 ꢁC.
tR ¼ 14.58 min, nmax (KBr) 1216 (C]S), 3411 (NH). 1H NMR (DMSO-
d6, 300 MHz)
d
¼ 7.16 (d, 2H, J ¼ 7.3 Hz, ArH), 7.32–7.44 (m, 3H,
ArH), 7.49 (d, 2H, J ¼ 7.7 Hz, ArH), 7.77–7.90 (m, 3H, ArH), 8.11 (s,1H,
ArH), 8.48 (s, 1H, ArH), 8.63 (s, 1H, ArH), 9.84 (s, 1H, NH), 9.95 (s, 1H,
4.2.11. N-(3-Chlorophenyl)-N0-[4-(3-methoxyanilino)quinazolin-6-
yl] thiourea (8d)
NH), 9.99 (s, 1H, NH). 13C NMR (DMSO-d6, 50 MHz)
d
¼ 115.5, 118.7,
120.6, 121.6, 123.4, 124.0, 124.6, 125.2, 128.3, 128.9, 130.5, 132.6,
133.1, 137.8, 139.6, 141.3, 148.0, 154.1, 157.6, 180.9. Mass (ESþ) m/
z ¼ 406.1 (Mþ þ 1). Anal. Calcd for C21H16ClN5S (exact mass:
405.0815): C, 62.14; H, 3.97; N, 17.25. Found: C, 62.34; H, 4.01;
N, 16.93.
Yield: 54% (0.44 g from 0.50 g) as an off-white solid, mp 184–
185 ꢁC. tR ¼ 16.06 min, nmax (KBr) 1257 (C]S), 3305 (NH) cmꢂ1
.
1H
NMR (DMSO-d6, 300 MHz)
d
¼ 3.76 (s, 3H, OCH3), 6.70 (d, 1H,
J ¼ 6.6 Hz, ArH), 7.19 (d, 1H, J ¼ 6.5 Hz, ArH), 7.28–7.52 (m, 5H, ArH),
7.68 (s, 1H, ArH), 7.76 (d, 1H, J ¼ 8.1 Hz, ArH), 7.83 (d, 1H, J ¼ 8.1 Hz,
ArH), 8.46 (s, 1H, ArH), 8.57 (s, 1H, ArH), 9.68 (s, 1H, NH), 10.02 (s, 1H,
4.2.16. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-(3-
fluorophenyl)thiourea (9b)
NH), 10.14 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 55.9, 108.9,
109.8, 115.3, 116.1, 119.3, 123.3, 124.5, 125.3, 128.8, 130.1, 130.9, 132.8,
133.4, 137.8, 141.2, 141.8, 148.5, 154.9, 158.3, 160.3, 181.4. Mass (ESþ) m/
z ¼ 436.1 (Mþ þ 1). Anal. Calcd for C22H18ClN5OS (exact mass:
435.0921): C, 60.61; H, 4.16; N,16.07. Found: C, 60.36; H, 4.43; N, 16.25.
Yield: 65% (0.32 g from 0.45 g) as an off-white solid, mp 156–
157 ꢁC. tR ¼ 15.71 min, nmax (KBr) 1217 (C]S), 3455 (NH) cmꢂ1. 1H
NMR (DMSO-d6, 300 MHz)
d
¼ 6.94–6.99 (m, 1H, ArH), 7.16 (dd, 1H,
J1 ¼7.9 Hz, J2 ¼1.2 Hz, ArH), 7.28 (d, 1H, J ¼ 8.4 Hz, ArH), 7.32–7.54
(m, 3H, ArH), 7.77–7.88 (m, 3H, ArH), 8.10 (s, 1H, ArH), 8.48 (s, 1H,
ArH), 8.63 (s, 1H, ArH), 9.83 (s, 1H, NH), 10.08 (s, 1H, NH), 10.13 (s,
4.2.12. N-(4-Chlorophenyl)-N0-[4-(3-methoxyanilino)quinazolin-6-
yl]thiourea (8e)
1H, NH). 13C NMR (DMSO-d6, 50 MHz)
d
¼ 110.7, 111.2, 111.3, 111.7,
Yield: 57% (0.47 g from 0.50 g) as a yellow solid, mp 192–193 ꢁC.
115.5,118.8, 119.9,120.6, 121.7, 123.5, 128.4, 130.3, 130.5, 132.5, 133.1,
137.6, 141.2, 141.4, 141.6, 148.1, 154.2, 157.6, 159.8, 164.6, 180.8. Mass
(ESþ) m/z ¼ 424.0 (Mþ þ 1). Anal. Calcd for C21H15ClFN5S (exact
mass: 423.0721): C, 59.50; H, 3.57; N, 16.52. Found: C, 59.33; H,
3.73; N, 16.75.
tR ¼ 19.27 min, nmax (KBr) 1205 (C]S), 3411 (NH) cmꢂ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
¼ 3.77 (s, 3H, OCH3), 6.70 (dd,1H, J1 ¼8.2 Hz,
J2 ¼ 2.1 Hz, ArH), 7.28 (t, 1H, J ¼ 8.1 Hz, ArH), 7.37 (d, 2H, J ¼ 8.8 Hz,
ArH), 7.49 (d,1H, J ¼ 8.0 Hz, ArH), 7.52–7.60 (m, 3H, ArH), 7.74 (d,1H,
J ¼ 8.9 Hz, ArH), 7.87 (dd,1H, J1 ¼8.8 Hz, J2 ¼ 1.7 Hz, ArH), 8.47 (s,1H,
ArH), 8.57 (s,1H, ArH), 9.67 (s,1H, NH),10.44 (s, 2H, 2 ꢀ NH).13C NMR
4.2.17. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-(3-
cyanophenyl)thiourea (9c)
(DMSO-d6, 50 MHz)
d
¼ 55.4, 108.3, 109.2, 114.7, 115.6, 118.6, 125.6,
125.9,128.1,128.6,128.7,129.6,132.4,137.8,139.0,140.8,147.9,154.3,
157.7, 159.7, 180.9. Mass (ESþ) m/z ¼ 436.1 (Mþ þ 1). Anal. Calcd for
C22H18ClN5OS (exact mass: 435.0921): C, 60.61; H, 4.16; N, 16.07; O,
3.67; S, 7.36. Found: C, 60.54; H, 3.84; N, 16.23.
Yield: 58% (0.46 g from 0.50 g) as a yellow solid, mp > 250 ꢁC.
nmax (KBr) 1216 (C]S), 2234 (CN), 3448 (NH) cmꢂ1 1H NMR
.
(DMSO-d6, 300 MHz)
d
¼ 7.16 (d, 1H, J ¼ 7.9 Hz, ArH), 7.41 (t, 1H,
J ¼ 8.8 Hz, ArH), 7.52–7.60 (m, 2H, ArH), 7.81–7.88 (m, 4H, ArH),
8.05 (s,1H, ArH), 8.10 (s,1H, ArH), 8.49 (s,1H, ArH), 8.64 (s,1H, ArH),
9.85 (s, 1H, NH), 10.20 (s, 1H, NH), 10.32 (s, 1H, NH). Mass (ESþ) m/
z ¼ 431.1 (Mþ þ 1). Anal. Calcd for C22H15ClN6S (exact mass:
430.0767): C, 61.54; H, 3.32; N, 19.78. Found: C, 61.32; H, 3.61;
N, 19.50.
4.2.13. N-(4-Bromophenyl)-N0-[4-(3-methoxyanilino)quinazolin-6-
yl]thiourea (8f)
Yield: 46% (0.25 g from 0.30 g) as a white solid, mp 190–191 ꢁC.
nmax (KBr) 1216 (C]S), 3444 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
300 MHz)
d
¼ 3.77 (s, 3H, OCH3), 6.70 (d, 1H, J ¼ 7.9 Hz, ArH), 7.28 (t,
1H, J ¼ 8.1 Hz, ArH), 7.47–7.54 (m, 6H, ArH), 7.76 (d, 1H, J ¼ 8.9 Hz,
ArH), 7.84 (d, 1H, J ¼ 7.6 Hz, ArH), 8.48 (s, 1H, ArH), 8.58 (s, 1H, ArH),
9.68 (s, 1H, NH), 9.97 (s, 1H, NH), 10.07 (s, 1H, NH). 13C NMR (DMSO-
4.2.18. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-(3-
chlorophenyl)thiourea (9d)
Yield: 53% (0.39 g from 0.45 g) as a yellow solid, mp 190–191 ꢁC.
d6, 75 MHz)
d
¼ 55.6, 108.5, 109.4, 114.8, 115.7, 117.3, 119.0, 126.1,
tR ¼ 15.41 min, nmax (KBr) 1263 (C]S), 3439 (NH) cmꢂ1
.
1H NMR
126.6, 128.4, 129.7,131.7,132.4, 137.5,139.3, 140.9, 148.1,154.4, 157.8,
159.9, 181.0. Mass (ESþ) m/z ¼ 480.0 (Mþ þ 1). Anal. Calcd for
C22H18BrN5OS (exact mass: 479.0415): C, 55.01; H, 3.78; N, 14.58.
Found: C, 55.41; H, 3.43; N, 14.46.
(DMSO-d6, 300 MHz)
d
¼ 7.17 (t, 2H, J ¼ 8.0 Hz, ArH), 7.33–7.43 (m,
3H, ArH), 7.68 (s, 1H, ArH), 7.77–7.87 (m, 3H, ArH), 8.10 (s, 1H, ArH),
8.48 (s, 1H, ArH), 8.63 (s,1H, ArH), 9.84 (s, 1H, NH),10.04 (s, 1H, NH),
10.16 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 116.0, 119.2,

A. Mishra et al. / European Journal of Medicinal Chemistry 44 (2009) 4404–4412
4409
121.0, 122.1, 123.2, 123.9, 124.4, 125.2, 128.9, 130.9, 132.8, 133.3,
133.6, 137.9, 141.7, 154.6, 158.0, 181.4. Mass (ESþ) m/z ¼ 440.0
(Mþ þ 1). Anal. Calcd for C21H15Cl2N5S (exact mass: 439.0425): C,
57.28; H, 3.43; N, 15.90. Found: C, 57.46; H, 3.20; N, 15.86.
7.27–7.55 (m, 4H, ArH), 7.62 (t, 1H, J ¼ 8.0 Hz, ArH), 7.80(d, 1H,
J ¼ 8.9 Hz, ArH), 7.88 (dd, 1H, J1 ¼8.8 Hz, J2 ¼ 1.9 Hz, ArH), 8.24 (d, 1H,
J ¼ 8.1 Hz, ArH), 8.31 (s, 1H, ArH), 8.50 (d, 1H, J ¼ 1.5 Hz, ArH), 8.64 (s,
1H, ArH), 9.97 (s, 1H, NH), 10.09 (s, 1H, NH), 10.14 (s, 1H, NH). 13C NMR
(DMSO-d6, 50 MHz)
d
¼ 110.7,111.2,111.3,111.7,115.5,118.3,118.8,119.9,
4.2.19. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-(4-
chlorophenyl)thiourea (9e)
121.9, 125.8, 127.3, 128.4, 129.3, 130.0, 130.3, 130.5, 132.6, 137.6, 140.5,
141.4, 141.6, 148.1, 154.2, 157.6, 159.8, 164.6, 180.9. Mass (ESþ) m/
z ¼ 458.1 (Mþ þ 1). Anal. Calcd for C22H15F4N5S (exact mass:
457.0984): C, 57.76; H, 3.31; N, 15.31. Found: C, 57.94; H, 3.66; N, 15.05.
Yield: 58% (0.43 g from 0.45 g) as a yellow solid, mp 170–171 ꢁC.
tR ¼ 16.47 min, nmax (KBr) 1188 (C]S), 3303 (NH) cmꢂ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
¼ 7.16 (dd, 1H, J1 ¼7.9 Hz, J2 ¼ 1.1 Hz, ArH),
7.38–7.43 (m, 3H, ArH), 7.53 (d, 2H, J ¼ 8.8 Hz, ArH), 7.77–7.88 (m, 3H,
ArH), 8.11 (s, 1H, ArH), 8.49 (s, 1H, ArH), 8.64 (s, 1H, ArH), 9.84 (s, 1H,
NH), 9.99 (s, 1H, NH), 10.09 (s, 1H, NH). 13C NMR (DMSO-d6, 50 MHz)
4.2.24. N-(3-Cyanophenyl)-N0-{4-[3-
(trifluoromethyl)anilino]quinazolin-6-yl}thiourea (10c)
Yield: 58% (0.44 g from 0.50 g) as a yellow solid, mp 159–160 ꢁC.
d
¼ 114.2, 117.4, 119.2, 120.3,122.1, 124.4, 124.9,127.0, 127.4, 127.8,129.1,
nmax (KBr) 1216 (C]S), 2231 (CN), 3448 (NH) cmꢂ1 1H NMR
.
131.1, 131.8, 136.3, 137.3, 139.9, 146.6, 152.8, 156.2, 179.6. Mass (ESþ) m/
z ¼ 440.0 (Mþ þ 1). Anal. Calcd for C21H15Cl2N5S (exact mass:
439.0425): C, 57.28; H, 3.43; N,15.90. Found: C, 57.03; H, 3.78; N,15.76.
(DMSO-d6, 300 MHz)
d
¼ 7.45 (d, 1H, J ¼ 7.4 Hz, ArH), 7.51–7.65 (m,
3H, ArH), 7.80–7.89 (m, 3H, ArH), 8.00 (s, 1H, ArH), 8.23 (d, 1H,
J ¼ 7.8 Hz, ArH), 8.31 (s, 1H, ArH), 8.51 (s, 1H, ArH), 8.64 (s, 1H, ArH),
9.98 (s, 1H, NH), 10.13 (s, 1H, NH), 10.28 (s, 1H, NH). 13C NMR
4.2.20. N-(4-Bromophenyl)-N0-[4-(3-chloroanilino)quinazolin-6-
yl] thiourea (9f)
(DMSO-d6, 50 MHz)
d
¼ 111.6, 115.6, 118.3, 119.0, 120.2, 122.9, 125.9,
126.5, 127.6, 128.6, 129.4, 129.9, 130.1, 130.2, 132.6, 137.5, 140.6,
140.8, 148.2, 154.3, 157.7, 181.2. Mass (ESþ) m/z ¼ 465.1 (Mþ þ 1).
Anal. Calcd for C23H15F3N6S (exact mass: 464.1031): C, 59.48; H,
3.26; N, 18.09. Found: C, 59.75; H, 3.57; N, 17.86.
Yield: 51% (0.31 g from 0.35 g) as a yellow solid, mp 151–153 ꢁC.
nmax (KBr) 1246 (C]S), 3301 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
300 MHz)
d
¼ 7.16 (d, 1H, J ¼ 7.8 Hz, ArH), 7.38–7.51 (m, 5H, ArH),
7.77–7.84 (m, 3H, ArH), 8.10 (s, 1H, ArH), 8.49 (s, 1H, ArH), 8.63 (s,
1H, ArH), 9.84 (s, 1H, NH), 10.00 (s, 1H, NH), 10.10 (s, 1H, NH). 13C
4.2.25. N-(3-Chlorophenyl)-N0-{4-[3-(trifluoromethyl)anilino]
quinazolin-6-yl}thiourea (10d)
NMR (DMSO-d6, 75 MHz)
d
¼ 115.2, 118.4, 120.2, 121.3, 123.1, 126.1,
128.0, 130.1, 131.3, 132.1, 132.8, 137.2, 138.8, 140.9, 147.7, 153.8, 157.2,
180.6. Mass (ESþ) m/z ¼ 485.9 (Mþ þ 2). Anal. Calcd for
C21H15BrClN5S (exact mass: 482.9920): C, 52.03; H, 3.12; N, 14.45.
Found: C, 52.10; H, 2.83; N, 14.66.
Yield: 47% (0.36 g from 0.50 g) as a white solid, mp 142–143 ꢁC.
tR ¼ 16.48 min, nmax (KBr) 1197 (C]S), 3332 (NH) cmꢂ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
¼ 7.46–7.62 (m, 6H, ArH), 7.79–7.86 (m, 2H,
ArH), 8.23 (d, 1H, J ¼ 6.4 Hz, ArH), 8.31 (s, 1H, ArH), 8.51 (s, 1H, ArH),
8.65 (s, 1H, ArH), 10.01 (s, 1H, NH), 10.11 (s, 1H, NH), 10.21 (s, 1H,
4.2.21. N-[4-(3-Chloroanilino)quinazolin-6-yl]-N0-(2-
naphthyl)thiourea (9g)
NH). 13C NMR (DMSO-d6, 50 MHz)
d
¼ 116.0, 118.7, 118.8, 119.3,
120.4, 122.4, 126.2, 126.7, 127.8, 129.0, 129.2, 129.6, 129.8, 130.5,
133.1, 138.2, 139.2, 141.1, 148.6, 154.6, 158.1. Mass (ESþ) m/z ¼ 474.1
(Mþ þ 1). Anal. Calcd for C22H15ClF3N5S (exact mass: 473.0689): C,
55.76; H, 3.19; N, 14.78. Found: C, 55.95; H, 3.33; N, 14.94.
Yield: 52% (0.35 g from 0.40 g) as an off-white solid, mp 129–
130 ꢁC. tR ¼ 16.55 min, nmax (KBr) 1216 (C]S), 3419 (NH) cmꢂ1. 1H
NMR (DMSO-d6, 300 MHz)
d
¼ 7.15 (d, 1H, J ¼ 7.7 Hz, ArH), 7.40 (t,
1H, J ¼ 8.1 Hz, ArH), 7.51–7.61 (m, 4H, ArH), 7.76 (d, 1H, J ¼ 8.8 Hz,
ArH), 7.85 (t, 2H, J ¼ 6.3 Hz, ArH), 7.95 (t, 2H, J ¼ 7.0 Hz, ArH), 8.03
(d,1H, J ¼ 8.1 Hz, ArH), 8.11 (s,1H, ArH), 8.47 (s, 1H, ArH), 8.62 (s,1H,
ArH), 9.84 (s, 1H, NH), 9.95 (s, 1H, NH), 10.06 (s, 1H, NH). 13C NMR
4.2.26. N-(4-Chlorophenyl)-N0-{4-[3-(trifluoromethyl)
anilino]quinazolin-6-yl}thiourea (10e)
Yield: 51% (0.36 g from 0.45 g) as a yellow solid, mp 179–181 ꢁC.
(DMSO-d6, 75 MHz)
d
¼ 115.8,119.4,120.9, 122.0, 123.8, 123.9, 126.3,
tR ¼ 17.31 min, nmax (KBr) 1178 (C]S), 3306 (NH) cmꢂ1
.
1H NMR
126.5, 126.9, 127.0, 127.8, 128.5, 128.9, 130.7, 130.9, 133.4, 133.5,
134.7, 135.7, 138.4, 154.5, 158.0, 182.8. Mass (ESþ) m/z ¼ 456.1
(Mþ þ 1). Anal. Calcd for C25H18ClN5S (exact mass: 455.0971): C,
65.85; H, 3.98; N, 15.36. Found: C, 65.63; H, 4.25; N, 15.15.
(DMSO-d6, 300 MHz)
d
¼ 7.38–7.46 (m, 3H, ArH), 7.52 (d, 2H,
J ¼ 8.8 Hz, ArH), 7.62 (t, 1H, J ¼ 8.0 Hz, ArH), 7.80 (d, 1H, J ¼ 8.9 Hz,
ArH), 7.86 (dd, 1H, J1 ¼8.9 Hz, J2 ¼ 1.8 Hz, ArH), 8.23 (d, 1H,
J ¼ 8.1 Hz, ArH), 8.32 (s, 1H, ArH), 8.51 (d, 1H, J ¼ 1.5 Hz, ArH), 8.64
(s, 1H, ArH), 10.00 (s, 1H, NH), 10.04 (s, 1H, NH), 10.14 (s, 1H, NH). 13C
4.2.22. N-Phenyl-N0-{4-[3-(trifluoromethyl)anilino]quinazolin-6-
yl}thiourea (10a)
NMR (DMSO-d6, 50 MHz)
d
¼ 116.0, 118.7, 118.8, 119.3, 120.4, 122.4,
126.2, 126.7, 127.8, 129.0, 129.2, 129.6, 129.8, 130.5, 133.1, 138.2,
139.2, 141.1, 148.6, 154.6, 158.1. Mass (ESþ) m/z ¼ 474.0 (Mþ þ 1).
Anal. Calcd for C22H15ClF3N5S (exact mass: 473.0689): C, 55.76; H,
3.19; N, 14.78. Found: C, 55.65; H, 3.36; N, 14.96.
Yield: 53% (0.19 g from 0.25 g) as a yellow solid, mp 182–183 ꢁC.
nmax (KBr) 1216 (C]S), 3428 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
300 MHz)
d
¼ 7.15 (t, 1H, J ¼ 7.2 Hz, ArH), 7.34 (t, 2H, J ¼ 7.5 Hz, ArH),
7.43–7.50 (m, 3H, ArH), 7.62 (t, 1H, J ¼ 7.7 Hz, ArH), 7.79 (d, 1H,
J ¼ 8.7 Hz, ArH), 7.88 (d, 1H, J ¼ 8.8 Hz, ArH), 8.24 (d, 1H, J ¼ 7.7 Hz,
ArH), 8.32 (s, 1H, ArH), 8.50 (s, 1H, ArH), 8.64 (s, 1H, ArH), 9.98 (s, 2H,
4.2.27. N-(4-Bromophenyl)-N0-{4-[3-(trifluoromethyl)
anilino]quinazolin-6-yl}thiourea (10f)
2 ꢀ NH), 10.02 (s, 1H, NH). 13C NMR (DMSO-d6, 50 MHz)
d
¼ 115.9,
Yield: 56% (0.43 g from 0.45 g) as a white solid, mp 142–143 ꢁC.
118.7, 119.1, 120.4, 125.0, 125.6, 126.2, 128.8, 129.3, 129.8, 130.5, 133.1,
138.3, 140.1, 141.0, 154.5, 158.0, 181.3. Mass (ESþ) m/z ¼ 440.1
(Mþ þ 1). Anal. Calcd for C22H16F3N5S (exact mass: 439.1078): C,
60.13; H, 3.67; N, 15.94. Found: C, 59.93; H, 3.48; N, 16.25.
tR ¼ 16.52 min, nmax (KBr) 1197 (C]S), 3332 (NH) cmꢂ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
¼ 7.46–7.51 (m, 5H, ArH), 7.61 (d, 1H,
J ¼ 7.2 Hz, ArH), 7.81 (s, 1H, ArH), 7.86 (s, 1H, ArH), 8.23 (d, 1H,
J ¼ 6.5 Hz, ArH), 8.32 (s, 1H, ArH), 8.51 (s, 1H, ArH), 8.65 (s, 1H, ArH),
9.98 (s,1H, NH),10.01 (s,1H, NH),10.10 (s,1H, NH). 13C NMR (DMSO-
4.2.23. N-(3-Fluorophenyl)-N0-{4-[3-(trifluoromethyl)
anilino]quinazolin-6-yl}thiourea (10b)
d6, 50 MHz)
d
¼ 116.0, 117.8, 118.8, 119.3, 120.4, 120.6, 126.3, 126.5,
127.0, 129.0, 130.5, 132.2, 133.1, 138.2, 139.7, 141.1, 148.5, 154.6, 158.1,
181.5. Mass (ESþ) m/z ¼ 519.9 (Mþ þ 2). Anal. Calcd for
C22H15BrF3N5S (exact mass: 517.0184): C, 50.98; H, 2.92; N, 13.51.
Found: C, 50.67; H, 2.83; N, 13.73.
Yield: 55% (0.37 g from 0.45 g) as a white solid, mp 139–140 ꢁC.
tR ¼ 16.36 min, nmax (KBr) 1216 (C]S), 3406 (NH) cmꢂ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
¼ 6.97 (dt, 1H, J1 ¼8.0 Hz, J2 ¼1.9 Hz, ArH),

4410
A. Mishra et al. / European Journal of Medicinal Chemistry 44 (2009) 4404–4412
4.2.28. N-{4-[3-(Trifluoromethyl)anilino]quinazolin-6-yl}-N0-(2-
naphthyl)thiourea (10g)
300 MHz)
d
¼ 3.76 (s, 6H, 2 ꢀ OCH3), 6.96 (d, 1H, J ¼ 7.5 Hz, ArH),
7.41–7.43 (m, 4H, ArH), 7.53 (d, 2H, J ¼ 7.9 Hz, ArH), 7.70–7.82 (m,
Yield: 61% (0.39 g from 0.40 g) as a white solid, mp 167–168 ꢁC.
2H, ArH), 8.44 (s, 1H, ArH), 8.51 (s, 1H, ArH), 9.62 (s, 1H, NH), 9.98 (s,
nmax (KBr) 1164 (C]S), 3401 (NH) cmꢂ1
.
1H NMR (DMSO-d6,
1H, NH), 10.06 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 56.4,
300 MHz)
d
¼ 7.45 (d, 1H, J ¼ 7.6 Hz, ArH), 7.51–7.65 (m, 5H, ArH),
56.7, 108.6, 112.7, 115.6, 116.0, 119.5, 126.7, 128.8, 129.2, 129.6, 132.7,
133.4, 137.8, 139.3, 146.3, 148.4, 149.3, 155.1, 158.3, 181.5. Mass (ESþ)
m/z ¼ 466 0 (Mþ þ 1). Anal. Calcd for C23H20ClN5O2S (exact mass:
465.1026): C, 59.29; H, 4.33; N, 15.03. Found: C, 59.18; H, 4.45;
N, 14.95.
7.78 (d, 1H, J ¼ 8.9 Hz, ArH), 7.86–7.88 (m, 1H, ArH), 7.93–7.97 (m,
2H, ArH), 8.04 (d, 1H, J ¼ 8.0 Hz, ArH), 8.24 (d, 1H, J ¼ 8.2 Hz, ArH),
8.32 (s, 1H, ArH), 8.49 (s, 1H, ArH), 8.63 (s, 1H, ArH), 9.98 (s, 1H, NH),
9.99 (s, 1H, NH), 10.09 (s, 1H, NH). 13C NMR (DMSO-d6, 50 MHz)
d
¼ 115.9, 118.7, 119.5, 120.4, 124.0, 126.2, 126.4, 126.6, 127.1, 127.9,
128.7, 129.0, 129.8, 130.5, 130.9, 133.5, 134.8, 135.8, 138.6, 141.1,
148.6, 154.6, 158.1, 182.9. Mass (ESþ) m/z ¼ 490.1 (Mþ þ 1). Anal.
Calcd for C26H18F3N5S (exact mass: 489.1235): C, 63.79; H, 3.71; N,
14.31. Found: C, 64.09; H, 3.95; N, 14.02.
4.2.33. N-(4-Chlorophenyl)-N0-[4-(3,4-dimethoxyanilino)
quinazolin-6-yl]thiourea (11e)
Yield: 45% (0.70 g from 1.00 g) as a brown solid, mp 177–
178 ꢁC. tR ¼ 16.79 min, nmax (KBr) 1247 (C]S), 3448 (NH) cmꢂ1. 1H
NMR (DMSO-d6, 300 MHz)
d
¼ 3.75 (s, 3H, OCH3), 3.76 (s, 3H,
4.2.29. N-[4-(3,4-Dimethoxyanilino)quinazolin-6-yl]-N0-
phenylthiourea (11a)
OCH3), 6.96 (d, 1H, J ¼ 8.6 Hz, ArH), 7.38–7.43 (m, 4H, ArH), 7.52
(d, 2H, J ¼ 8.8 Hz, ArH), 7.73 (d, 1H, J ¼ 8.8 Hz, ArH), 7.80 (dd, 1H,
J1 ¼8.9 Hz, J2 ¼1.6 Hz, ArH), 8.43 (s, 1H, ArH), 8.51 (s, 1H, ArH),
9.63 (s, 1H, NH), 9.99 (s, 1H, NH), 10.07 (s, 1H, NH). 13C NMR
Yield: 57% (0.33 g from 0.40 g) as a yellow solid, mp 169–170 ꢁC.
tR ¼ 15.54 min, nmax (KBr) 1217 (C]S), 3401 (NH) cmꢂ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
¼ 3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 6.97
(DMSO-d6, 75 MHz)
d
¼ 56.4, 56.7, 108.6, 112.7, 115.6, 119.4, 126.7,
(d, 1H, J ¼ 8.6 Hz, ArH), 7.15 (t, 1H, J ¼ 7.2 Hz, ArH), 7.35 (t, 2H,
J ¼ 7.6 Hz, ArH), 7.41–7.51 (m, 4H, ArH), 7.73 (d, 1H, J ¼ 8.8 Hz, ArH),
7.84 (d, 1H, J ¼ 8.5 Hz, ArH), 8.45 (s, 1H, ArH), 8.52 (s, 1H, ArH), 9.64
(s, 1H, NH), 9.96 (s, 1H, NH), 9.98 (s, 1H, NH). 13C NMR (DMSO-d6,
128.7, 129.2, 129.6, 137.8, 139.2, 146.3, 149.3, 158.4, 181.5. Mass
(ESþ) m/z ¼ 466 0 (Mþ þ 1). Anal. Calcd for C23H20ClN5O2S (exact
mass: 465.1026): C, 59.29; H, 4.33; N, 15.03. Found: C, 59.65; H,
4.14; N, 15.12.
50 MHz)
d
¼ 56.4, 56.7, 108.5, 112.7, 115.5, 116.0, 119.4, 124.6, 125.1,
125.7, 128.7, 129.4, 132.8, 133.4, 138.0, 140.2, 146.3, 148.4, 149.3,
155.0, 158.3, 181.4. Mass (ESþ) m/z ¼ 432.1 (Mþ þ 1). Anal. Calcd for
C23H21N5O2S (exact mass: 431.1416): C, 64.02; H, 4.91; N, 16.23.
Found: C, 64.23; H, 4.63; N, 16.54.
4.2.34. N-(4-Bromophenyl)-N0-[4-(3,4-dimethoxyanilino)
quinazolin-6-yl]thiourea (11f)
Yield: 45% (0.39 g from 0.50 g) as a brown solid, mp 177–178 ꢁC.
tR ¼ 16.79 min, nmax (KBr) 1216 (C]S), 3423 (NH) cmꢂ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
¼ 3.75 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 6.97
4.2.30. N-(3-Fluorophenyl)-N0-[4-(3,4-dimethoxyanilino)
quinazolin-6-yl]thiourea (11b)
(d, 1H, J ¼ 8.6 Hz, ArH), 7.40–7.51 (m, 6H, ArH), 7.72 (d, 1H,
J ¼ 8.8 Hz, ArH), 7.81 (d, 1H, J ¼ 8.6 Hz, ArH), 8.44 (s, 1H, ArH), 8.51
(s, 1H, ArH), 9.63 (s, 1H, NH), 10.19 (s, 1H, NH), 10.22 (s, 1H, NH). 13C
Yield: 55% (0.42 g from 0.50 g) as a yellow solid, mp 125–126 ꢁC.
tR ¼ 16.96 min, nmax (KBr) 1236 (C]S), 3677 (NH) cmꢂ1
.
1H NMR
NMR (DMSO-d6, 75 MHz)
d
¼ 56.0, 56.2, 108.0, 112.2, 115.1, 115.6,
(DMSO-d6, 300 MHz)
d
¼ 3.75 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 6.96
117.0, 118.8, 126.2, 128.2, 131.6, 132.3, 133.1, 137.6, 139.5, 145.8, 147.9,
148.8, 154.6, 157.9, 180.8. Mass (ESþ) m/z ¼ 512 0 (Mþ þ 2). Anal.
Calcd for C23H20BrN5O2S (exact mass: 509.0521): C, 54.12; H, 3.95;
N, 13.72. Found: C, 54.08; H, 3.91; N, 13.68.
(d, 2H, J ¼ 8.4 Hz, ArH), 7.27–7.44 (m, 4H, ArH), 7.54 (d, 1H,
J ¼ 11.3 Hz, ArH), 7.73 (d, 1H, J ¼ 8.8 Hz, ArH), 7.81 (d, 1H, J ¼ 8.8 Hz,
ArH), 8.43 (s, 1H, ArH), 8.51 (s, 1H, NH), 9.62 (s, 1H, NH), 10.14 (br s,
2H, 2 ꢀ NH). 13C NMR (DMSO-d6, 50 MHz)
d
¼ 56.4, 56.6, 108.5,
111.2, 111.5, 111.8, 112.0, 112.6, 115.5, 116.0, 119.4, 120.3, 128.7, 130.8,
130.9,132.7,133.3,137.7,142.0,146.3,148.4,149.2,155.1,158.3,161.0,
164.2, 173.2, 181.3. Mass (ESþ) m/z ¼ 450.1 (Mþ þ 1). Anal. Calcd for
C23H20FN5O2S (exact mass: 449.1322): C, 61.46; H, 4.48; N, 15.58.
Found: C, 61.35; H, 4.67; N, 15.67.
4.2.35. N-[4-(3,4-Dimethoxyanilino)quinazolin-6-yl]-N0-(2-
naphthyl)thiourea (11g)
Yield: 53% (0.43 g from 0.50 g) as a yellow solid, mp 129–130 ꢁC.
nmax (KBr) 1231 (C]S), 3449 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
300 MHz)
d
¼ 3.76 (s, 6H, 2 ꢀ OCH3), 6.96 (d, 1H, J ¼ 8.1, Hz, ArH),
7.40–7.72 (m, 7H, ArH), 7.87–8.05 (m, 4H, ArH), 8.43 (s, 1H, ArH),
8.50 (s, 1H, ArH), 9.62 (s, 1H, NH), 9.93 (s, 1H, NH), 10.04 (s, 1H, NH).
4.2.31. N-(3-Cyanophenyl)-N0-[4-(3,4-dimethoxyanilino)
quinazolin-6-yl]thiourea (11c)
13C NMR (DMSO-d6, 75 MHz)
d
¼ 56.0, 56.2, 108.0, 112.2, 115.0,
Yield: 56% (0.33 g from 0.38 g) as a yellow solid, mp 178–179 ꢁC.
115.5, 123.6, 126.0, 126.2, 126.6, 127.4, 128.6, 134.4, 135.4, 147.9,
148.9, 157.9, 163.4. Mass (ESþ) m/z ¼ 482.1 (Mþ þ 1). Anal. Calcd for
C27H23N5O2S (exact mass: 481.1572): C, 67.34; H, 4.81; N, 14.54.
Found: C, 67.68; H, 5.14; N, 14.62.
nmax (KBr) 1216 (C]S), 2234 (CN), 3422 (NH) cmꢂ1 1H NMR
.
(DMSO-d6, 300 MHz)
d
¼ 3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 6.96
(d, 1H, J ¼ 8.7 Hz, ArH), 7.37 (dd, 1H, J1 ¼8.7 Hz, J2 ¼ 2.3 Hz, ArH),
7.41–7.44 (m, 2H, ArH), 7.50 (t, 1H, J ¼ 7.9 Hz, ArH), 7.71 (d, 2H,
J ¼ 8.8 Hz, ArH), 7.83 (dd, 1H, J1 ¼8.9 Hz, J2 ¼1.8 Hz, ArH), 8.04 (s,
1H, ArH), 8.44 (s, 1H, ArH), 8.47 (d, 1H, J ¼ 1.7 Hz, ArH), 9.13 (s, 1H,
NH), 9.27 (s, 1H, NH), 9.58 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
4.2.36. N-[4-(4-Methoxyanilino)quinazolin-6-yl]-N0-
phenylthiourea (12a)
Yield: 61% (0.65 g from 0.70 g) as a yellow solid, mp 170–171 ꢁC.
d
¼ 56.4, 56.6, 108.7, 111.7, 112.5, 115.8, 116.4, 119.8, 121.8, 123.9,
tR ¼ 13.73 min, nmax (KBr) 1216 (C]S), 3621 (NH) cmꢂ1
.
1H NMR
126.3, 127.4, 129.1, 131.1, 133.5, 137.9, 141.5, 146.2, 146.6, 149.2, 153.5,
153.9, 158.3. Mass (ESþ) m/z ¼ 457.1 (Mþ þ 1). Anal. Calcd for
C24H20N6O2S (exact mass: 456.1368): C, 63.14; H, 4.42; N, 18.41.
Found: C, 63.45; H, 4.23; N, 18.22.
(DMSO-d6, 300 MHz)
d
¼ 3.77 (s, 3H, OCH3), 6.97 (d, 2H, J ¼ 8.9 Hz,
ArH), 7.15 (t, 1H, J ¼ 7.3 Hz, ArH), 7.35 (t, 2H, J ¼ 7.8 Hz, ArH), 7.49 (d,
2H, J ¼ 7.6 Hz, ArH), 7.67–7.74 (m, 3H, ArH), 7.83 (d, 1H, J ¼ 8.8 Hz,
ArH), 8.43 (s, 1H, ArH), 8.49 (s, 1H, ArH), 9.68 (s, 1H, NH), 9.94 (s, 1H,
NH), 9.98 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 56.0, 114.5,
4.2.32. N-(3-Chlorophenyl)-N0-[4-(3,4-dimethoxyanilino)
quinazolin-6-yl]thiourea (11d)
115.8, 119.2, 124.8, 125.0, 125.6, 128.5, 129.3, 132.6, 132.8, 137.8,
140.1, 148.3, 155.0, 156.6, 158.3, 181.3. Mass (ESþ) m/z ¼ 402.1
(Mþ þ 1). Anal. Calcd for C22H19N5OS (exact mass: 401.1310): C,
65.81; H, 4.77; N, 17.44. Found: C, 65.74; H, 4.68; N, 17.73.
Yield: 45% (0.70 g from 1.00 g) as a yellow solid, mp 176–178 ꢁC.
nmax (KBr) 1270 (C]S), 3439 (NH) cmꢂ1 1H NMR (DMSO-d6,
.

A. Mishra et al. / European Journal of Medicinal Chemistry 44 (2009) 4404–4412
4411
4.2.37. N-(3-Fluorophenyl)-N0-[4-(4-methoxyanilino)quinazolin-6-
yl]thiourea (12b)
mass: 479.0415): C, 55.01; H, 3.78; N, 14.58. Found: C, 55.34; H,
3.96; N, 14.37.
Yield: 52% (0.55 g from 0.67 g) as a white solid, mp 132–133 ꢁC.
tR ¼ 14.60 min, nmax (KBr) 1244 (C]S), 3196 (NH) cmꢂ1
.
1H NMR
4.2.42. N-[4-(4-Methoxyanilino)quinazolin-6-yl]-N0-(2-
naphthyl)thiourea (12g)
(DMSO-d6, 300 MHz)
d
¼ 3.77 (s, 3H, OCH3), 6.97 (d, 3H, J ¼ 8.5 Hz,
ArH), 7.27–7.39 (m, 2H, ArH), 7.54 (d, 1H, J ¼ 10.7 Hz, ArH), 7.67–
7.83 (m, 4H, ArH), 8.44 (s, 1H, ArH), 8.49 (s, 1H, ArH), 9.66 (s, 1H,
NH), 10.04 (s, 1H, NH), 10.10 (s, 1H, NH). 13C NMR (DMSO-d6,
Yield: 54% (0.65 g from 0.70 g) as an off-white solid, mp 109–
110 ꢁC. nmax (KBr) 1219 (C]S), 3404 (NH) cmꢂ1. 1H NMR (DMSO-d6,
300 MHz)
d
¼ 3.76 (s, 3H, OCH3), 6.96 (d, 2H, J ¼ 9.0 Hz, ArH), 7.51–
75 MHz)
d
¼ 56.0, 111.2, 111.5, 112.0, 114.5, 115.9, 119.4, 119.6, 120.3,
7.61 (m, 3H, ArH), 7.67–7.72 (m, 3H, ArH), 7.88 (dd, 2H, J1 ¼9.2 Hz,
J2 ¼ 2.3 Hz, ArH), 7.96 (d, 2H, J ¼ 8.7 Hz, ArH), 8.03 (d, 1H, J ¼ 8.0 Hz,
ArH), 8.43 (s, 1H, ArH), 8.47 (s, 1H, ArH), 9.65 (s, 1H, NH), 9.90 (s, 1H,
125.1, 128.7, 130.7, 130.8, 132.6, 132.8, 137.6, 141.9, 142.1, 148.3, 155.1,
156.7, 158.4, 181.3. Mass (ESþ) m/z ¼ 420.1 (Mþ þ 1). Anal. Calcd for
C22H18FN5OS (exact mass: 419.1216): C, 62.99; H, 4.33; N, 16.70.
Found: C, 62.76; H, 4.64; N, 16.58.
NH), 10.02 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 56.0, 114.4,
115.8, 119.6, 123.9, 124.9, 126.3, 126.4, 126.9, 127.0, 127.7, 128.4,
128.9, 130.8, 132.9, 133.0, 134.7, 135.8, 138.0, 148.3, 154.9, 156.5,
158.3, 163.1, 182.8. Mass (ESþ) m/z ¼ 452.1 (Mþ þ 1). Anal. Calcd for
C26H21N5OS (exact mass: 451.1467): C, 69.16; H, 4.69; N, 15.51.
Found: C, 69.34; H, 4.43; N, 15.74.
4.2.38. N-(3-Cyanophenyl)-N0-[4-(4-methoxyanilino)quinazolin-6-
yl]thiourea (12c)
Yield: 58% (0.46 g from 0.50 g) as a yellow solid, mp 145–147 ꢁC.
nmax (KBr) 1248 (C]S), 2234 (CN), 3324 (NH) cmꢂ1.1H NMR (DMSO-d6,
300 MHz)
d
¼ 3.73 (s, 3H, OCH3), 6.94 (d, 2H, J ¼ 8.9 Hz, ArH), 7.48–7.57
5. Materials and methods
(m, 4H, ArH), 7.70–7.75 (m, 2H, ArH), 7.82 (d, 1H, J ¼ 8.6 Hz, ArH), 7.94
(s,1H, ArH), 8.33 (s,1H, ArH), 8.41 (s,1H, ArH), 9.71 (s,1H, NH),10.11 (s,
5.1. In vitro antimalarial assay
1H, NH),10.19 (s,1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 56.6,112.4,
115.2, 116.3, 119.6, 120.0, 126.2, 128.6, 128.9, 129.7, 130.4, 131.2, 132.8,
138.1, 141.6, 148.3, 155.6, 157.5, 159.2, 182.1. Mass (ESþ) m/z ¼ 427.1
(Mþ þ 1). Anal. Calcd for C23H18N6OS (exact mass: 426.1263): C, 64.77;
H, 4.25; N, 19.70. Found: C, 64.86; H, 4.53; N, 19.57.
The in vitro antimalarial activity of the compounds was assessed
against CQ-sensitive 3D7 strain of P. falciparum and compared with
that of chloroquine. Both schizontocidal activities (MIC) and 50%
inhibitory concentration (IC50) were obtained as per the methods
mentioned by us earlier.
4.2.39. N-(3-Chlorophenyl)-N0-[4-(4-methoxyanilino)quinazolin-6-
yl]thiourea (12d)
5.2. Cytotoxicity assay
Yield: 54% (0.63 g from 1.14 g) as a yellow solid, mp 138–139 ꢁC.
nmax (KBr) 1249 (C]S), 3314 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
Cytotoxicity of the compounds was carried out using Vero cell
line (C1008; Monkey kidney fibroblast) and MTT was used as
reagent for the detection of cytotoxicity as mentioned earlier [1].
50% cytotoxic concentration (CC50) values represented the concen-
tration of compound required to kill 50% of the fibroblast cells.
300 MHz)
d
¼ 3.76 (s, 3H, OCH3), 6.96 (d, 2H, J ¼ 8.3 Hz, ArH), 7.18 (d,
1H, J ¼ 7.3 Hz, ArH), 7.33–7.40 (m, 2H, ArH), 7.66–7.81 (m, 5H, ArH),
8.43 (s, 1H, ArH), 8.48 (s, 1H, ArH), 9.66 (s, 1H, NH), 10.02 (s, 1H, NH),
10.15 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 56.1, 114.5, 115.9,
119.4, 123.3, 124.4, 125.1, 128.8, 130.8, 132.5, 132.8, 133.3, 137.5, 141.8,
148.4, 155.1, 156.7, 158.4, 181.3. Mass (ESþ) m/z ¼ 436.1 (Mþ þ 1).
Anal. Calcd for C22H18ClN5OS (exact mass: 435.0921): C, 60.61; H,
4.16; N, 16.07. Found: C, 60.96; H, 4.34; N, 15.79.
CC50
IC50
SI ¼
:
5.3. In vivo antimalarial assay
4.2.40. N-(4-Chlorophenyl)-N0-[4-(4-methoxyanilino)quinazolin-6-
yl]thiourea (12e)
Swiss mice (25 ꢃ1 g) of either sex were inoculated with 1 ꢀ106
P. yoelii nigeriensis MDR/P. yoelii N67 chloroquine resistant parasit-
ized cells on day zero. A group of five mice was administered
aqueous suspension of the test compounds at 50 mg/kg or 100 mg/
kg dose from day 0 to 4 via oral route; while another five mice were
administered the vehicle alone. Thin blood smears from the tail vein
of treated as well as control mice were observed on day 4, 7, 14, 21
and 28 to record the degree of parasitaemia till 28 days or until
animals survived.
Yield: 56% (0.64 g from 0.70 g) as a yellow solid, mp 189–190 ꢁC.
nmax (KBr) 1244 (C]S), 3317 (NH) cmꢂ1 1H NMR (DMSO-d6,
.
200 MHz)
d
¼ 3.76 (s, 3H, OCH3), 6.96 (d, 2H, J ¼ 8.3 Hz, ArH), 7.35–
7.41 (m, 2H, ArH), 7.47–7.55 (m, 2H, ArH), 7.65–7.83 (m, 4H, ArH),
8.43 (s, 1H, ArH), 8.48 (s, 1H, ArH), 9.67 (s, 1H, NH), 9.97 (s, 1H, NH),
10.07 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
d
¼ 56.4, 108.6,
112.7, 115.6, 116.0, 119.5, 126.7, 128.8, 129.2, 129.6, 132.7, 133.4,
137.8, 139.3, 146.3, 148.4, 149.3, 155.1, 158.3, 181.5. Mass (ESþ) m/
z ¼ 436.1 (Mþ þ 1). Anal. Calcd for C22H18ClN5OS (exact mass:
435.0921): C, 60.61; H, 4.16; N, 16.07. Found: C, 60.96; H, 4.34; N,
15.79.
Acknowledgments
One of the authors (A.M.) acknowledges the financial support
from CSIR, New Delhi in the form of fellowship. This work was
supported by supra-institutional grant on anti-infectious diseases
to this institute.
4.2.41. N-(4-Bromophenyl)-N0-[4-(4-methoxyanilino)quinazolin-6-
yl]thiourea (12f)
Yield: 57% (0.72 g from 0.70 g) as a yellow solid; mp 159–161 ꢁC.
tR ¼ 17.26 min, nmax (KBr) 1242 (C]S), 3347 (NH) cmꢂ1
.
1H NMR
(DMSO-d6, 300 MHz)
d
¼ 3.76 (s, 3H, OCH3), 6.96 (d, 2H, J ¼ 8.8 Hz,
References
ArH), 7.45–7.53 (m, 4H, ArH), 7.65–7.73 (m, 3H, ArH), 7.81 (d, 1H,
J ¼ 8.2 Hz, ArH), 8.42 (s, 1H, ArH), 8.48 (s, 1H, ArH), 9.68 (s, 1H, NH),
9.96 (s, 1H, NH), 10.05 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz)
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