A Series of 2,4(1H,3H)-Quinazolinedione derivatives: Synthesis and biological evaluation as potential anticancer agents

Article abstract of DOI:10.2174/1570180812666150529204909

A series of 6,7-disubstituted-3-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}quinazoline- 2,4(1H,3H)-dione derivatives (7-34) were synthesized and their structures were elucidated on the basis of analytical and spectral (UV, IR, ¹H-NMR, ¹

Full text of DOI:10.2174/1570180812666150529204909

Send Orders for Reprints to reprints@benthamscience.ae
64
Letters in Drug Design & Discovery, 2016, 13, 64-76
A Series of 2,4(1H,3H)-Quinazolinedione Derivatives: Synthesis and Bio-
logical Evaluation as Potential Anticancer Agents
Hulya Akguna,*, Demet Us Yilmaza, Rengul Cetin Atalayb, and Damla Gozenb
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, 34755, Kayis-
dagi, Istanbul, Turkey
bDepartment of Molecular Biology and Genetics, BilGen, Genetics and Biotechnology Research Cen-
ter, Faculty of Science, Bilkent University, 06800, Bilkent, Ankara, Turkey
Abstract: A series of 6,7-disubstituted-3-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}quinazoline-
2,4(1H,3H)-dione derivatives (7-34) were synthesized and their structures were elucidated on the basis
1
of analytical and spectral (UV, IR, H-NMR, 13C-NMR and MS) data. These synthesized compounds
were evaluated for their in vitro cytotoxicities against a panel of three human cancer cell lines. Ac-
cording to the cytotoxicity screening results, 3-{2-[4-(4-chlorobenzyl)piperazin-1-yl]-2-oxoethyl}
quinazoline-2,4(1H,3H)-dione (7) presented the highest activity against HUH-7, MCF-7 and HCT-116
cell line with the IC50 values of 2.5, 6.8 and 4.9 µM, respectively.
Keywords: Quinazoline, quinazoline-2,4(1H,3H)-dione, piperazine, cytotoxicity, anticancer, sulforhodamine B method.
1. INTRODUCTION
quinazolinedione derivatives were recently submitted to NCI
antitumor screening program. Four of them (1, Fig. 2) sig-
nificantly inhibited growth of 60 human tumor cell in vitro
with IC50 values ranging from 0.4 to 0.8 µM [7]. 3-
Substituted-2,4-quinazolinedione derivative (2, Fig. 2) was
patented for its cytotoxicity with IC50 value below than 10
nM againts human ovarian cancer (SKOV3) cell line [8].
Cancer is one of the potentially fatal diseases, which is
characterized by uncontrolled division of a group of cells
leading to metastasis and invasion to adjacent tissues. Al-
though many chemotherapeutic agents are in clinical use,
synthesizing new anticancer agents with less side effect and
increased selectivity is still ongoing area of interest in me-
dicinal chemistry. Since the discovery of gefitinib (Fig. 1),
quinazolines has attracted considerable attention in the de-
sign of new chemotherapeutic agents. Some 4-
anilinoquinazolines (erlotinib, vandetanib, lapatinib, afatinib
and trimetrexate) and 4-quinazolinone derivative (raltitrexed)
(Fig. 1) have been introduced into clinical use for the treat-
ment of several types of cancer. It was reported that, quina-
zolines which act as adenosine triphosphate (ATP)-mimic
compounds show their tyrosine kinase enzyme inhibition
activities by occupying the ATP-binding pocket with high
affinity [1-4]. Quinazolines may also exhibit their anticancer
activity by both p53 modulation and thyroid-stimulating
hormone receptor (TSHR) agonistic activity [5, 6].
On the other hand, a comprehensive literature study
shows that piperazines are a significant class of heterocyclic
compound with their various biological properties (Fig. 3),
especially potential antitumour activity. Tahmatzopoulos et
al. reported that the doxazosin and terazosin, α1-
adrenoceptor antagonists, could generate apoptosis in benign
and malignant prostate cells, also decrease tumor vascularity
in prostate tumors and suppress prostate tumorigenic growth
in vivo [59].
In the light of these observations, with the aim of discov-
ering new anticancer agents, a series of 6,7-disubstituted-
3-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}quinazoline-
2,4(1H,3H)-dione derivatives were synthesized (Fig. 4) and
their in vitro cytotoxicities were evaluated against three hu-
man cancer cell lines, hepatoma (HUH-7), breast cancer
(MCF-7) and colorectal cancer (HCT-116) by using Sulfor-
hodamine B test.
Various literatures report numerous 2,4(1H,3H)-
quinazolinedione analogues showing a wide variety of bio-
logical activities such as anticancer [7-20], antimicrobial
[21-37], antihypertensive [38-40], anticonvulsant [41-49],
anti-inflammatory [50], 5-hydroxytryptamine 3 (5-HT3) re-
ceptor antagonist [51], phosphodiesterase (PDE) 4 inhibition
[52,53], calcium-independent phosphodiesterase enzyme
inhibition (CaIPDE) [54], cyclin-dependent kinase 5 (CDK5)
inhibition [55], 5-HT3A receptor antagonist [56], antioxidant
[57] and antiplatelet [58]. Some 3,6,7-trisubstituted-2,4-
2. RESULTS AND DISCUSSION
2.1. Chemistry
The synthetic routes for 3-substituted-2,4(1H,3H)-
quinazolinedione derivatives are summarized in Scheme (1).
Synthesis of 2,4(1H,3H)-quinazolinedione ring deriva-
tives started with the nucleophilic addition reaction of the 2-
aminobenzoic acid derivatives to ethyl isocyanatoacetate
*Address correspondence to this author at the Faculty of Pharmacy, Yed-
itepe University, Istanbul, Turkey; Tel/ Fax: +90 532 703 8399,
+90 216 578 0068; E-mail: hakgun@yeditepe.edu.tr
1875-628X/16 $58.00+.00
©2016 Bentham Science Publishers

A Series of 2,4(1H,3H)-Quinazolinedione Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 65
H3CO
O
N
H3CO
N
CH
N
N
N
O
HN
Cl
F
O
H3CO
HN
O
Gefitinib
Erlotinib
F
O
S
O
CH3
N
H3C
N
N
F
O
NH
Cl
NH
O
HN
Br
O
N
H3CO
N
Lapatinib
NH2
Vandetanib
N
O
H3CO
H3CO
N
Cl
O
H3C
OCH3
N
H3C
H3C
O
HN
F
N
NH
H2N
N
NH2
CH3
Afatinib
Trimetrexate
N
O
S
NH
N
HO
CH3
NH
O
O
O
Raltitrexed
HO
Fig. (1). Structures of some commercially available drugs bearing quinazoline and quinazolinone skeleton.
H3C
CH3
O
O
H
O
CH3
R2
R1
O
N
S
O
N
N
R3
O
N
N
H
N
H
N
H
N
H
O
OCH3
2
1(a-d)
a: R1=2-chlorophenylethyl, R2=methoxy, R3=2-chloro
b: R1=3-chlorophenylethyl, R2=4-methylpiperazine-1-yl, R3=3-chloro
c: R1=2-chlorophenylethyl, R2=4-methoxypiperazine-1-yl, R3=3-chloro
d: R1=phenyl, R2=methoxy, R3=2-chloro
Fig. (2). Some cytotoxic 2,4(1H,3H)-quinazolinedione derivatives.
leading to the formation of corresponding 2-(3-ethoxy-
carbonylmethylureido)benzoic acid derivatives. Reactions
were carried out by stirring the reactants in saturated potas-
sium bicarbonate solution at room temperature to give mod-
erate yields of urea derivatives (30-54%, 1-3). Spectral data
and melting point of the compound 1 were in accordance
with the values of published before [60].
for 2 hours to give 2,4-dioxo-1,4-dihydroquinazolin-3(2H)-
yl)acetic acid derivatives (4-6) in moderate to good yields of
36-73%. The compounds were easily seperated from the
reaction media without using any purification techniques.
Ring closure reaction was carried out by heating compound
1-3 in acidic media, as well as the ester functional group
were hydrolysed to carboxylic acid to yield compound 4-6.
2-(3-Ethoxycarbonylmethylureido)benzoic acid deriva-
tives (1-3) were refluxed in concentrated hydrochloric acid
Final compounds (7-34) were prepared by the amidation
reaction of 2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)acetic

66 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Akgun et al.
O
NH
Cl
CH3
NH
N
N
CH3
HN
O
N
N
N
S
N
N
H
H3C
N
N
H3C
N
N
HO
Imatinib
Dasatinib
CH3
N
N
S
S
O
O
CH3
N
OH
N
O
N
O
F3C
N
N
N
O
Cl
OH
N
O
HN
N
Fluphenazine
Cetirizine
CH3
CH3
Sildenafil
NH2
H3CO
H3CO
O
N
O
O
N
N
N
N
OCH3
OCH3
O
N
N
N
O
H2N
Doxazosin
Terazosin
Fig. (3). Some clinically used piperazine derivatives.
acid derivatives (4-6) with various 1-substitutedpiperazines.
Reactants were stirred with the coupling reagent N,N'-
dicyclohexylcarbodiimide (DCC) in nitrogen atmosphere at
cold (0-5 °C) to room temperature for 10-16 hours. Reaction
solvent was evaporated to dryness. The residue was dis-
solved in hot acetonitrile then cooled in refrigerator to get
the N,N′-dicyclohexylurea (DCU) precipitated. White crys-
talline DCU was removed by filtration. The liquid part was
evaporated and crystallized from appropriate solvents. Com-
pounds 7-34 were obtained in varied yields (5-84%).
using Sulforhodamine B assay. According to the cytotoxicity
data, some compounds exhibited cytotoxic activitiy between
the values of 2.5-19.0 µM (Table 1).
3-{2-[4-(4-Chlorobenzyl)piperazin-1-yl]-2-oxoethyl}qui-
nazoline-2,4(1H,3H)-dione (compound 7) presented the
highest activity against HUH-7, MCF-7 and HCT-116 with
the IC50 values of 2.5, 6.8 and 4.9 µM, respectively. 6-
Chloro derivative (compound 15) of this compound exhib-
ited lower activity against these three cell lines than com-
pound 7 with IC50 values of 7.0 µM, 13.1 µM and 9.4 µM,
whereas 6,7-dimethoxy derivative (compound 25) showed
moderate cytotoxicity against HCT116 with IC50 value of
16.9 µM and no cytotoxicity against HUH-7 and MCF-7 cell
lines (Table 2).
A
O
N
R1
R2
N
N
O
Compound 8 presented cytotoxicity over HUH-7, MCF-7
and HCT-116 cell lines with IC50 values of 11.5, 12.2 and
35.3 µM, respectively. But 6-chloro (compound 17) and 6,7-
dimethoxy derivative (compound 27) of this compound did
not show any activity against these three cell lines.
N
H
O
Fig. (4). General formula of target compounds.
2.2. Tumor Cell Growth Inhibition Studies
Compound 16 bearing 6-chloro atom on the 2,4-
quinazolinedione ring exhibited moderate activity against
HUH-7 and MCF-7 cell lines with IC50 values of 12.8 and
All synthesized compounds were examined for their cy-
totoxic activity against hepatoma (HUH-7), breast cancer
(MCF-7) and colorectal cancer (HCT-116) cell line with

A Series of 2,4(1H,3H)-Quinazolinedione Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 67
O
R1
OH
O
R1
OC2H5
R2
NH
OH
i.
OCN
+
O
O
NH
R2
NH2
O
OC2H5
Compound 1-3
ii.
A
O
N
O
R1
R2
N
R1
R2
OH
iii.
N
N
O
O
N
H
O
N
H
O
Compound 7-34
Compound 4-6
i. saturated KHCO3 solution, rt, 1h.
ii. concd. HCl, reflux, 2h.
iii. 1-substitutedpiperazine, DCC, DCM, 0 oC (0.5h)- rt (10-16h)
Scheme (1). General synthetic pathway of the target compounds 7-34.
Table 1. IC50 values for tested compounds 7-34 against hepatoma cell line (HUH-7), breast cancer cell line (MCF-7) and colorectal
b
cancer cell line (HCT-116) using Sulforhodamine B assay. (aCamptothecin was positive control, 5-fluorouracil was refer-
ence drug, -: no inhibition).
A
O
N
R1
R2
N
N
O
N
H
O
IC50 Values (µM)
MCF-7
R1
R2
A
HUH-7
HCT-116
7
-H
-H
-H
-H
-H
-H
-H
-H
-Cl
-Cl
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
4-chlorobenzyl
2.5
6.8
4.9
8
1,3-benzodioxol-5-ylmethyl
2-furoyl
11.5
12.2
35.3
9
-
-
-
-
10
11
12
13
14
15
16
cyclohexyl
-
-
-
2-cyanophenyl
diphenylmethyl
benzoyl
-
-
-
-
15.2
-
-
-
4-pyridyl
-
-
-
4-chlorobenzyl
3-trifluoromethylphenyl
7.0
12.8
13.1
18.6
9.4
-

68 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Table 1. contd…
Akgun et al.
IC50 Values (µM)
MCF-7
R1
R2
A
HUH-7
HCT-116
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
-Cl
-Cl
-H
-H
1,3-benzodioxol-5-ylmethyl
2-furoyl
-
-
-
-
-
-
-Cl
-H
cyclohexyl
-
-
-
-Cl
-H
2-cyanophenyl
diphenylmethyl
4-methoxyphenyl
benzoyl
-
-
-
-Cl
-H
9.2
13.0
9.0
-Cl
-H
-
-
-
-Cl
-H
-
-
-
-Cl
-H
4-pyridyl
-
-
-
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
4-chlorobenzyl
3-trifluoromethylphenyl
1,3-benzodioxol-5-ylmethyl
2-furoyl
-
-
16.9
-
-
6.0
-
-
-
-
-
-
cyclohexyl
-
-
11.4
2-cyanophenyl
diphenylmethyl
4-methoxyphenyl
benzoyl
-
-
19.0
-
-
9.9
-
-
-
-
-
-
-
-
-
4-pyridyl
Camptothecina
5-Flourouracilb
0.00131
30.70
2.4×10-6
3.5
9.2×10-7
18.78
Table 2. IC50 values (µM) of compounds 7, 15 and 25.
O
N
R1
R2
N
N
Cl
O
N
H
O
Compound
R1
R2
HUH-7
MCF-7
HCT-116
7
-H
-Cl
-H
-H
2.5
7.0
-
6.8
13.1
-
4.9
9.4
15
25
-OCH3
-OCH3
16.9
18.6 µM, whereas no activity against these cell lines was
observed for the 6,7-dimethoxy derivative (compound 26).
Compound 26 only presented cytotoxic activity against
HCT-116 with IC50 value of 6.0 µM.
Diphenylmethyl derivative of 6-chloro-2,4-quinazoline-
dione (compound 21) showed cytotoxicity against HUH-7,
MCF-7 and HCT-116 cell lines with IC50 values of 9.2 µM,
13 µM and 9 µM, respectively. Its non-substituted derivative

A Series of 2,4(1H,3H)-Quinazolinedione Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 69
Table 3. IC50 values (µM) of compound 25, 26 and 29-31.
A
N
O
H3CO
H3CO
N
N
O
N
H
O
Compound
A
HUH-7
MCF-7
HCT-116
25
26
29
30
31
4-chlorobenzyl
3-(trifluoromethyl)phenyl
cyclohexyl
-
-
-
-
-
-
-
-
-
-
16.9
6.0
11.4
19.0
9.9
2-cyanophenyl
diphenylmethyl
(compound 12) only exhibited cytotoxicity over MCF-7 cell
line with IC50 value of 15.2 µM, whereas 6,7-dimethoxy de-
rivative (compound 31) only showed cytotoxicity over HCT-
116 cell line with IC50 value of 9.9 µM.
IR: (KBr, vmax, cm-1): 3398, 2993, 1725, 1683, 1663, 1536.
1H-NMR: (400 MHz) (DMSO-d6/TMS, ppm): δ 1.17-1.19 (t,
3H, CH3, J=6.8 Hz), 3.8 (dd, 2H, NHCH2), 4.1 (q, 2H,
CH2CH3), 6.95 (m, 1H, benzene CH), 7.45 (m, 1H, benzene
CH), 7.85 (t, 1H, CONHCH2), 7.9 (dd, 1H, benzene CH),
8.35 (d, 1H, benzene CH), 10.2 (s, 1H, CNHCO), 13.2 (s,
1H, COOH).
Only the compounds 25, 26 and 29-31 presented IC50
values ranging from 6 to19 µM against HCT-116 cell line.
But generally, 6,7-dimethoxy derivatives (compound 25-34)
was non-cytotoxic over HUH-7, MCF-7 cell lines (Table 3).
5-Chloro-2-[3-(2-ethoxy-2-oxoethyl)ureido]benzoic acid
(2). 2-Amino-5-chlorobenzoic acid (4.547 g, 0.026 mol) and
ethyl isocyanoacetate (3.3 ml) were reacted according to the
general procedure for compounds 1-3. Light yellow needle
3. MATERIALS AND METHODS
3.1. Chemical Methods
crystals; mp: 178.9 °C, yield: 2.950 g (37%). IR: (KBr, vmax
,
1
cm-1): 3336, 3041, 2980, 2928, 1732, 1690, 1650. H-NMR
(400 MHz) (DMSO-d6/TMS, ppm): δ 1.18 (t, 3H, CH3,
J=7.2 Hz), 3.81 (d, 2H, NHCH2CO, J=6.0 Hz), 4.10 (q, 2H,
CH2CH3, J=7.2 Hz), 7.53 (q, 1H, benzene CH, J=8.8 Hz,
J=2.8 Hz), 7.83 (d, 1H, benzene CH, J=2.4 Hz), 7.95 (s, 1H,
CONHCH2), 8.37 (d, 1H, benzene CH, J=8.8 Hz), 10.16 (s,
1H, CNHCO), 13.60 (s, 1H, COOH). Anal. calc. for
C12H13ClN2O5 (300.6948); C, 47.93; H, 4.36; N, 9.32.
Found: C, 47.53; H, 4.00; N, 9.39.
Infrared Spectra were recorded on a Perkin-Elmer Spec-
trum One series FT-IR apparatus (Version 5.0.1), using po-
tassium bromide pellets, the frequencies were expressed in
cm-1. The 1H-NMR and 13C-NMR spectra were recorded
with a Varian Mercury-400 FT-NMR spectrometer (Varian
Inc., Palo Alto, CA, USA), using tetramethylsilane (TMS) as
the internal reference, with deuterated-dimethyl sulfoxide
(DMSO-d6) as solvent, the chemical shifts were reported in
parts per million (ppm). Elemental analyses were performed
on LECO 932 CHNS (Leco-932, St. Joseph, MI, USA) in-
strument. Liquid chromatography-mass spectrometry (LC-
MS) spectra were recorded with a Waters 2695 Alliance Mi-
cromass ZQ instrument using electrospray ionization (ESI)
technique.
2-[3-(2-Ethoxy-2-oxoethyl)ureido]-4,5-dimethoxybenzo-
ic acid (3). 2-Amino-4,5-dimethoxybenzoic acid (5.226 g,
0.026 mol) and ethyl isocyanoacetate (3.3 ml) were reacted
according to the general procedure for compounds 1-3. Light
brown colored needle shaped crystals; mp: 172.5 °C, yield:
4.688 g, (54%). IR (KBr, vmax, cm-1): 3397, 3020, 2912,
1
1738, 1684, 1615, 1539. H-NMR (400 MHz) (DMSO-d6):
General procedure for compounds 1-3. A solution of
2-aminobenzoic acid derivative (0.026 mol) in 35 ml of satu-
rated potassium bicarbonate (KHCO3) solution was stirred
with 3.3 ml of ethyl isocyanatoacetate for an hour at room
temperature. The solution was acidified with concentrated
hydrochloric acid and filtered. The precipitate was crystal-
lized from ethanol.
1.20 (t, 3H, OCH2CH3, J=7.2 Hz), 3.73 (s, 3H, OCH3), 3.77
(s, 3H, OCH3), 3.82 (d, 2H, NHCH2, J=6.0 Hz), 4.11 (q, 2H,
OCH2CH3, J=7.2 Hz), 7.37 (s, 1H, benzene CH), 7.92 (s, 1H,
NHCH2), 8.16 (s, 1H, benzene CH), 10.34 (s, 1H, CNHCO),
13.07 (s, 1H, COOH). Anal. calc. for C14H18N2O7.1/2H2O:
C, 50.15; H, 5.71; N, 8.35. Found: C, 49.73; H, 5.30; N,
8.39.
2-[3-(2-Ethoxy-2-oxoethyl)ureido]benzoic acid (1). 2-
Aminobenzoic acid (7.056 g, 0.026 mol) and ethyl isocyana-
toacetate (3.3 ml) were reacted according to the general pro-
cedure for compounds 1-3. White needle crystals [61,62];
mp: 170 °C (171-172.5 °C [60]), yield: 2.117 g (30%).
General procedure for compounds 4-6. Compounds 1-
3 (0.011 mol) and 30 ml of concentrated hydrochloric acid
were refluxed for 2 hours. The mixture was cooled and di-
luted with water to give compounds 4-6.

70 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Akgun et al.
2-(2,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)acetic
acid (4). Compound 1 (3 g, 0.011 mol) was reacted accord-
ing to the general procedure for compounds 1-3. White pow-
dered compound; mp: 295 °C (290-292 °C [63], 297-299 °C
[64]), yield: 1.742 g (73%). IR (KBr, vmax, cm-1): 3285, 3010,
2945, 1716, 1657, 1625, 1494. 1H-NMR (400 MHz)
(DMSO-d6): 4,56 (s, 2H, CH2), 7.21-7.27 (m, 2H, benzene
CH), 7.87-7.73 (m, 1H, benzene CH), 7.95 (dd, 1H, benzene
CH, J=8.0 Hz, J=1.2 Hz), 11.62 (s, 1H, NH), 13.35 (s, 1H,
COOH).
J=8.4 Hz, J=1.6 Hz, benzyl CH), 7.67-7.71 (m, 1H, benzene
CH), 7.90-7.93 (m, 1H, benzene CH), 11.53 (bs, 1H, NH).
Anal. calc. for C21H21ClN4O3: C, 61.09; H, 5.13; N, 13.57.
Found: C, 60.98; H, 5.013; N, 13.52.
3-{2-[4-(Benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl]-
2-oxoethyl}quinazoline-2,4(1H,3H)-dione (8). Compound 4
(0.220 g, 1 mmol) and 1-piperonylpiperazine (0.220 g, 1
mmol) were reacted according to the general procedure for
compounds 7-34 and the crude product was crystallized from
ethanol to give compound 8 as white powdered compound;
mp: 218.2 °C, yield: 28 mg (7%). IR (KBr, vma1x, cm-1): 3292,
3071, 3009, 2928, 2850, 1731, 1643, 1494. H-NMR (400
MHz) (DMSO-d6): 2.32 (t, 2H, CH2 piperazine, J=4.8 Hz),
2.42 (t, 2H, CH2 piperazine, J=4.8 Hz), 3.44 (m, 4H,
piperazine CH2 and OCH2O), 3.56 (t, 2H, piperazine CH2,
J=4.8 Hz), 4.73 (s, 2H, CH2CO), 6.0 (s, 2H, NCH2C6H5),
6.76-7.25 (m, 3H, CH benzodioxol), 7.20-7.25 (m, 2H, ben-
zene CH), 7.67-7.71 (m, 1H, benzene CH), 7.90-7.93 (m,
1H, benzene CH), 11.53 (bs, 1H, NH). Anal. calc. for
C22H22N4O5 . 1/2 H2O: C, 61.24; H, 5.37; N, 12.99. Found:
C, 61.13; H, 5.064; N, 12.88.
2-(6-Chloro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-
yl)acetic acid (5). Compound 2 (3.4 g, 0.011 mol) was re-
acted according to the general procedure for compounds 1-3.
Light yellow needle shaped crytalline compound; mp: 300
°C (dec) (327-329 °C [64,65]), yield: 1.027 g (36%). IR
1
(KBr, vmax, cm-1): 3071, 2930, 1716, 1656. H-NMR (400
MHz) (DMSO-d6): 4.56 (s, 2H, CH2), 7.25 (d, 1H, benzene
CH, J=8.8 Hz), 7.77 (dd, 1H, benzene CH, J=8.8 Hz, J=2.8
Hz), 7.89 (d, 1H, benzene CH, J=2.8 Hz), 11.78 (s, 1H, NH),
13.09 (s, 1H, COOH). Anal. calc. for C10H7ClN2O4: C,
47.17; H, 2.77; N, 11.00. Found: C, 47.13; H, 3.06; N, 10.98.
2-(6,7-Dimethoxy-2,4-dioxo-1,2-dihydroquinazolin-3(4-
H)-yl)acetic acid (6). Compound 3 (3.69 g, 0.0113 mol) was
reacted according to the general procedure for compounds 1-
3. Light creamy colored powdered crystalline compound;
mp: 300 °C (dec), yield: 1.251 g (40%). IR (KBr, vmax, cm-1):
3-{2-[4-(2-Furoyl)piperazin-1-yl]-2-oxoethyl}quinazoli-
ne-2,4(1H,3H)-dione (9). Compound 4 (0.220 g, 1 mmol)
and 1-(2-furoyl)piperazine (0.180 g, 1 mmol) were reacted
according to the general procedure for compounds 7-34 and
the crude product was crystallized from n-hexane-ethanol
mixture to give light yellow powdered compound; mp: 228
°C, yield: 320 mg (84%). IR vmax (cm-1): 3327, 3061, 2928,
1
3017, 2959, 1702, 1620, 1513, 1468. H-NMR (400 MHz)
(DMSO-d6): 3.80 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.54
(s, 2H, CH2), 6.71 (s, 1H, benzene CH), 7.29 (s, 1H, benzene
CH), 11.38 (s, 1H, NH), 12.96 (s, 1H, COOH). Anal. calc.
for C12H12N2O6: C, 51.43; H, 4.32; N, 10.00. Found: C,
51.24; H, 4.03; N, 9.94.
1
2851, 1718, 1655, 1625, 1492, 1244. H-NMR (400 MHz)
(DMSO-d6/TMS, δ, ppm): 3.54 (t, 4H, piperazine CH2), 3.70
(t, 4H, piperazine CH2), 4.80 (s, 2H, CH2CO), 6.65 (t, 1H,
furoyl CH, J=1.6 Hz), 7.05-7.06 (m, 1H, furoyl CH), 7.21-
7.25 (m, 2H, benzene CH), 7.68-7.71 (m, 1H, benzene CH),
7.88-7.94 (m, 2H, benzene CH and furoyl CH), 11.55 (bs,
1H, NH). Anal. calc. for C19H18N4O5 . 1/9 H2O: C, 59.37; H,
4.78; N, 14.58. Found: C, 59.18; H, 4.20; N, 14.35.
General procedure for compounds 7-34. A mixture of
compound 4-6 (1 mmol) in 5 ml of dry DCM and piperazine
derivative (1 mmol) was cooled in an ice bath. Then, 1.1
mmol of DCC in 5 ml of dry dichloromethane was added to
the mixture under nitrogen (N2) atmosphere. Reaction mix-
ture was stirred for 0.5 hour in an ice bath, then 10-16 hours
at room temperature. Reaction solvent was evaporated to the
dryness. Residue was dissolved in hot acetonitrile then
cooled in refrigerator to get the DCU precipitated. White
crystalline DCU was removed by filtration. Liquid part was
evaporated and crystallized from appropriate solvents to give
compound 7-34
3-[2-(4-Cyclohexylpiperazin-1-yl)-2-oxoethyl]quinazoli-
ne-2,4(1H,3H)-dione (10). Compound 4 (0.220 g, 1 mmol)
and 1-cyclohexylpiperazine (0.168 g, 1 mmol) were reacted
according to the general procedure for compounds 7-34 and
the crude product was crystallized from methanol-ether mix-
ture to give white powdered compound; mp: 260.1 °C,
yield: 23 mg (6%). IR (KBr, vmax, cm-1): 3327, 3060, 2928,
2852, 1719, 1657, 1623, 1493. 1H-NMR (400 MHz)
(DMSO-d6/TMS, δ, ppm): 1.06-1.21 (m, 5H, cyclohexyl
CH2), 1.54-1.72 (m, 5H, cyclohexyl CH2), 2.26-2.31 (m, 1H,
cyclohexyl CH), 2.42 (t, 2H, piperazine CH2, J=4.8 Hz),
2.52 (t, 2H, piperazine CH2, J=4.8 Hz), 3.38 (t, 2H,
piperazine CH2, J=4.8 Hz), 3.49 (t, 2H, piperazine CH2,
J=4.8 Hz), 4.70 (s, 2H, CH2CO), 7.17-7.22 (m, 2H, benzene
CH), 7.64-7.68 (m, 1H, benzene CH), 7.89 (dd, 1H, benzene
CH, J=7.6 Hz, J=1.6 Hz), 11.49 (bs, 1H, NH). Anal. calc. for
C20H26N4O3: C, 64.84; H, 7.07; N, 15.12. Found: C, 65.26;
H, 7.28; N, 15.35.
3-{2-[4-(4-Chlorobenzyl)piperazin-1-yl]-2-oxoethyl}qui-
nazoline-2,4(1H,3H)-dione (7). Compound 4 (0.220 g, 1
mmol) and 1-(4-chlorobenzyl)piperazine (0.211 g, 1 mmol)
were reacted according to the general procedure for com-
pounds 7-34 and the crude product was crystallized from
methanol-ether mixture to give compound 7 as white pow-
der; mp: 300 °C (dec), yield: 91 mg (11%). ). IR (KBr, vmax
,
1
cm-1): 3276, 3030, 2928, 2850, 1729, 1639, 1491. H-NMR
(400 MHz) (DMSO-d6/TMS, δ, ppm): 2.34 (t, 2H, piperazine
CH2, J=4.4 Hz), 2.43 (t, 2H, piperazine CH2, J=4.4 Hz),
3.44 (t, 2H, piperazine CH2, J=4.4 Hz), 3.52 (s, 2H, benzyl
CH2), 3.57 (t, 2H, piperazine CH2, J=4.4 Hz), 4.74 (s, 2H,
CH2CO), 7.20-7.24 (m, 2H, benzene CH), 7.35-7.42 (dd, 4H,
2-{4-[(2,4-Dioxo-1,4-dihydroquinazolin-3(2H)-yl)acet-
yl]piperazin-1-yl}benzonitrile (11). Compound 4 (0.220 g, 1
mmol) and 1-(2-cyanophenyl)piperazine (0.187 g, 1 mmol)

A Series of 2,4(1H,3H)-Quinazolinedione Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 71
were reacted according to the general procedure for com-
pounds 7-34 and the crude product was crystallized from
methanol-ether mixture to give yellow powdered compound;
mp: 256.4 °C, yield: 173 mg (45%). IR (KBr, vmax, cm-1):
3273, 3072, 3003, 2962, 2872, 2214, 1727, 1670, 1640,
1489, 1455. 1H-NMR (400 MHz) (DMSO-d6/TMS, δ, ppm):
3.13 (t, 2H, piperazine CH2), 3.25 (t, 2H, piperazine CH2),
3.63 (t, 2H, piperazine CH2), 3.77 (t, 2H, piperazine CH2),
4.81 (s, 2H, CH2CO), 7.13 (t, 1H, 2-cyanophenyl CH, J=7.6
Hz), 7.19-7.23 (m, 3H, 2-cyanophenyl CH and benzene
CHs), 7.59-7.73 (m, 3H, 2-cyanophenyl CH and benzene
CH), 7.92 (dd, 1H, benzene CH, J=7.2 Hz, J=1.2 Hz), 11.47
(bs, 1H, NH). 13C-NMR (400 MHz) (DMSO-d6/TMS, δ,
ppm): 41.91, 42.12, 44.77, 51.31, 51.98, 105.59, 113.90,
115.68, 118.57, 119.88, 122.95, 123.11, 127.85, 134.67,
134.84, 135.67, 139.88, 150.48, 155.32, 162.19, 165.41. MS
(ESI+, m/z): 390.2 ([M+], base peak), 162.7 (C8H6N2O2,
%10), 229.2 (C13H15N3O, %12). Anal. calc. for C21H19N5O3:
C, 64.77, H, 4.92; N, 17.98. Found: C, 65.54; H, 4.70; N,
17.64.
2944, 1708, 1659, 1514. 1H-NMR (400 MHz) (DMSO-
d6/TMS, δ, ppm): 3.35 (t, 2H, piperazine CH2), 3.45 (t, 2H,
piperazine CH2), 3.58 (t, 2H, piperazine CH2), 3.75 (t, 2H,
piperazine CH2), 4.80 (s, 2H, CH2CO), 6.85 (dd, 2H, pyri-
dine CH, J=4.0 Hz, J=1.2 Hz), 7.23 (m, 2H, benzene CH),
7.70 (m, 1H, benzene CH), 7.95 (dd, 1H, benzene CH), 8.20
(dd, 2H, pyridine CH), 11.55 (bs, 1H, NH). Anal. calc. for
C19H19N5O3 . 2/3 H2O (365.3861 g/mol); C, 60.47; H, 5.43;
N, 18.56. Found: C, 60.27; H, 5.49; N, 18.65.
3-{2-[4-(4-Chlorobenzyl)piperazin-1-yl]-2-oxoethyl}-6-
chloro-quinazoline-2,4(1H,3H)-dione (15). Compound 5
(0.255 g, 1 mmol) and 1-(4-chlorobenzyl)piperazine (0.211
g, 1 mmol) were reacted according to the general procedure
for compounds 7-34 and the crude product was crystallized
from methanol-ether mixture to give white powdered com-
pound; mp: 300 °C (dec), yield: 39 mg (9%). IR (KBr, vmax
,
1
cm-1): 3503, 3060, 2916, 1726, 1662, 1457. H-NMR (400
MHz) (DMSO-d6/TMS, δ, ppm): 2.32 (t, 2H, piperazine
CH2, J=4.4 Hz), 2.41 (t, 2H, piperazine CH2, J=4.4 Hz),
3.42 (t, 2H, piperazine CH2, J=4.8 Hz), 3.50 (s, 2H, benzyl
CH2), 3.54 (t, 2H, piperazine CH2, J=4.4 Hz), 4.71 (s, 2H,
CH2CO), 7.22 (d, 1H, benzene CH, J=9.2 Hz), 7.33-7.40 (m,
4H, benzyl CH), 7.75 (dd, 1H, benzene CH, J=8.8 Hz, J=2.8
Hz), 7.84 (d, 1H, benzene CH, J=2.4 Hz), 11.67 (bs, 1H,
NH). Anal. calc. for C21H20Cl2N4O3. 1/2 H2O (447.3141
g/mol): C, 55.27; H, 4.64; N, 12.28. Found: C, 55.00; H,
4.55; N, 12.29.
3-{2-[4-(Diphenylmethyl)piperazin-1-yl]-2-oxoethyl}qui-
nazoline-2,4(1H,3H)-dione (12). Compound 4 (0.220 g, 1
mmol) and 1-(diphenylmethyl)piperazine (0.252 g, 1 mmol)
were reacted according to the general procedure for com-
pounds 7-34 and the crude product was crystallized from
acetone-ether mixture to give white powdered compound;
mp: 300 °C (dec), yield: 80 mg (18%). IR (KBr, vmax, cm-1):
1
3207, 3061, 3025, 2924, 2859, 2805, 1727, 1655, 1492. H-
6-Chloro-3-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]pip-
erazin-1-yl}ethyl) quinazoline-2,4(1H,3H)-dione (16). Com-
pound 5 (0.255 g, 1 mmol) and 1-(3-trifluoromethylphenyl)
piperazine (0,230 g, 1 mmol) were reacted according to the
general procedure for compounds 7-34 and the crude product
was crystallized from methanol-ether mixture to give white
powdered compound; mp: 300 °C (dec), yield: 38 mg (9%).
IR (KBr, vmax, cm-1): 3067, 2927, 1725, 1668, 1232, 1118,
NMR (400 MHz) (DMSO-d6/TMS, δ, ppm): 2.29 (t, 2H,
piperazine CH2), 2.37 (t, 2H, piperazine CH2), 3.47 (t, 2H,
piperazine CH2), 3.60 (t, 2H, piperazine CH2), 4.38 (s, 1H,
CH), 4.71 (s, 2H, CH2CO), 7.19-7.24 (m, 2H, benzene CH),
7.30-7.34 (m, 6H, diphenyl CH), 7.46 (d, 4H, diphenyl CH,
J=7.6 Hz), 7.66-7.70 (m, 1H, benzene CH), 7.91 (q, 1H,
benzene CH, J=8.0 Hz, J=1.2 Hz), 11.51 (bs, 1H, NH).
Anal. calc. for C27H26N4O3 . 1/3 H2O: C, 70.42; H, 5.84; N,
12.17. Found: C, 70.37; H, 5.81; N, 12.12.
1
1075. H-NMR (400 MHz) (DMSO-d6/TMS, δ, ppm): 2.23
(t, 2H, piperazine CH2, J=4.8 Hz), 3.35 (t, 2H, piperazine
CH2), 3.59 (t, 2H, piperazine CH2, J=4.8 Hz), 3.73 (t, 2H,
piperazine CH2, J=4.8 Hz), 4.80 (s, 2H, CH2CO), 7.10 (d,
1H, 3-(trifluoromethyl)phenyl CH, J=7.2 Hz), 7.21-7.26 (m,
2H, 3-(trifluoromethyl)phenyl CH), 7.23 (d, 1H, benzene
CH, J=8.8 Hz), 7.44 (t, 1H, 3-(trifluoromethyl)phenyl CH,
J=8.0 Hz), 7.74 (dd, 1H, benzene CH, J=8.8 Hz, J=2.4 Hz),
7.85 (d, 1H, benzene CH, J=2.4 Hz), 11.70 (bs, 1H, NH).
Anal. calc. for C21H18ClF3N4O3 (466.8407 g/mol): C, 54.03;
H, 3.89; N, 12.00. Found: C, 53.75; H, 3.77; N, 12.07.
3-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]quinazoline-
2,4(1H,3H)-dione (13). Compound 4 (0.220 g, 1 mmol) and
1-benzoylpiperazine (0.190 g, 1 mmol) were reacted accord-
ing to the general procedure for compounds 7-34 and the
crude product was crystallized from methanol-ether mixture
to give white powdered compound; mp: 257 °C, yield: 110
mg (28%). IR (KBr, vmax, cm-1): 3274, 3065, 3001, 2959,
1
2911, 2860, 1726, 1676, 1617, 1492. H-NMR (400 MHz)
(DMSO-d6/TMS) δ ppm: 3.30-3.60 (m, 8H, piperazine CH2),
4.79 (s, 2H, CH2CO), 7.20-7.25 (m, 2H, benzene CH), 7.45-
7.49 (m, 5H, benzoyl CH), 7.67-7.72 (m, 1H, benzene CH),
7.93 (dd, 1H, benzene CH, J=4 Hz, J=1.2 Hz), 11.55 (bs,
1H, NH). Anal. calc. for C21H20N4O4: C, 64.28; H, 5.14; N,
14.28. Found: C, 4.12; H, 4.75; N; 14.08.
3-{2-[4-(Benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl]-
2-oxoethyl}-6-chloroquinazoline-2,4(1H,3H)-dione
(17).
Compound 5 (0.255 g, 1 mmol) and 1-piperonylpiperazine
(0.220 g, 1 mmol) were reacted according to the general pro-
cedure for compounds 7-34 and the crude product was
washed with acetone and hot methanol to give white pow-
dered compound; mp: 300 °C (dec), yield: 22 mg (5%). IR
3-[2-Oxo-2-(4-pyridin-4-ylpiperazin-1-yl)ethyl]quinazo-
line-2,4(1H,3H)-dione (14). Compound 4 (0.220 g, 1 mmol)
and 1-(4-pyridyl)piperazine (0.163 g, 1 mmol) were reacted
according to the general procedure for compounds 7-34 and
the crude product was crystallized from methanol-ether mix-
ture to give white powdered compound, mp: 300 °C (dec),
yield: 24 mg (7%). IR (KBr, vmax, cm-1): 3178, 3089, 3003,
1
(KBr, vmax, cm-1): 3058, 2915, 1719, 1659, 1491. H-NMR
(400 MHz) (DMSO-d6/TMS, δ, ppm): 2.31 (t, 2H, piperazine
CH2), 2.40 (t, 2H, piperazine CH2), 3.42 (s, 4H, piperazine
CH2 and OCH2O), 3.53 (t, 2H, piperazine CH2), 4.71 (s, 2H,
CH2CO), 5.97 (s, 2H, NCH2C6H3), 6.74-6.87 (m, 3H,

72 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Akgun et al.
benzodioxol CH), 7.22 (d, 1H, benzene CH, J=8.4 Hz), 7.72
(dd, 1H, benzene CH, J=8.8 Hz, J=2.4 Hz), 7.84 (d, 1H,
benzene CH, J=2.0 Hz), 11.70 (bs, 1H, NH). Anal. calc. for
C22H21ClN4O5 . 2/3 H2O (456.8788 g/mol): C, 54.61; H,
5.00; N, 11.58. Found: C, 54.46; H, 5.19; N, 11.25.
6-Chloro-3-{2-[4-(diphenylmethyl)piperazin-1-yl]-2-
oxoethyl}quinazoline-2,4(1H,3H)-dione (21). Compound 5
(0.255 g, 1 mmol) and 1-(diphenylmethyl)piperazine (0.252
g, 1 mmol) were reacted according to the general procedure
for compounds 7-34 and the crude product was washed with
hot methanol to give white powdered compound; mp: 300 °C
(dec), yield: 45 mg (18%). IR (KBr, vmax, cm-1): 3187, 3062,
2851, 2928, 1727, 1655, 1491. 1H-NMR (400 MHz)
(DMSO-d6/TMS, δ, ppm): 2.29 (t, 2H, piperazine CH2), 2.37
(t, 2H, piperazine CH2), 3.46 (t, 2H, piperazine CH2), 3.59 (t,
2H, piperazine CH2), 4.38 (s, 1H, CH), 4.71 (s, 2H, CH2CO),
7.19-7.24 (m, 1H, benzene CH), 7.30-7.34 (m, 6H, diphenyl
CH), 7.45-7.47 (m, 4H, diphenyl CH), 7.74 (dd, 1H, benzene
CH, J=8.8 Hz, J=2.4 Hz), 7.86 (d, 1H, benzene CH, J=2.8
Hz), 11.69 (bs, 1H, NH). Anal. calc. for C27H25ClN4O3 . 2/3
H2O (488.9653 g/mol): C, 64.73; H, 5.30; N, 11.18. Found:
C, 64.86; H, 5.29; N, 10.85.
6-Chloro-3-{2-[4-(2-furoyl)piperazin-1-yl]-2-oxoethyl}-
quinazoline-2,4(1H,3H)-dione (18). Compound 5 (0.255 g,
1 mmol) and 1-(2-furoyl)piperazine (0.180 g, 1 mmol) were
reacted according to the general procedure for compounds 7-
34 and the crude product was washed with hot methanol to
give white powdered compound; mp: 294.5 °C, yield: 89 mg
(21%). IR (KBr, vmax, cm-1): 3054, 2931, 1718, 1655, 1486.
1H-NMR (400 MHz) (DMSO-d6 / TMS) δ ppm: 3.28 (t, 2H,
piperazine CH2), 3.52 (t, 2H, piperazine CH2), 3.67-3.75 (m,
4H, piperazine CH2), 4.78 (s, 2H, CH2CO), 6.64 (dd, 1H,
furoyl CH, J=3.6 Hz, J=2.0 Hz), 7.04 (d, 1H, furoyl CH,
J=2.8 Hz), 7.23 (d, 1H, benzene CH, J=8.4 Hz), 7.74 (dd,
1H, benzene CH, J=8.8 Hz, J=2.4 Hz), 7.85-7.86 (m, 2H,
benzene CH and furoyl CH), 11.75 (bs, 1H, NH). Anal. calc.
for C19H17ClN4O5 (416.8149 g/mol): C, 53.97; H, 4.21; N,
13.25. Found: C, 54.18; H, 4.12; N, 13.35.
6-Chloro-3-{2-[4-(4-methoxyphenyl)piperazin-1-yl]-2-
oxoethyl}quinazoline-2,4(1H,3H)-dione (22). Compound 5
(0.255 g, 1 mmol) and 1-(4-methoxyphenyl)piperazine
(0.192 g, 1 mmol) were reacted according to the general pro-
cedure for compounds 7-34 and the crude product was
washed with acetone and hot methanol to give white pow-
dered compound; mp: 300 °C (dec), yield: 102 mg (24%). IR
6-Chloro-3-[2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl]
quinazoline-2,4(1H,3H)-dione (19). Compound 5 (0.255 g,
1 mmol) and 1-cyclohexylpiperazine (0.168 g, 1 mmol) were
reacted according to the general procedure for compounds 7-
34 and the crude product was washed with hot methanol to
give white powdered compound; mp: 300 °C (dec), yield: 36
1
(KBr, vmax, cm-1): 3067, 2928, 1724, 1655, 1512. H-NMR
(400 MHz) (DMSO-d6/TMS, δ, ppm): 2.97 (t, 2H, piperazine
CH2), 3.01 (t, 2H, piperazine CH2), 3.57 (t, 2H, piperazine
CH2), 3.68 (s, 3H, OCH3), 3.70 (t, 2H, piperazine CH2), 4.78
(s, 2H, CH2CO), 6.82-6.94 (m, 4H, methoxyphenyl CH),
7.23 (d, 1H, benzene CH, J=8.8 Hz), 7.73 (dd, 1H, benzene
CH, J=8.8 Hz, J=2.4 Hz), 7.84 (d, 1H, benzene CH, J=2.8
Hz), 11.63 (bs, 1H, NH). Anal. calc. for C21H21ClN4O4 . 2/3
H2O (428.8687g/mol): C, 57.21; H, 5.11; N, 12.71. Found:
C, 56.95; H, 4.84; N, 12.68.
1
mg (9%). IR (KBr, vmax, cm-1): 3068, 2925, 1722, 1660. H-
NMR (400 MHz) (DMSO-d6/TMS, δ, ppm): 1.16-1.22 (m,
5H, cyclohexyl), 1.54-1.73 (m, 5H, cyclohexyl), 2.26 (1H,
m, cyclohexyl CH), 2.43 (t, 2H, piperazine CH2, J=4.4 Hz),
2.53 (t, 2H, piperazine CH2, J=4.8 Hz), 3.39 (t, 2H,
piperazine CH2, J=4.8 Hz), 3.50 (t, 2H, piperazine CH2,
J=4.8 Hz), 4.71 (s, 2H, CH2CO), 7.22 (d, 1H, benzene CH,
J=8.8 Hz), 7.72 (dd, 1H, benzene CH, J=8.8 Hz, J=2.4 Hz),
7.83 (d, 1H, benzene CH, J=2.0 Hz), 11.68 (bs, 1H, NH).
Anal. calc. for C20H25ClN4O3 .1/3 H2O (404.8904 g/mol): C,
58.46; H, 6.30; N, 13.64. Found: C, 58.02; H, 6.00; N, 13.53.
3-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-chloroqu-
inazoline-2,4(1H,3H)-dione (23). Compound 5 (0.255 g, 1
mmol) and 1-benzoylpiperazine (0.190 g, 1 mmol) were re-
acted according to the general procedure for compounds 7-
34 and the crude product was washed with acetone and hot
methanol to give white powdered compound; mp: 300 °C
(dec), yield: 35 mg (8%). IR (KBr, vmax, cm-1): 3057, 2930,
2-{4-[2-(6-Chloro-2,4-dioxo-1,2-dihydroquinazolin-
3(4H)-yl)acetyl]piperazin-1-yl}benzonitrile (20). Compound
5 (0.255 g, 1 mmol) and 1-(2-cyanophenyl)piperazine (0.187
g, 1 mmol) were reacted according to the general procedure
for compounds 7-34 and the crude product was washed with
hot methanol to give white powdered compound; mp: higher
than 300 °C, yield: 172 mg (41%). IR (KBr, vmax, cm-1):
1
1715, 1660, 1618. H-NMR (400 MHz) (DMSO-d6/TMS, δ,
ppm): 3.50 (t, 4H, piperazine CH2), 3.63 (t, 4H, piperazine
CH2), 4.76 (s, 2H, CH2CO), 7.23 (d, 1H, benzene CH, J=8.8
Hz), 7.42-7.46 (m, 5H, benzoyl CH), 7.73 (dd, 1H, benzene
CH, J=8.8 Hz, J=2.4 Hz), 7.84 (d, 1H, benzene CH, J=2.4
Hz), 11.64 (bs, 1H, NH). Anal. calc. for C21H19ClN4O4 . 2/3
H2O (426.8528 g/mol): C, 57.47; H, 4.67; N, 12.77. Found:
C, 57,05; H, 4,62; N, 12,69.
1
3188, 3069, 2961, 2928, 2860, 2224, 1714, 1663, 1489. H-
NMR (400 MHz) (DMSO-d6/TMS, δ, ppm): 3.14 (t, 2H,
piperazine CH2), 3.24 (t, 2H, piperazine CH2), 3.64 (t, 2H,
piperazine CH2), 3.78 (t, 2H, piperazine CH2), 4.83 (s, 2H,
CH2CO), 7.15 (t, 1H, 2-cyanophenyl CH, J=7.6 Hz), 7.21-
7.26 (m, 2H, benzene CH and 2-cyanophenyl CH), 7.62-7.66
(m, 1H, benzene CH), 7.74-7.78 (m, 2H, 2-cyanophenyl
CH), 7.87 (d, 1H, benzene CH, J=2.8 Hz), 11.72 (s, 1H,
NH). 13C-NMR (400 MHz) (DMSO-d6/TMS, δ, ppm): 42.06,
42.17, 44.81, 51.28, 51.94, 105.58, 115.33, 117.98, 119.88,
118.54, 122.92, 126.74, 127.12, 134.66, 134.80, 135.58,
138.76, 150.17, 155.29, 161.21, 165.22. MS (ESI+, m/z):
426.2 ([M+2]+) 424.1 ([M+], base peak). Anal. calc. for
C21H18ClN5O3 . 1/5 H2O (423.8522 g/mol): C, 59.01; H,
4.34; N, 16.38. Found: C, 58.97; H, 4.26; N, 16.30.
6-Chloro-3-[2-oxo-2-(4-pyridin-4-ylpiperazin-1-yl)eth-
yl]quinazoline-2,4(1H,3H)-dione (24). Compound 5 (0.255
g, 1 mmol) and 1-(4-pyridyl)piperazine (0.163 g, 1 mmol)
were reacted according to the general procedure for com-
pounds 7-34 and the crude product was crystallized from
methanol-ether mixture to give white powdered compound;
mp: 300 °C (dec), yield: 24 mg (6%). IR (KBr, vmax, cm-1):
3068, 2932, 1715, 1657, 1595. 1H-NMR (400 MHz)
(DMSO-d6/TMS, δ, ppm): 3.34 (t, 2H, piperazine CH2), 3.44
(t, 2H, piperazine CH2, J=4.8 Hz), 3.56 (t, 2H, piperazine
CH2, J=4.8 Hz), 3.71 (t, 2H, piperazine CH2, J=4.8 Hz), 4.80

A Series of 2,4(1H,3H)-Quinazolinedione Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 73
(s, 2H, CH2CO), 6.83 (dd, 2H, pyridine CH, J=5.2 Hz, J=1.2
Hz), 7.23 (d, 1H, benzene CH, J=8.4 Hz), 7.75 (dd, 1H, ben-
zene CH, J=8.8 Hz, J=2.4 Hz), 7.85 (d, 1H, benzene CH,
J=2.8 Hz), 8.18 (d, 2H, pyridine CH, J=6.8 Hz), 11.70 (bs,
1H, NH). Anal. calc. for C19H18ClN5O3 (399.8308 g/mol): C,
57.07; H, 4.54; N, 17.52. Found: C, 57.49; H, 4.45; N, 17.13.
3-{2-[4-(2-Furoyl)piperazin-1-yl]-2-oxoethyl}-6,7-dime-
thoxyquinazoline-2,4(1H,3H)-dione (28). Compound
6
(0.280 g, 1 mmol) and 1-(2-furoyl)piperazine (0.180 g, 1
mmol) were reacted according to the general procedure for
compounds 7-34 and the crude product was crystallized from
ethanol to give white powdered crystalline compound; mp:
300 °C (dec), yield: 79 mg (18%). IR (KBr, vmax, cm-1):
3-{2-[4-(4-Chlorobenzyl)piperazin-1-yl]-2-oxoethyl}-
6,7-dimethoxyquinazoline-2,4(1H,3H)-dione (25). Com-
pound 6 (0.280 g, 1 mmol) and 1-(4-chlorobenzyl)piperazine
(0.211 g, 1 mmol) were reacted according to the general pro-
cedure for compounds 7-34 and the crude product was crys-
tallized from methanol-ether mixture to give white powdered
crystalline compound; mp: 300 °C (dec), yield: 25 mg (5%).
1
3017, 2934, 1714, 1658, 1624, 1514. H-NMR (400 MHz)
(DMSO-d6/TMS) δ ppm: 3.54 (t, 4H, piperazine CH2), 3.70
(t, 4H, piperazine CH2), 3.80 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 4.78 (s, 2H, CH2CO), 6.65-6.66 (m, 1H, furoyl CH),
6.71 (s, 1H, benzene CH), 7.06 (d, 1H, furoyl CH, J=3.6
Hz), 7.28 (s, 1H, benzene CH), 7.88 (d, 1H, furoyl CH,
J=0.8 Hz), 11.34 (s, 1H, NH). Anal. calc. for
C21H22N4O7.3H2O (442.4221 g/mol): C, 50.80; H, 5.68; N,
11.29. Found: C, 51.08; H, 5.77; N, 11.34.
1
IR (KBr, vmax, cm-1): 3096, 2955, 1718, 1657, 1513. H-
NMR (400 MHz) (DMSO-d6/TMS, δ, ppm): 2.30 (t, 2H,
piperazine CH2), 2.40 (t, 2H, piperazine CH2), 3.41 (t, 2H,
piperazine CH2), 3.49 (s, 2H, benzyl CH2), 3.54 (t, 2H,
piperazine CH2), 3.76 (s, 3H, OCH3), 3.82 (s, 3H, OCH3),
4.68 (s, 2H, CH2CO), 6.68 (s, 1H, benzene CH), 7.24 (s, 1H,
benzene CH), 7.35 (dd, 4H, benzyl CH, J=17.6 Hz, J=8.8
Hz), 11.27 (s, 1H, NH). Anal. calc. for C23H25ClN4O5 . 2/3
H2O (472.9213 g/mol): C, 56.97; H, 5.47; N, 11.55. Found:
C, 56.88; H, 5.85; N, 11.38.
3-[2-(4-Cyclohexylpiperazin-1-yl)-2-oxoethyl]-6,7-dime-
thoxyquinazoline-2,4(1H,3H)-dione (29). Compound
6
(0.280 g, 1 mmol) and 1-cyclohexylpiperazine (0.168 g, 1
mmol) were reacted according to the general procedure for
compounds 7-34 and the crude product was crystallized from
methanol-ether mixture to give white powdered crystalline
compound; mp: 239.7 °C, yield: 74 mg (17%). IR (KBr, vmax
,
1
cm-1): 3084, 3008, 2926, 2856, 1702, 1661, 1512. H-NMR
(400 MHz) (DMSO-d6/TMS, δ, ppm): 1.09-1.74 (m, 10H,
cyclohexyl CH2), 2.30 (m, 1H, cyclohexyl CH), 2.45 (t, 2H,
piperazine CH2, J=4.0 Hz), 2.54 (t, 2H, piperazine CH2),
3.41 (t, 2H, piperazine CH2, J=3.6 Hz), 3.52 (t, 2H,
piperazine CH2), 3.79 (s, 3H, OCH3), 3.85 (s, 3H, OCH3),
4.70 (s, 2H, CH2CO), 6.70 (s, 1H, benzene CH), 7.26 (s, 1H,
benzene CH), 11.30 (s, 1H, NH). Anal. calc. for C22H30N4O5
. 1/4 H2O (430.4976 g/mol): C, 60.74; H, 7.07; N, 12.88.
Found: C, 60.57; H, 7.19; N, 12.79.
6,7-Dimethoxy-3-(2-oxo-2-{4-[3-(trifluoromethyl)phen-
yl]piperazin-1-yl}ethyl)quinazoline-2,4(1H,3H)-dione (26).
Compound 6 (0.280 g, 1 mmol) and 1-(3-trifluoromethyl-
phenyl)piperazine (0,230 g, 1 mmol) were reacted according
to the general procedure for compounds 7-34 and the crude
product was crystallized from methanol-ether mixture to
give white powdered crystalline compound; mp: 228 °C,
yield: 41 mg (8%). IR (KBr, vmax, cm-1): 3079, 2958, 1705,
1
1671, 1646, 1512. H-NMR (400 MHz) (DMSO-d6/TMS, δ,
ppm): 3.24 (t, 2H, piperazine CH2, J=4.8 Hz), 3.32 (t, 2H,
piperazine CH2), 3.60 (t, 2H, piperazine CH2), 3.75 (t, 2H,
piperazine CH2), 3.80 (s, 3H, OCH3), 3.85 (s, 3H, OCH3),
4.80 (s, 2H, CH2CO), 6.71 (s, 1H, benzene CH), 7.12 (d, 1H,
3-(trifluoromethyl)phenyl CH, J=8.0 Hz), 7.23 (s, 1H, ben-
zene CH), 7.26-7.29 (m, 2H, 3-(trifluoromethyl)phenyl CH),
7.46 (t, 1H, 3-(trifluoromethyl)phenyl CH, J=8.0 Hz), 11.34
(s, 1H, NH). Anal. calc. for C23H23F3N4O5 (492.4479 g/mol):
C, 56.10; H, 4.71; N, 11.38. Found: C, 56.13; H, 4.80; N,
11.30.
2-{4-[(6,7-Dimethoxy-2,4-dioxo-1,4-dihydroquinazolin-
3(2H)-yl)acetyl]piperazin-1-yl}benzonitrile (30). Compound
6 (0.280 g, 1 mmol) and 1-(2-cyanophenyl)piperazine (0.187
g, 1 mmol) were reacted according to the general procedure
for compounds 7-34 and the crude product was crystallized
from methanol-ether mixture to give white powdered crystal-
line compound; mp: 300 °C (dec), yield: 21 mg (5%). IR
1
(KBr, vmax, cm-1): 3094, 2955, 2214, 1720, 1663, 1514. H-
NMR (400 MHz) (DMSO-d6/TMS, δ ppm): 3.13 (t, 2H,
piperazine CH2), 3.24 (t, 2H, piperazine CH2), 3.64 (t, 2H,
piperazine CH2), 3.78 ( t, 2H, piperazine CH2), 3.80 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 4.80 (s, 2H, CH2CO), 6.72 (s,
1H, benzene CH), 7.15 (t, 1H, 2-cyanophenyl CH, J=7.6
Hz), 7.22 (d, 1H, 2-cyanophenyl CH, J=8.0 Hz), 7.28 (s, 1H,
benzene CH), 7.62-7.66 (m, 1H, 2-cyanophenyl CH), 7.76
(dd, 1H, 2-cyanophenyl CH, J=8.0 Hz, J=1.6 Hz), 11.33 (s,
1H, NH). Anal. calc. for C23H23N5O5 . H2O (449.4594
g/mol): C, 59.09; H, 5.39; N, 14.98. Found: C, 58.85; H,
5.24; N, 14.84.
3-{2-[4-(Benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl]-
2-oxoethyl}-6,7-dimethoxy quinazoline-2,4(1H,3H)-dione
(27). Compound 6 (0.280 g, 1 mmol) and 1-piperonyl-
piperazine (0.220 g, 1 mmol) were reacted according to the
general procedure for compounds 7-34 and the crude product
was crystallized from methanol-ether mixture to give white
powdered crystalline compound; mp: 211.3 °C, yield: 64 mg
(15%). IR (KBr, vmax, cm-1): 3092, 2946, 1709, 1662, 1469.
1H-NMR (400 MHz) (DMSO-d6/TMS, δ, ppm): 2.31 (t, 2H,
piperazine CH2, J=4.8 Hz), 2.41 (t, 2H, piperazine CH2),
3.31 (t, 2H, piperazine CH2), 3.43 (s, 2H, OCH2O), 3.55 (t,
2H, piperazine CH2), 3.79 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 4.70 (s, 2H, CH2CO), 6.00 (s, 2H, NCH2-benzene),
6.70 (s, 1H, benzene CH), 6.76-6.89 (m, 3H, benzodioxol
CH), 7.27 (s, 1H, benzene CH), 11.30 (s, 1H, NH). Anal.
calc. for C22H22N4O5 (422.434 g/mol): C, 59.74; H, 5.43; N,
11.61. Found: C, 59.87; H, 5.20; N, 11.59.
3-{2-[4-(Diphenylmethyl)piperazin-1-yl]-2-oxoethyl}-
6,7-dimethoxyquinazoline-2,4(1H,3H)-dione (31). Com-
pound
6 (0.280 g, 1 mmol) and 1-(diphenylmethyl)
piperazine (0.252 g, 1 mmol) were reacted according to the
general procedure for compounds 7-34 and the crude product
was crystallized from methanol-ether mixture to give white
powdered crystalline compound; mp: 262.4°C, yield: 21 mg

74 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Akgun et al.
(4%). IR (KBr, vmax, cm-1): 3057, 2961, 2889, 1709, 1666,
J=4.8 Hz), 3.77 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.76 (s,
2H, CH2CO), 6.68 (s, 1H, benzene CH), 6.82 (dd, 2H, pyri-
dine CH, J=5.2 Hz, J=1.6 Hz), 7.25 (s, 1H, benzene CH),
8.16 (dd, 2H, pyridine CH, J=5.2 Hz, J=1.6 Hz), 11.30 (s,
1H, NH). Anal. calc. for C21H23N5O5 . 2 H2O (425.438
g/mol): C, 54.66; H, 5.90; N, 15.18. Found: C, 54.72; H,
5.79; N, 15.16.
1
1511. H-NMR (400 MHz) (DMSO-d6/TMS, δ, ppm): 2.29
(t, 2H, piperazine CH2), 2.36 (t, 2H, piperazine CH2), 3.46 (t,
2H, piperazine CH2), 3.60 (t, 2H, piperazine CH2), 3.79 (s,
3H, OCH3), 3.84 (s, 3H, OCH3), 4.38 (s, 1H, diphenyl CH),
4.68 (s, 2H, CH2CO), 6.70 (s, 1H, benzene CH), 7.20 (t, 2H,
diphenylmethyl CH, J=7.2 Hz), 7.26 (s, 1H, benzene CH),
7.32 (t, 4H, diphenylmethyl CH, J=7.6 Hz), 7.46 (d, 4H,
diphenylmethyl CH, J=7.2 Hz), 11.29 (s, 1H, NH). Anal.
calc. for C29H30N4O5 (514.5725 g/mol): C, 67.69; H, 5.88; N,
10.89. Found: C, 67.33; H, 6.01; N, 11.01.
3.2. Biological Methods
3.2.1. Anticancer Activity Test Procedure: Sulforhodamine
B Assay
6,7-Dimethoxy-3-{2-[4-(4-methoxyphenyl)piperazin-1-
yl]-2-oxoethyl}quinazoline-2,4(1H,3H)-dione (32). Com-
pound 6 (0.280 g, 1 mmol) and 1-(4-methoxyphenyl)
piperazine (0.192 g, 1 mmol) were reacted according to the
general procedure for compounds 7-34 and the crude product
was washed with hot acetonitrile and methanol to give white
powdered crystalline compound; mp: 283.5 °C, yield: 120
mg (26%). IR (KBr, vmax, cm-1): 3194, 3065, 3013, 2948,
2886, 2830, 1723, 1659, 1513. 1H-NMR (400 MHz)
(DMSO-d6/TMS, δ, ppm): 2.99 (t, 2H, piperazine CH2, J=3.6
Hz), 3.09 (t, 2H, piperazine CH2, J=3.6 Hz), 3.59 (t, 2H,
piperazine CH2, J=3.6 Hz), 3.70 (s, 3H, 4-methoxyphenyl
OCH3), 3.73 (t, 2H, piperazine CH2, J=3.6 Hz), 3.80 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 4.79 (s, 2H, CH2CO), 6.72 (s,
1H, benzene CH), 6.91 (dd, 4H, 4-methoxyphenyl CH), 7.28
(s, 1H, benzene CH), 11.33 (s, 1H, NH). 13C-NMR (400
MHz) (DMSO-d6/TMS, δ, ppm): 41.72, 42.05, 44.62, 50.27,
50.71, 55.62, 56.19, 56.31, 97.99, 105.98, 107.92, 114.75,
118.58, 135.63, 145.58, 145.68, 150.58, 153.85, 155.56,
161.69, 165.34. MS (ESI+, m/z): 455.2 ([M+], base peak),
207.2 (C10H9NO4), 249.2 (C13H19N3O2), 262.9 (C12H11N2O5).
Anal. calc. for C23H26N4O6 . 1/4 H2O (454.4759 g/mol): C,
60.19; H, 5.82; N, 12.21. Found: C, 60.17; H, 5.84; N, 12.20.
Cells were plated in 96-well plates (1000-5000 cell/well
in 200 μl) and grown for 24 hours at 37 °C before being
treated with various concentrations of the tested compounds
(from 2.5 to 40 μM). After 72 hours of incubation the me-
dium was aspirated, washed once with PBS (CaCl2-, MgCl2-
free) (Gibco, Invitrogen), and then 50 μl of a cold (4 °C)
solution of 10% (v/v) trichloroacetic acid (Merck) was
added. Microplates were left for 1 hour at 4 °C. After aspira-
tion of the solution, plates were washed five times with
deionized water and left to dry. 50 μl of a 0.4% (w/v) of sul-
forhodamine B solution was removed and the plates were
washed five times with 1% acetic acid before air-drying.
Bound sulforhodamine B solubilize in a 200 μl 10 mM Tris-
base solution and the plates were left on a plate shaker for 10
minutes. The absorbance was read in a 96-well plate reader
at 515 nm.
CONCLUSION
In conclusion, synthesized compounds generally showed
moderate or no in vitro cytotoxic activity against HUH-7,
MCF-7 and HCT-116 cell lines. 4-Chlorobenzyl, 3-
trifluoromethylphenyl and diphenyl derivatives generally
exhibited better IC50 values when compered to others. For
our further studies, 4-chlorobenzyl derivative (compound 7)
was selected as a promising lead in order to generate more
effective anticancer agents. In addition, when the hydrogens
at sixth and seventh position of the 2,4-(1H,3H)-
quinazolinedione ring replaced by methoxy groups, cyto-
toxic activity did not increased but some selectivity was pro-
vided againts HCT-116 cell lines. This result will lead us to
synthesize more selective derivatives in our future studies.
3-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6,7-dimetho-
xyquinazoline-2,4(1H,3H)-dione (33). Compound 6 (0.280
g, 1 mmol) and 1-benzoylpiperazine (0.190 g, 1 mmol) were
reacted according to the general procedure for compounds 7-
34 and the crude product was crystallized from methanol-
ether mixture to give white powdered crystalline compound;
mp: 168.5 °C, yield: 32 mg (7%). IR (KBr, vmax, cm-1): 3010,
2958, 1712, 1660, 1623, 1513. 1H-NMR (400 MHz)
(DMSO-d6/TMS, δ, ppm): 3.51 (t, 4H, piperazine CH2), 3.66
(t, 4H, piperazine CH2), 3.79 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 4.76 (s, 2H, CH2CO), 6.71 (s, 1H, benzene CH),
7.27 (s, 1H, benzene CH), 7.45-7.49 (m, 5H, benzoyl CH),
11.32 (s, 1H, NH). Anal. calc. for C23H24N4O6. 3 H2O
(452.46 g/mol): C, 54.54; H, 5.97; N, 11.06. Found: C,
54.68; H, 5.99; N, 11.15.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
6,7-Dimethoxy-3-[2-oxo-2-(4-pyridin-4-ylpiperazin-1-
yl)ethyl]quinazoline-2,4(1H,3H)-dione (34). Compound 6
(0.280 g, 1 mmol) and 1-(4-pyridyl)piperazine (0.163 g, 1
mmol) were reacted according to the general procedure for
compounds 7-34 and the crude product was crystallized from
methanol-ether mixture to give white powdered crystalline
The authors are thankful to Prof. Dr. Hakan Goker for the
instrumental analysis.
REFERENCES
compound; mp: 300 °C (dec), yield: 32 mg (8%). IR (KBr,
[1]
Rewcastle, G.W.; Palmer, B.D.; Bridges, A.J.; Showalter, H.D.;
Sun, L.; Nelson, J.; McMichael, A.; Kraker, A.J.; Fry, D.W.;
Denny, W.A. Tyrosine kinase inhibitors. 9. Synthesis and
evaluation of fused tricyclic quinazoline analogues as ATP site
inhibitors of the tyrosine kinase activity of the epidermal growth
factor receptor. J. Med. Chem,. 1996, 16, 918-928.
1
v
max, cm-1): 3068, 2932, 1715, 1657, 1510. H-NMR (400
MHz) (DMSO-d6/TMS, δ, ppm): 3.33 (t, 2H, piperazine
CH2), 3.43 (t, 2H, piperazine CH2, J=4.4 Hz), 3.54 (t, 2H,
piperazine CH2, J=4.8 Hz), 3.70 (t, 2H, piperazine CH2,

A Series of 2,4(1H,3H)-Quinazolinedione Derivatives
Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1 75
[2]
Goldstein, D.M.; Gray, N.S.; Zarrinkar, P.P. High-throughput
kinase profiling as a platform for drug discovery. Nat. Rev. Drug
Discov., 2008, 7, 391-397.
antibacterial activities versus multidrug-resistant gram-positive and
fastidious organism groups. Antimicrob. Agents Chemother., 2007,
51, 1191-1201.
German, N.; Malik, M.; Rosen, J.D.; Drlica, K.; Kerns, R.J. Use of
gyrase resistance mutants to guide selection of 8-methoxy-
quinazoline-2,4-diones. Antimicrob. Agents Chemother., 2008, 52,
3915-3921.
Malik, M.; Hoatam, G.; Chavda, K.; Kerns, R.J.; Drlica, K. Novel
approach for comparing the abilities of quinolones to restrict the
emergence of resistant mutants during quinolone exposure.
Antimicrob. Agents Chemother., 2010, 54, 149-156.
Malik, M.; Marks, K.R.; Mustaev, A.; Zhao, X.; Chavda, K.;
Kerns, R.J.; Drlica, K. Fluoroquinolone and quinazolinedione ac-
tivities against wild-type and gyrase mutant strains of Mycobacte-
rium smegmatis. Antimicrob. Agents Chemother., 2011, 55, 2335-
2343.
Oppegard, L.M.; Streck, K.R.; Rosen, J.D.; Schwanz, H.; Drlica,
K.; Kerns, R.J.; Hiasa, H. Comparison of in vitro activities of
fluoroquinolone-like 2,4- and 1,3-diones. Antimicrob. Agents
Chemother. 2010, 54, 3011-3014.
Pan, X.S.; Gould, K.; Fisher, L.M. Probing the Differential
Interactions of Quinazolinedione PD 0305970 and Quinolones with
Gyrase and Topoisomerase IV. Antimicrob. Agents Chemother.,
2009, 53, 3822-3831.
Okumura, R.; Hirata, T.; Onodera, Y.; Hoshino, K.; Otani, T.;
Yamamoto, T. J. Dual-targeting properties of the 3-aminopyrrolidyl
quinolones, DC-159a and sitafloxacin, against DNA gyrase and
topoisomerase IV: contribution to reducing in vitro emergence of
quinolone-resistant Streptococcus pneumoniae. Antimicrob.
Chemother., 2008, 62, 98-104.
Pan, X.S.; Fisher, L.M. Probing the differential interactions of
quinazolinedione PD 0305970 and quinolones with gyrase and
topoisomerase IV. Antimicrob. Agents Chemother., 1998, 42, 2810-
2816.
Strahilevitz, J.; Hooper, D.C. Dual targeting of topoisomerase IV
and gyrase to reduce mutant selection: direct testing of the para-
digm by using WCK-1734, a 167 new fluoroquinolone, and cipro-
floxacin. Antimicrob. Agents Chemother., 2005, 49, 1949-1956.
Hassan, M.A.; Mohamed, A.; Younes, A.M.M.; Taha, M.M.; Bakr,
A.; Abdel, H. Synthesis and reactions of 3-aminotetrachloroquina-
zolin-2,4-dione. Eur. J. Chem., 2011, 2, 514-518.
Hassan, M.A.; Younes, A.M.M.; Taha, M.M.; Abdel-Monsef, A.
Synthesis and reactions of 3-(2-chloromethyl-carbonylamino)-
tetrachloroquinazolin-2,4-dione. Org, Chem. Int., 2012, 2, 1-4.
Clark, R.L.; Clements, C.J.; Barrett, M.P.; Mackay, S.P.; Rathnam,
R.P.; Owusu-Dapaah, G.; Spencer, J.; Huggan, J.K. Identification
and development of the 1,4-benzodiazepin-2-one and quinazoline-
2,4-dione scaffolds as submicromolar inhibitors of HAT. Bioorg.
Med. Chem., 2012, 20, 6019-6033.
[3]
[4]
Narang, A.S.; Desai, D.S. Anticancer Drug Development. Pharm.
Perspect. Cancer Ther., 2009, 49-92.
[23]
[24]
[25]
Marzaro, G.; Guiotto, A.; Chilin, A. Quinazoline derivatives as
potential anticancer agents: a patent review (2007 - 2010). Expert
Opin. Ther. Pat., 2012, 22, 223-252.
Sutherland, H.; Hwang, I.; Marshall, E.; Lindsay, B.; Denny, W.;
Gilchrist, C.; Joseph, W.; Greenhalgh, D.; Richardson, E.; Kestell,
P.; Ding, A.; Baguley, B. Therapeutic reactivation of mutant p53
protein by quinazoline derivatives. Invest. New Drugs, 2012, 30,
2035-2045.
Englund, E.E.; Neumann, S.; Eliseeva, E.; McCoy, J.G.; Titus, S.;
Zheng, W.; Southall, N.; Shin, P.; Leister. W.; Thomas, C. J.;
Inglese, J.; Austin, C.P.; Gershengorn, M.C.; Huang, W. The
synthesis and evaluation of dihydroquinazolin-4-ones and
quinazolin-4-ones as thyroid stimulating hormone receptor
agonists. Med. Chem. Comm., 2011, 2, 1016-1020.
Zhou, X.; Xie, X.; Liu, G. Quinazoline-2,4(1H, 3H)-diones inhibit
the growth of multiple human tumor cell lines. Mol. Divers., 2013,
17, 197-219.
McDonald, A.; Bergnes, G.; Morgans, D.J. Compounds,
compositions and methods. U.S. Patent WO2004026226 (A2),
2004.
El-Deeb, I. M.; Bayoumi, S.M.; El-Sherbeny, M.; Abdel-Aziz,
M.A. El-Deeb, I.M.; Bayoumi, S.M.; El-Sherbeny, M.; Abdel-Aziz,
M. A. Synthesis and antitumor evaluation of novel cyclic
arylsulfonylureas: ADME-T and pharmacophore prediction. Eur. J.
Med. Chem., 2010, 45, 2516-2530.
Richter, S.; Gioffreda, B. Synthesis, molecular modelling and
biological evaluation of 4-amino-2(1H)-quinazolinone and
2,4(1H,3H)-quinazolidone derivatives as antitumor agents. Arch.
Pharm., 2011, 344, 810-820.
Choo, H.P.; Kim, M.; Lee, S.K.; Kim, S.W.; Chung, I.K. Solid-
phase combinatorial synthesis and cytotoxicity of 3-aryl-2,4-
quinazolindiones. Bioorg. Med. Chem., 2002, 10, 517-523.
Jin, H. Z.; Du, J. L.; Zhang, W. D.; Yan, S. K.; Chen, H. S.; Lee, J.
H.; Lee, J. J. A new quinazolinedione alkaloid from the fruits of
Evodia officinalis. Fitoterapia, 2008, 79, 317-318.
Betti, M.; Genesio, E.; Panico, A.; Coccone, S.S.; Wiedenau, P.
Process development and scale-up for the preparation of the 1-
methyl-quinazoline-2,4-dione Wnt inhibitor SEN461. Org. Process
Res. Dev., 2013, 17, 1042-1051.
Kakuta, H.; Tanatani, A.; Nagasawa, K.; Hashimoto, Y. Specific
nonpeptide inhibitors of puromycin-sensitive aminopeptidase with
[5]
[6]
[26]
[27]
[28]
[7]
[8]
[9]
[10]
[29]
[30]
[11]
[12]
[13]
[31]
[32]
[33]
[14]
[15]
a
2,4(1H,3H)-quinazolinedione skeleton. Chem. Pharm. Bull.,
2003, 51, 1273-1282.
Hashimoto, Y. Structural development of biological response
modifiers based on retinoids and thalidomide. Mini Rev. Med.
Chem., 2002, 2, 543-551.
[34]
[35]
Ji, Q.G.; Yang, D.; Deng, Q.; Ge, Z.Q.; Yuan, L.J. Design, synthe-
sis, and evaluation of novel 1-methyl-3-substituted quinazoline-2,4-
dione derivatives as antimicrobial agents. Med. Chem. Res., 2013,
23, 2169-2177.
[16]
[17]
Appels, N.M.; Beijnen, J.H.; Schellens, J.H. Development of farne-
syl transferase inhibitors: a review. Oncologist, 2005, 10, 565-578.
Tizot, A.; Tucker, G.C.; Pierré, A.; Hickman, J.; Goldstein, S.
Controlled exploration of structural databases: the case of farnesyl
transferase inhibitors. Med. Chem., 2009, 5, 208-215.
Lane, K,T.; Beese, L.S. Thematic review series: lipid posttransla-
tional modifications. Structural biology of protein farnesyltrans-
ferase and geranylgeranyltransferase type I. J. Lipid Res., 2006, 47,
681-699.
Carrico, D.; Blaskovich, M.; Bucher, C.J.; Sebti, S.M.; Hamilton,
A.D. Design, synthesis, and evaluation of potent and selective ben-
zoyleneurea-based inhibitors of protein geranylgeranyltransferase-
I. Bioorg. Med. Chem., 2005, 13, 677-688.
Leysen, J.E.; Awouters, F.; Kennis, L.; Laduron, P.M.;
Vandenberk, J.; Janssen, P.A.J. Receptor binding profile of
R41468, a novel antagonist at 5-HT2 receptor. Life Sci., 1981, 28,
1015-1022.
Zaranappa; Vagdevi, H.M.; Jayanna N.D. Synthesis, characteriza-
tion and evaluation of antibacterial activity of some 3-
substitutedphenylquinazoline-2,4-diones. Der Pharma Chemica,
2012, 4, 1754-1758.
Malancona, S.; Donghi, M.; Ferrara, M.; Martin Hernando, J.I.;
Pompei, M.; Pesci, S.; Ontoria, J.M.; Koch, U.; Rowley, M.;
Summa, V. Allosteric inhibitors of hepatitis C virus NS5B polym-
erase thumb domain site II: structure-based design and synthesis of
new templates. Bioorg. Med. Chem., 2010, 18, 2836-2848.
Combrink, K.D.; Gulgeze, H.B.; Thuring, J.W.; Yu, K.L.; Civiello,
R.L.; Zhang, Y.; Pearce, B.C.; Yin, Z.; Langley, D.R.; Kadow,
K.F.; Cianci, C.W.; Li,Z.; Clarke, J.; Genovesi, E.V.; Medina, I.;
Lamb, L.; Yang, Z.; Zadjura, L.; Krystal, M.; Meanwell, N. Respi-
ratory syncytial virus fusion inhibitors. Part 6: an examination of
the effect of structural variation of the benzimidazol-2-one hetero-
cycle moiety. Bioorg. Med. Chem. Lett., 2007, 17, 4784-4790.
Kuran, B.; Krawiecka, M.; Kossakowski, J.; Pindel, Ł.;
Młynarczyk, G.; Cieślak, M.; Kaźmierczak-Barańska, J. Synthesis
[18]
[19]
[20]
[21]
[22]
[36]
[37]
[38]
and biological activity of
a
novel series of 6,7-
dimethoxyquinazoline-2,4(1H,3H)-dione derivatives. Acta Pol.
Pharm., 2012, 69, 145-148.
Wenting, G.J.; Man in't Veld, A.J.; Woittiez, A.J.; Boomsma, F.;
Schalekamp, M.A. Treatment of hypertension with ketanserin, a
new selective 5-HT2 receptor antagonist. Br. Med. J., 1982, 284,
537-539.
Huband, M.D.; Cohen, M.; Zurack, M.; Hanna, D.L.; Skerlos, L.;
Sulavik, M.C.; Gibson, G.W.; Gage, J.W.; Ellsworth, E.; Stier, M.;
Gracheck, S.J. In vitro and in vivo activities of PD 0305970 and PD
0326448, new bacterial gyrase/topoisomerase inhibitors with potent

76 Letters in Drug Design & Discovery, 2016, Vol. 13, No. 1
Akgun et al.
[39]
[40]
[41]
[42]
Hedner, T.; Persson, B.; Berglund, G. Ketanserin, a novel 5-
hydroxytryptamine antagonist: monotherapy in essential hyperten-
sion. Br. J. Clin. Pharmacol., 1983, 16, 121-125.
[52]
[53]
Elansary, A.K.; Kadry, H.H.; Ahmed, E.M.; Sonousi, A.S.M. De-
sign, synthesis, and biological activity of certain quinazolinedione
derivatives as potent phosphodiestrase-4 inhibitors. Med. Chem.
Res., 2012, 21, 3557-3567.
Redondo, M.; Zarruk, J.G.; Ceballos, P.; Pérez, D.I.; Pérez, C.;
Perez-Castillo, A.; Moro, M.; Brea, J.; Val, C.; Cadavid, M.I.;
Loza, M.I.; Campillo, N.E.; Martínez, A.; Gil, C. Neuroprotective
efficacy of quinazoline type phosphodiesterase-7 inhibitors in cel-
lular cultures and experimental stroke model. Eur. J. Med. Chem.,
2012, 47, 175-185.
Lowe, J.; Archer, R.L.; Chapin, D.S.; Chen, J.B.; Helweg, D.;
Johnson, J.L.; Koe, B.K.; Lebel, L.; Moore, P.F.; Nielsen, J. Struc-
ture-activity relationship of quinazolinedione inhibitors of calcium-
independent phosphodiesterase. J. Med. Chem., 1991, 34, 624-628.
Rzasa, R.M.; Kaller, M.R.; Liu, G.; Magal, E.; Nguyen, T.T.;
Osslund, T.D.; Powers, D.; Santora, V.J.; Viswanadhan, V.N.;
Wang, H.L.; Xiong, X.; Zhong, W.; Norman, M.H. Structure-
activity relationships of 3,4-dihydro-1H-quinazolin-2-one deriva-
tives as potential CDK5 inhibitors. Bioorg. Med. Chem., 2007, 15,
6574-6595.
Lee, B.H.; Choi, M.J.; Jo, M.N.; Seo, H.J.; Nah, S.Y.; Cho, Y.S.;
Nam, G.; Pae, A.N.; Rhim, H.; Choo, H. Quinazolindione deriva-
tives as potent 5-HT3A receptor antagonists. Bioorg. Med. Chem.,
2009, 17, 4793-4796.
Vagdevi, H.M.; Rajanna, M.; Gowdarshivannanavar, B.C. Synthe-
sis and antioxidant activity of 3-substituted schiff bases of quina-
zoline-2,4-diones. Int. J. Chem. Tech. Res., 2012, 4, 1527-1533.
Liverton, N.J.; Armstrong, D.J.; Claremon, D.; Remy, D.C.;
Baldwin, J.J.; Lynch, R.J.; Zhang, G.; Gould, R.J. Nonpeptide gly-
coprotein IIb/IIIa inhibitors: substituted quinazolinediones and
quinazolinones as potent fibrinogen receptor antagonists. Bioorg.
Med. Chem. Lett., 1998, 8, 483-486.
Tahmatzopoulos, A.; Rowland, R.G.; Kyprianou, N. The role of
alpha-blockers in the management of prostate cancer. Expert. Opin.
Pharmacother., 2008, 5, 1279-1285.
Papadopoulos, E.P. Reactions of o-aminonitriles with isocyanates.
2. A facile synthesis of imidazo[1,2-c]quinazoline-2,5-(3H,6H)-
dione. J. Heterocyclic Chem., 1981, 18, 515-518.
Havera, H.J. Derivatives of 1,3-disubstituted 2,4(1H,3H)-
quinazolinediones as possible peripheral vasodilators or antihyper-
tensive agents. J. Med. Chem., 1979, 22, 1548-1550.
Usifoh, C.O.; Scriba, G.K. Synthesis and anticonvulsant activity of
acetylenic quinazolinone derivatives. Arch. Pharm., 2000, 333,
261-266.
Prashanth, M.K.; Madaiah, M.; Revanasiddappa, H.D.; Veeresh, B.
Synthesis, anticonvulsant, antioxidant and binding interaction of
novel N-substituted methylquinazoline-2,4(1H,3H)-dione deriva-
tives to bovine serum albumin: a structure-activity relationship
study. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2013, 110,
324-332.
Koller, M.; Lingenhoehl, K.;, Schmutz, M.; Vranesic, I.T.; Kallen,
J.; Auberson, Y.P.; Carcache, D.; Mattes, H.; Ofner, S.; Orain, D.;
Urwyler, S. Quinazolinedione sulfonamides: a novel class of com-
petitive AMPA receptor antagonists with oral activity. Bioorg.
Med. Chem. Lett., 2011, 21, 3358-3361.
Abdel Ghany, A.E. Synthesis and anticonvulsant activity of 1,3-
disubstituted 2,4(1H,3H)quinazolinedione. Bull. Pharm. Sci., 2005,
28, 45-56.
Catarzi, D.; Lenzi, O.; Colotta, V.; Varano, F.; Poli, D.; Filac-
chioni, G.; Lingenhöhl, K. Pharmacological characterization of
some selected 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-
2-carboxylates and 3-hydroxyquinazoline-2,4-diones as (S)-2-
amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid recep-
tor antagonists. Chem. Pharm. Bull., 2010, 58, 908-911.
Colotta, V.; Catarzi, D.; Varano, F.; Calabri, F.R. Filacchioni, G.;
Costagli, C.; Galli, A. 3-Hydroxy-quinazoline-2,4-dione as a useful
scaffold to obtain selective Gly/NMDA and AMPA receptor an-
tagonists. Bioorg. Med. Chem. Lett., 2004, 14, 2345-2349.
Colotta, V.; Catarzi, D.; Varano, F.; Lenzi, O.; Filacchioni, G.;
Costagli, C.; Galli, A.; Ghelardini, C.; Galeotti, N.; Gratteri, P.;
Sgrignani, J.; Deflorian, F.; Moro, S. Structural investigation of the
7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain
AMPA and kainate receptor selective antagonists. Synthesis, phar-
macological, and molecular modeling studies. J. Med. Chem.,
2006, 49, 6015-6026.
Orain, D.; Ofner, S.; Koller, M.; Carcache, D.A.; Froestl, W.;
Allgeier, H.; Rasetti, V.; Nozulak, J.; Mattes, H.; Soldermann, N.;
Floersheim, P.; Desrayaud, S.; Kallen, J.; Lingenhoehl, K.;
Urwyler, S. 6-Amino quinazolinedione sulfonamides as orally ac-
tive competitive AMPA receptor antagonists. Bioorg. Med. Chem.
Lett., 2012, 22, 996-999.
Kirincich, S.J.; Xiang, J.; Green, N.; Tam, S.; Yang, H.Y.; Shim, J.;
Shen, M.W.H.; Clark, J.D.; McKew, J.C. Benzhydrylquinazolin-
ediones: novel cytosolic phospholipase A2alpha inhibitors with
improved physicochemical properties. Bioorg. Med. Chem., 2009,
17, 4383-4405.
[54]
[55]
[43]
[44]
[45]
[56]
[57]
[58]
[46]
[47]
[59]
[60]
[61]
Tran, T.P.; Ellsworth, E.L.; Sanchez, J.P.; Watson, B.M.; Stier, M.;
Showalter, H.D.H.; Domagala, J.M.; Shapiro, M.; Joannides, E.T.;
Gracheck, S.J.; Nguyen, D.Q.; Bird, P.; Yip, J.; Sharadendu, A.;
Ha, C.; Ramezani, S.; Wu, X.; Singh, R. Structure-activity relation-
ships of 3-aminoquinazolinediones, a new class of bacterial type-2
topoisomerase (DNA gyrase and topo IV) inhibitors. Bioorg. Med.
Chem. Lett., 2007, 17, 1312-1320.
Akgun, H.; Hollstein, U.; Hurwitz, L. Synthesis of some substituted
quinazolinediones as potential inhibitors of smooth muscle contrac-
tion. J. Pharm. Sci., 1988, 77, 735-739.
[48]
[49]
[62]
[63]
[64]
Sharafi-Kolkeshvandi, M.; Nikpour, F. A facile and convenient
approach for the one-pot synthesis of 2,4(1H,3H)-
quinazolinediones. Chinese Chem. Lett., 2012, 23, 431-433.
El-hashash, M.A.; Rizk, S.A.; El-bassiouny, F.A. Uses of 2-ethoxy-
4(3H)-quinazolinone in synthesis of quinazoline and quinazolinone
derivatives of antimicrobial activity: the solvent effect. Glob. J.
Health Sci., 2012, 4, 162-173.
[50]
[51]
Chandrika, P.M.; Rao, A.R.R.; Narsaiah, B.; Raju, M.B. Quina-
zoline derıvatives with potent anti-inflammatory and anti-allergic
activities. Int. J. Chem. Sci., 2008, 6, 1119-1146.
Langlois, M.; Soulier, J.L.; Rampillon, V.; Gallais, C.; Brémont,
B.; Shen, S.; Yang, D.; Giudice, A.; Sureau, F. Synthesis of
quinazoline-2,4-dione and naphthalimide derivatives as new 5-HT3
receptor antagonists. Eur. J. Med. Chem., 1994, 29, 925-940.
[65]
Komatsu, M.; Nishii, S.; Ueda, H. Process for producing dioxo-
quinazolines. Eur. Patent EP 0789020 A1, 1997.
Received: March 22, 2015
Revised: May 23, 2015
Accepted: May 29, 2015