Synthesis and β-glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-ones

Article abstract of DOI:10.1016/j.bmc.2014.04.039

2-Arylquinazolin-4(3H)-ones 1-25 were synthesized by reacting anthranilamide with various benzaldehydes using CuCl₂·2H ₂O as a catalyst in ethanol under reflux. Synthetic 2-arylquinazolin-4(3H)-ones 1-25 were evaluated for their β-glucuronidase inhibitory potential. A trend of inhibition IC₅₀ against the enzyme in the range of 0.6-198.2 μM, was observed and compared with the standard d-saccharic acid 1,4-lactone (IC₅₀ = 45.75 ± 2.16 μM). Compounds 13, 19, 4, 12, 14, 22, 23, 25, 15, 8, 17, 11, 21, 1, 3, 18, 9, 2, and 24 with the IC₅₀ values within the range of 0.6-44.0 μM, indicated that the compounds have superior activity than the standard. The compounds showed no cytotoxic effects against PC-3 cells. A structure-activity relationship is established.

Full text of DOI:10.1016/j.bmc.2014.04.039

Accepted Manuscript
Synthesis and β-glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-
ones
Khalid Mohammed Khan, Syed Muhammad Saad, Nimra Naveed Shaikh,
Shafqat Hussain, Muhammad Imran Fakhri, Shahnaz Perveen, Muhammad
Iqbal Choudhary
PII:
S0968-0896(14)00304-6
DOI:
http://dx.doi.org/10.1016/j.bmc.2014.04.039
BMC 11534
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 March 2014
17 April 2014
18 April 2014
Please cite this article as: Khan, K.M., Saad, S.M., Shaikh, N.N., Hussain, S., Fakhri, M.I., Perveen, S., Choudhary,
M.I., Synthesis and β-glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-ones, Bioorganic & Medicinal
Chemistry (2014), doi: http://dx.doi.org/10.1016/j.bmc.2014.04.039
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Synthesis and β-glucuronidase inhibitory activity of 2-arylquinazolin-
4(3H)-ones
a
Khalid Mohammed Khan,∗ Syed Muhammad Saad,a Nimra Naveed Shaikh,a Shafqat
Hussain,a Muhammad Imran Fakhri,a Shahnaz Perveen,b Muhammad Iqbal Choudharya,c
aH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi-75270, Pakistan
bPCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-
75280, Pakistan
cDepartment of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah-2254,
Saudi Arabia
Abstract
2-Arylquinazolin-4(3H)-ones 1-25 were synthesized by reacting anthranilamide with various
benzaldehydes using CuCl2.2H2O as a catalyst in ethanol under reflux. Synthetic 2-
arylquinazolin-4(3H)-ones 1-25 were evaluated for their β-glucuronidase inhibitory potential.
A trend of inhibition IC50 against the enzyme in the range of 0.6 - 198.2 µM, was observed
and compared with the standard D-saccharic acid 1,4-lactone (IC50 = 45.75 2.16 µM).
Compounds 13, 19, 4, 12, 14, 22, 23, 25, 15, 8, 17, 11, 21, 1, 3, 18, 9, 2, and 24 with the IC50
values within the range of 0.6 to 44.0 µM, indicated that the compounds have superior
activity than the standard. The compounds showed no cytotoxic effects against PC-3 cells. A
structure-activity relationship is established.
Keywords
2-Arylquinazolin-4(3H)-ones, β-Glucuronidase inhibition, Structure-Activity Relationship,
Cytotoxicity
1. Introduction
Quinazolines are the nitrogenous heteroaromatic compounds formed by the fusion of benzene
with a pyrimidine ring. These fused bicyclic organic compounds are also called
benzopyrimidines. Quinazoline nucleus has been of a great interest to the medicinal chemists
because of its diversified pharmacological properties.1-10 Many drugs contain quinazoline
∗Corresponding authors: hassaan2@super.net.pk; khalid.khan@iccs.edu; Tel.: 0092-21-34824910; Fax: 0092-
21-34819018
1

skeleton as the key feature.11-17 Quinazolines are known to possess antimicrobial,18
anticonvulsant,19 antiinflammatory,20 antiallergic,21 leishmanicidal22 and hypolipidemic
properties.23
β-Glucuronidase (EC 3.2.1.31) is an inducible enzyme found in anaerobic Escherichia,
Bacteroides, Clostridia and Peptostreptococcus genera which catalyzes the cleavage of β-
glucuronosyl-O-bonds.24 The enzyme exists in many human body fluids and organs such as
bile, kidney, serum, spleen, and urine.25,26 β-Glucuronidase has enhanced activity in a variety
of pathological conditions, including epilepsy,27 renal diseases,28 urinary tract infection,29-32
transplantation rejection33 and neoplasm of bladder,34 breast,35 larynx35 and testes.35
Moreover, β-glucuronidase has been reported to be released in the synovial fluid in the
inflammatory joint diseases, for instance, rheumatoid arthritis.36,37 The involvement of β-
glucuronidase in the colon cancer and higher intestinal levels of the enzyme is correlated to
the higher incidence of colon carcinoma.38 Therefore, inhibition of β-glucuronidase enzyme
is effective in preventing various diseases.
2. Results and Discussion
2.1. Chemistry
For the study of β-glucuronidase inhibition, twenty-five derivatives of 2-arylquinazolin-
4(3H)-ones were prepared by reacting anthranilamide with various benzaldehyde derivatives,
catalyzed by CuCl2.2H2O in ethanol under reflux (Scheme-1 and Table-1). Precipitates were
formed upon addition of water into the reaction mixture, which were filtered, washed with
water, and dried under vacuum. The structures of the derivatives were deduced by 1H-NMR
and EI mass spectrometry. All compounds furnished satisfactory elemental analyses.
2.2. Enzyme Inhibitory Studies
Enzymatic inhibition is a key area of medicinal chemistry which is directly relevant to drug
discovery and development against a variety of diseases. Our research group has recently
reported the β-glucuronidase inhibitory activity of substituted benzimidazoles.39 Based on
close structural similarities of 2-arylquinazolin-4(3H)-ones with the substituted
benzimidazoles, we synthesized twenty-five 2-arylquinazolin-4(3H)-one derivatives 1-25 and
evaluated their potential against β-glucuronidase (Scheme-1 and Table-1).
2

Compounds 1-25 demonstrated a varying degree of inhibition of the enzyme with IC50 values
in the range of 0.6 0.45 - 198.2 2.88 µM, when compared with the standard D-saccharic
acid 1,4-lactone (IC50 = 45.75 2.16 µM). Compounds 13 (IC50 = 0.6 0.45 µM), 19 (IC50 =
0.7 0.12 µM), 4 (IC50 = 1.1 0.05 µM), 12 (IC50 = 1.17 0.12 µM), 14 (IC50 = 1.5 0.05
µM), 22 (IC50 = 1.8 0.11 µM), 23 (IC50 = 1.8 0.02 µM), 25 (IC50 = 2.1 0.07 µM), 15
(IC50 = 2.1 0.06 µM), 8 (IC50 = 2.8 0.05 µM), 17 (IC50 = 3.2 0.11 µM), 11 (IC50 = 5.5
0.14 µM), 21 (IC50 = 10.0 0.54 µM), 1 (IC50 = 20.1 0.92 µM), 3 (IC50 = 22.2 0.31 µM),
18 (IC50 = 30.9 2.64 µM), 9 (IC50 = 37.7 1.21 µM), 2 (IC50 = 39.8 2.88 µM), and 24
(IC50 = 44.0 3.12 µM) exhibited superior activities than the standard D-saccharic acid 1,4-
lactone (IC50 = 45.75 2.16 µM). Compounds 7 (IC50 = 50.4 1.40 µM), and 16 (IC50
=
61.03 6.26 µM) possess activity comparable to the standard. Nonetheless, compounds 10
(IC50 = 120.5 2.54 µM), 5 (IC50 = 172.7 4.84 µM), 20 (IC50 = 170.0 5.04 µM), and 6
(IC50 = 198.2 2.88 µM) displayed weak inhibition of the enzyme.
Structure-activity relationship studies suggested that the β-glucuronidase inhibitory activities
of this class of compounds are mainly dependent upon the substitutions on the phenyl ring,
present at C-2 of the quinazolin-4(3H)-one skeleton.
Compound 13 (IC50 = 0.6 0.45 µM) showed the highest β-glucuronidase inhibition amongst
the series which is 76-folds higher than the standard D-saccharic acid 1,4-lactone. The two
methoxy groups at C-3′ and C-4′ demonstrated most appropriate arrangement to interact with
the enzyme. When one methoxy group at C-3′ was replaced with a hydrogen as in compound
4 (IC50 = 1.1 0.05 µM), the activity decreased to almost half. Replacement of hydroxyl
group at C-3′ with a methoxy group, as in compound 8 (IC50 = 2.8 0.05 µM), the activity
declined five times. Replacement of both the methoxy groups of compound 13 by hydroxyl
groups, as in compound 15 (IC50 = 2.1 0.06 µM), a decline trend in activity was observed.
When both methoxy groups were replaced with the hydrogens, as in compound 20 (IC50
=
177.0 5.04 µM) a four times weaker activity than the standard was observed. The
trisubstitution of methoxy groups at C-3′, C-4′, and C-5′ of the phenyl moiety, as in compound
10 (IC50 = 120.5 2.54 µM), substantially lowered the activity. Compound 19 (IC50 = 0.7
0.01 µM) exhibited 65-folds more potent activity than the standard. Replacement of ethoxy
group with nitro or chloro, as in compounds 14 (IC50 = 1.5 0.05 µM) or 23 (IC50 = 1.8
0.02 µM), resulted in two-fold decline in activity. Similarly, the exchange of ethoxy with
hydroxyl group as in compound 21 (IC50 = 10.0 0.54 µM), lowered the activity by 14-folds.
3

Replacement of ethoxy group from C-2′ to C-4′ as in compound 25 (IC50 = 2.1 0.07 µM),
also lowered the activity. In context of compound 4, when its methoxy group was replaced
with dimethylamino group, as in compound 11 (IC50 = 5.5 0.14 µM), the activity was
lowered to five times. Similarly, replacing the methoxy group with nitro or hydroxyl groups,
as in compounds 1 (IC50 = 20.1 0.92 µM) or 3 (IC50 = 22.2 0.31 µM), the activity further
decreased. Placement of chloro group instead of dimethlamino, as in compound 2 (IC50
=
39.8 2.88 µM), further lowered the activity, but still more potent than in comparison with
the standard. Presence of methyl group at C-4′, as in compound 5 (IC50 = 172.7 4.84 µM),
exhibited second weakest inhibitory activity among all the derivatives.
2.3. Cytotoxicity Studies
Compounds 1–25 were tested against PC-3 cells for cytotoxicity the results are shown in
Table-2. The IC50 values of compounds showed no cytotoxicity effects towards PC-3 cells.
3. Conclusions
We have synthesized twenty-five differently substituted 2-arylquinazolin-4(3H)-ones and
evaluated their inhibitory potential against β-glucuronidase. Compounds, 13, 19, 4, 12, 14,
22, 23, 25, 15, 8, 17, 12, 21, 1, 3, 18, 9, and 2 exhibited IC50 values in the range of 0.6 to 39.8
µM, and hence were found to have excellent activity in comparison of standard D-saccharic
acid 1,4-lactone. This series can serve as lead for the development of novel class of β-
glucuronidase inhibitors. Further optimization based on SAR is required to genuinely lead to
a range of compounds to explore their β-glucuronidase inhibiting potentials.
4. Experimental
4.1. Material and methods
β-Glucuronidase (E.C. 3.2.1.31 from E. coli, G7396) and p-nitrophenyl-β-D-glucuronide (N-
1627) were acquired from Sigma-Aldrich Chemical Co. (U.S.A.). Anthranilamide,
substituted benzaldehydes, and CuCl2.2H2O were purchased from TCI (Japan) and were of
analytical grade. Ethanol was dried by using magnesium turnings/I2. All reagents were of
reagent grade and used directly without purification.
1H-NMR experiments were performed on Avance Bruker AM 400 MHz equipment. Electron
Impact Mass Spectrometry (EIMS) experiments were carried out on a Finnigan MAT-311A
4

(Germany) mass spectrometer. CHN analyses were performed on a Carlo Erba
Strumentazion-Mod-1106, Italy. Thin layer chromatography (TLC) was performed on
pre-coated silica gel aluminum plates (Kieselgel 60, 254, E. Merck, Germany).
Chromatograms were visualized under UV at 254 and 365 nm or by iodine vapours spray.
4.2. Assay for β-Glucuronidase Inhibitory Activity
β-Glucuronidase inhibitory activity was evaluated by measuring the absorbance at 405 nm of
p-nitrophenol formed from the substrate by the spectrophotometeric method. The total
reaction volume was 250 µL. The reaction mixture contained 0.1 M acetate buffer (185 µL),
°
test compound solution (5 µL), and enzyme solution (10 µL) were incubated at 37 C for 30
min. The plates were read on a multiplate reader (SpectraMax plus 384, Molecular Devices,
USA) at 405 nm after the addition of 0.4 mM p-nitrophenyl-β-D-glucuronide (50 µL).40 All
experiments were performed in triplicate.
4.3. Assay for Cytotoxicity
Cytotoxic activity of compounds was evaluated in 96-well flat-bottomed micro-plates by
using the standard MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide]
colorimetric assay. For this purpose, PC-3 cells (Prostate Cancer) / 3T3( Mouse fibroblast)
were cultured in Dulbecco’s Modified Eagle’s Medium, supplemented with 5% of foetal
bovine serum (FBS), 100 IU/mL of penicillin and 100 µg/mL of streptomycin in 25 cm3 flask
and kept in 5% CO2 incubator at 37 °C. Exponentially growing cells were harvested, counted
with haemocytometer and diluted with a particular medium. Cell culture with the
concentration of 1 x 105 cells/mL was prepared and introduced (100 µL/well) into 96-well
plates. After overnight incubation, medium was removed and 200 µL of fresh medium was
added with different concentrations of compounds (1-100 µM). After 72 h, 50 µL MTT (2
mg/mL) was added to each well and incubated further for 4 h. Subsequently, 100 µL of
DMSO was added to each well. The extent of MTT reduction to formazan within cells was
calculated by measuring the absorbance at 570 nm, using a microplate ELISA reader (Spectra
Max plus, Molecular Devices, CA, USA). The cytotoxicity was recorded as concentration
causing 50% growth inhibition for PC-3/ 3T3 cells.41
4.4. General procedure for the synthesis of compounds 1–25
5

In a typical procedure, 2-arylquinazolin-4(3H)-ones 1-25 were synthesized by mixing
anthranilamide (2 mmol), substituted benzaldehydes (2.1 mmol) and CuCl2.2H2O (4 mmol)
in ethanol (15 mL). The mixtures were refluxed for 16 h, while progress of the reaction was
monitored through thin layer chromatography. After completion of reaction, the reaction
mixtures were cooled to room temperature and distilled water was added until the formation
of precipitates. The precipitates were filtered and washed with distilled water. This reaction
afforded good yields of title compounds.
4.4.1. 2-(4′-Nitrophenyl)quinazolin-4(3H)-one (1)
Yield: 90%; 1H-NMR: (400 MHz, DMSO-d6): δH 12.84 (s, 1H, NH), 8.42 (m, 4H, H-3′, H-5′,
H-2′, H-6′), 8.18 (d, 1H, J5,6 = 8.0 Hz, H-5), 7.89 (m, 1H, H-7), 7.80 (d, 1H, J8,7 = 7.6 Hz, H-
8), 7.59 (t, 1H, J6(5,7) = 8 Hz, H-6); EI-MS: m/z (rel. abund. %), 267 (M+, 100), 221 (83.1),
119 (87.3). Anal. Calcd for C14H9N3O3: C, 62.92; H, 3.39; N, 15.72; O, 17.96; Found: C,
62.91; H, 3.40; N, 15.71.
4.4.2. 2-(4′-Chlorophenyl)quinazolin-4(3H)-one (2)
1
Yield: 94%; H-NMR: (400 MHz, DMSO-d6): δH 12.60 (s, 1H, NH), 8.20 (d, 1H, J5,6 = 8.4
Hz, H-5), 8.15 (d, 2H, J3′,2′ = J5′,6′ = 8.0 Hz, H-3′, H-5′), 7.86 (t, 1H, J7(6,8) = 7.2 Hz, H-7), 7.74
(d, 1H, J8,7 = 8.0 Hz, H-8), 7.63 (d, 2H, J2′,3′ = J6′,5′ = 8.8 Hz, H-2′, H-6′), 7.54 (t, 1H, J6(5,7)
=
7.2 Hz, H-6); EI-MS: m/z (rel. abund. %), 258 (M++2, 30.8), 256 (M+, 100), 119 (89.9). Anal.
Calcd for C14H9ClN2O: C, 65.51; H, 3.53; Cl, 13.81; N, 10.91; O, 6.23; Found: C, 65.50; H,
3.52; N, 10.92.
4.4.3. 2-(4′-Hydroxyphenyl)quinazolin-4(3H)-one (3)
1
Yield: 99%; H-NMR: (400 MHz, DMSO-d6): δH 12.29 (s, 1H, NH), 10.14 (s, 1H, 4′-OH),
8.11 (m, 1H, H-5), 8.03 (d, 2H, J2′,3′ = J6′,5′ = 8.4 Hz, H-2′, H-6′), 7.80 (t, 1H, J7(6,8) = 7.2 Hz,
H-7), 7.67 (d, 1H, J8,7 = 8.0 Hz, H-8), 7.47 (t, 1H, J6(5,7) = 7.2 Hz, H-6), 6.89 (d, 2H, J3′,2′
=
J5′,6′ = 8.8 Hz, H-3′, H-5′); EI-MS: m/z (rel. abund. %), 238 (M+, 100), 237 (5.4), 221 (4.6),
119 (82.6). Anal. Calcd for C14H10N2O2: C, 70.58; H, 4.23; N, 11.76; O, 13.43; Found: C,
70.57; H, 4.24; N, 11.77.
4.4.4. 2-[4′-(Methyloxy)phenyl]quinazolin-4(3H)-one (4)
Yield: 84%; 1H-NMR: (400 MHz, DMSO-d6): δH 12.40 (s, 1H, NH), 8.18 (m, 3H, H-5, H-2′,
H-6′), 7.80 (m, 2H, H-7, H-8), 7.47 (s, 1H, H-6), 7.10 (d, 2H, J3′,2′ = J5′,6′ = 7.6 Hz H-3′, H-5′),
6

3.85 (s, 3H, 4′-OCH3); EI-MS: m/z (rel. abund. %), 252 (M+, 100), 237 (3.2), 235 (2.9), 119
(64.8). Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10; O, 12.68; Found: C, 71.43;
H, 4.78; N, 11.11.
4.4.5. 2-(4′-Methylphenyl)quinazolin-4(3H)-one (5)
Yield: 89%; 1H-NMR: (400 MHz, DMSO-d6): δH 12.45 (s, 1H, NH), 8.12 (m, 3H, H-5, H-2′,
H-6′), 7.82 (t, 1H, J7(6,8) = 7.2 Hz, H-7), 7.72 (d, 1H, J8,7 = 8.0 Hz, H-8), 7.51 (t, 1H, J6(5,7)
=
7.6 Hz, H-6), 7.36 (d, 2H, J3′,2′ = J5′,6′ = 8.4 Hz, H-3′, H-5′), 2.38 (s, 3H, 4′-CH3); EI-MS: m/z
(rel. abund. %), 236 (M+, 100), 219 (4.1), 119 (96.7). Anal. Calcd for C15H12N2O: C, 76.25;
H, 5.12; N, 11.86; O, 6.77; Found: C, 76.24; H, 5.11; N, 11.85.
4.4.6. 2-(3′-Hydroxyphenyl)quinazolin-4(3H)-one (6)
1
Yield: 88%; H-NMR: (400 MHz, DMSO-d6): δH 12.42 (s, 1H, NH), 9.74 (s, 1H, 3′-OH),
8.14 (m, 1H, H-5), 7.84 (m, 1H, H-7), 7.72 (d, 1H, J8,7 = 8.0 Hz, H-8), 7.59 (m, 2H, H-6, H-
2′), 7.52 (m, 1H, H-6′), 7.34 (m, 1H, H-5′), 6.97 (m, 1H, H-4′); EI-MS: m/z (rel. abund. %),
238 (M+, 81.6), 237 (8.5), 221 (7.3), 119 (100). Anal. Calcd for C14H10N2O2: C, 70.58; H,
4.23; N, 11.76; O, 13.43; Found: C, 70.59; H, 4.25; N, 11.76.
4.4.7. 2-(3′-Nitrophenyl)quinazolin-4(3H)-one (7)
Yield: 64%; 1H-NMR: (400 MHz, DMSO-d6): δH 12.87 (s, 1H, NH), 9.02 (s, 1H, H-2′), 8.61
(d, 1H, J4′,5′ = 8.0 Hz, H-4′), 8.43 (d, 1H, J6′,5′ = 7.2 Hz, H-6′), 8.18 (d, 1H, J5′,6′ = 7.6 Hz, H-
5′), 7.87 (m, 3H, H-7, H-8, H-6), 7.58 (t, 1H, J5′(4′,6′) = 7.6 Hz, H-5′); EI-MS: m/z (rel. abund.
%), 267 (M+, 100), 221 (78.5), 119 (29.6). Anal. Calcd for C14H9N3O3: C, 62.92; H, 3.39; N,
15.72; O, 17.96; Found: C, 62.93; H, 3.38; N, 15.70.
4.4.8. 2-[3′-Hydroxy-4′-(methyloxy)phenyl]quinazolin-4(3H)-one (8)
1
Yield: 100%; H-NMR: (400 MHz, DMSO-d6): δH 12.30 (s, 1H, NH), 9.35 (s, 1H, 3′-OH),
8.09 (s, 1H, H-5), 7.77 (m, 5H, H-7, H-8, H-6, H-6′, H-5′), 7.04 (s, 1H, H-2′), 3.85 (s, 3H, 4′-
OCH3); EI-MS: m/z (rel. abund. %), 268 (M+, 100), 253 (25.9), 119 (82.3). Anal. Calcd for
C15H12N2O3: C, 67.16; H, 4.51; N, 10.44; O, 17.89; Found: C, 67.15; H, 4.52; N, 10.44.
7

4.4.9. 2-(2′,6′-Dichlorophenyl)quinazolin-4(3H)-one (9)
1
Yield: 96%; H-NMR: (400 MHz, DMSO-d6): δH 12.79 (s, 1H, NH), 8.19 (d, 1H, J5,6 = 7.2
Hz, H-5), 7.89 (m, 1H, H-7), 7.73 (d, 1H, J8,7 = 8.0 Hz, H-8), 7.65 (m, 4H, H-6, H-4′, H-3′, H-
5′); EI-MS: m/z (rel. abund. %), 292 (M++2, 65.3), 290 (M+, 100), 273 (6.1), 255 (68.8), 220
(5.7), 119 (8.5). Anal. calcd for C14H8Cl2N2O: C, 57.76; H, 2.77; Cl, 24.36; N, 9.62; O, 5.50;
Found: C, 57.78; H, 2.75; N, 9.63.
4.4.10. 2-[3′,4′,5′-Tris(methyloxy)phenyl]quinazolin-4(3H)-one (10)
1
Yield: 99%; H-NMR: (400 MHz, DMSO-d6): δH 12.51 (s, 1H, NH), 8.15 (d, 1H, J5,6 = 7.2
Hz, H-5), 7.82 (m, 1H, H-7), 7.75 (d, 1H, J8,7 = 8.0 Hz, H-8), 7.55 (s, 2H, H-5′, H-6′), 7.52
(m, 1H, H-6), 3.89 (s, 6H, 3′-OCH3, 5′-OCH3), 3.73 (s, 3H, 4′-OCH3); EI-MS: m/z (rel. abund.
%), 312 (M+, 100), 297 (35.5), 281 (6.8), 119 (6.6). Anal. Calcd for C17H16N2O4: C, 65.38; H,
5.16; N, 8.97; O, 20.49; Found: C, 65.39; H, 5.18; N, 8.94.
4.4.11. 2-[4′-(Dimethylamino)phenyl]quinazolin-4(3H)-one (11)
Yield: 99%; 1H-NMR: (400 MHz, DMSO-d6): δH 12.26 (s, 1H, NH), 8.10 (m, 3H, H-5, H-2′,
H-6′), 7.79 (m, 1H, H-7), 7.67 (d, 1H, J8,7 = 8.4 Hz, H-8), 7.45 (m, 1H, H-6), 6.81 (d, 2H, J3′,2′
= J5′,6′ = 8.8 Hz, H-3′, H-5′), 3.02 (s, 6H, 4′-N(CH3)2); EI-MS: m/z (rel. abund. %), 265 (M+,
100), 250 (6.1), 221 (5.2), 119 (33.5). Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N,
15.84; O, 6.03; Found: C, 72.45; H, 5.68; N, 15.81.
4.4.12. 2-[3′-(Ethyloxy)-4′-hydroxyphenyl]quinazolin-4(3H)-one (12)
1
Yield: 98%; H-NMR: (400 MHz, DMSO-d6): δH 12.32 (s, 1H, NH), 9.67 (s, 1H, 4′-OH),
8.11 (d, 1H, J5,6 = 7.6 Hz, H-5), 7.77 (m, 3H, H-7, H-8, H-2′), 7.68 (d, 1H, J6′,5′ = 8.0 Hz, H-
6′), 7.47 (t, 1H, J6(5,7) = 7.2 Hz, H-6), 6.91 (d, 1H, J5′,6′ = 8.4 Hz, H-5′), 4.16 (q, 2H, J(CH2,CH3)
=
6.8 Hz, CH2), 1.39 (t, 3H, J(CH3,CH2) = 7.2 Hz, CH3); EI-MS: m/z (rel. abund. %), 282 (M+,
100), 267 (29.3), 254 (80.9), 238 (11.9), 119 (46.8). Anal. Calcd for C16H14N2O3: C, 68.07;
H, 5.00; N, 9.92; O, 17.00; Found: C, 68.05; H, 5.04; N, 9.94.
8

4.4.13. 2-[3′,4′-Bis(methyloxy)phenyl]quinazolin-4(3H)-one (13)
Yield: 100%; 1H-NMR: (400 MHz, DMSO-d6): δH 12.43 (s, 1H, NH), 8.13 (d, 1H, J5,6 = 7.6
Hz, H-5), 7.86 (m, 3H, H-7, H-8, H-2′), 7.71 (d, 1H, J8,7 = 8.0 Hz, H-8), 7.49 (d, 1H, J6′,5′
=
7.6 Hz, H-6′), 7.11 (d, 1H, J5′,6′ = 8.4 Hz, H-5′), 3.87 (s, 3H, 4′-OCH3), 3.83 (s, 3H, 3′-OCH3);
EI-MS: m/z (rel. abund. %), 282 (M+, 100), 267 (21.4), 251 (25.7), 119 (20.6). Anal. Calcd
for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92; O, 17.00; Found: C, 68.05; H, 5.04; N, 9.94.
4.4.14. 2-(2′-Nitrophenyl)quinazolin-4(3H)-one (14)
1
Yield: 92%; H-NMR: (400 MHz, DMSO-d6): δH 12.82 (s, 1H, NH), 8.21 (m, 2H, H-3′,5),
7.90 (m, 4H, H-5′, H-6′, H-4′, H-7), 7.65 (d, 1H, J8,7 = 8.4 Hz, H-8), 7.59 (t, 1H, J6(5,7) = 7.2
Hz, H-6); EI-MS: m/z (rel. abund. %), 267 (M+, 100), 250 (5.5), 221 (20.8), 119 (57.6). Anal.
Calcd for C14H9N3O3: C, 62.92; H, 3.39; N, 15.72; O, 17.96; Found: C, 62.91; H, 3.40; N,
15.74.
4.4.15. 2-(3′,4′-Dihydroxyphenyl)quinazolin-4(3H)-one (15)
1
Yield: 96%; H-NMR: (400 MHz, DMSO-d6): δH 12.21 (s, 1H, NH), 9.64 (s, 1H, 4′-OH),
9.29 (s, 1H, 3′-OH), 8.10 (d, 1H, J5,6 = 8.0 Hz, H-5), 7.78 (d, 1H, J8,7 = 7.2 Hz, H-8), 7.66 (m,
2H, H-7, H-2′), 7.54 (d, 1H, J6′,5′ = 8.0 Hz, H-6′), 7.46 (t, 1H, J6(5,7) = 7.6 Hz, H-6), 6.83 (d,
1H, J5′,6′ = 8.0 Hz, H-5′); EI-MS: m/z (rel. abund. %), 254 (M+, 8.0), 146 (100), 119 (25.5).
Anal. calcd for C14H10N2O3: C, 66.14; H, 3.96; N, 11.02; O, 18.88; Found: C, 66.12; H, 3.93;
N, 11.05.
4.4.16. 2-(2′,4′-Dichlorophenyl)quinazolin-4(3H)-one (16)
1
Yield: 99%; H-NMR: (400 MHz, DMSO-d6): δH 12.65 (s, 1H, NH), 8.17 (d, 1H, J5,6 = 7.6
Hz, H-5), 7.85 (m, 2H, H-7, H-3′), 7.71 (m, 2H, H-8, H-6), 7.59 (m, 2H, H-6′, H-5′); EI-MS:
m/z (rel. abund. %), 292 (M++2, 44.3), 290 (M+, 66.4), 273 (3.7), 255 (5.9), 220 (3.0), 119
(100). Anal. Calcd for C14H8Cl2N2O: C, 57.76; H, 2.77; Cl, 24.36; N, 9.62; O, 5.50; Found:
C, 57.75; H, 2.80; N, 9.60.
9

4.4.17. 2-(2′,5′-Dihydroxyphenyl)quinazolin-4(3H)-one (17)
1
Yield: 95%; H-NMR: (300 MHz, DMSO-d6): δH 12.60 (s, 1H, NH), 12.29 (s, 1H, 2′-OH),
9.08 (s, 1H, 5′-OH), 8.14 (d, 1H, J5,6 = 7.5 Hz, H-5), 7.86 (t, 1H, J7(6,8) = 7.5 Hz, H-7), 7.73
(d, 1H, J8,7 = 8.1 Hz, H-8), 7.60 (s, 1H, H-6′), 7.54 (t, 1H, J6(5,7) = 7.2 Hz, H-6), 6.92 (m, 2H,
H-3′, H-4′); EI-MS: m/z (rel. abund. %), 254 (M+, 100), 119 (36.3). Anal. Calcd for
C14H10N2O3: C, 66.14; H, 3.96; N, 11.02; O, 18.88; Found: C, 66.16; H, 3.95; N, 11.03.
4.4.18. 2-[2′-Hydroxy-3′-(methyloxy)phenyl]quinazolin-4(3H)-one (18)
1
Yield: 100%; H-NMR: (300 MHz, DMSO-d6): δH 13.94 (s, 1H, NH), 12.46 (s, 1H, 2′-OH),
8.16 (d, 1H, J5,6 = 7.5 Hz, H-5), 7.86 (m, 3H, H-7, H-6, H-4′), 7.56 (t, 1H, J6′(4′,5′) = 7.2 Hz, H-
6′), 7.17 (d, 1H, J8,7 = 8.1 Hz, H-8), 6.90 (t, 1H, J5′(4′,6′) = 8.1 Hz, H-5′), 3.82 (s, 3H, 3′-OCH3);
EI-MS: m/z (rel. abund. %), 268 (M+, 100), 239 (50.2), 225 (53.9), 119 (39.1). Anal. Calcd
for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44; O, 17.89; Found: C, 67.17; H, 4.54; N, 10.42.
4.4.19. 2-[2′-(Ethyloxy)phenyl]quinazolin-4(3H)-one (19)
Yield: 97%; 1H-NMR: (400 MHz, DMSO-d6): δH 12.03 (s, 1H, NH), 8.14 (t, 1H, J5(6,7) = 6.8
Hz, H-5), 7.84 (m, 1H, H-7), 7.76 (dd, 1H, J6′,5′ = 7.2 Hz, J6′,4′ = 1.2 Hz, H-6′), 7.70 (d, 1H,
J8,7 = 8.0 Hz, H-8), 7.53 (m, 2H, H-6, H-3′), 7.18 (d, 1H, J3′,4′ = 8.4 Hz, H-3′), 7.09 (t, 1H,
J4′(3′,5′) = 7.2 Hz, H-4′), 4.16 (q, 2H, J(CH2,CH3) = 7.2 Hz, CH2), 1.35 (t, 3H, J(CH3,CH2) = 6.8 Hz,
CH3); EI-MS: m/z (rel. abund. %), 266 (M+, 23.9), 251 (51.8), 238 (14.6), 222 (21.2), 119
(100). Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52; O, 12.02; Found: C, 72.15;
H, 5.32; N, 10.55.
4.4.20. 2-Phenylquinazolin-4(3H)-one (20)
Yield: 97%; 1H-NMR: (300 MHz, DMSO-d6): δH 12.54 (s, 1H, NH), 8.18 (m, 3H, H-5, H-7,
H-8), 7.83 (d, 1H, J8,7 = 7.2 Hz, H-8), 7.75 (d, 1H, J4′,3′ = J4′,5′ = 7.8 Hz, H-4′), 7.56 (m, 4H,
H-2′, H-6′, H-3′, H-5′); EI-MS: m/z (rel. abund. %), 222 (M+, 83.3), 119 (100). Anal. Calcd for
C14H10N2O: C, 75.66; H, 4.54; N, 12.60; O, 7.20; Found: C, 75.64; H, 4.56; N, 12.64.
10

4.4.21. 2-(2′-Hydroxyphenyl)quinazolin-4(3H)-one (21)
1
Yield: 58%; H-NMR: (300 MHz, DMSO-d6): δH 13.70 (s, 1H, NH), 12.61 (s, 1H, 2′-OH),
8.23 (d, 1H, J5,6 = 7.8 Hz, H-5), 8.16 (d, 1H, J6′,5′ = 7.5 Hz, H-6′), 7.87 (t, 1H, J7(6,8) = 7.2 Hz,
H-7), 7.77 (d, 1H, J8,7 = 8.1 Hz, H-8), 7.56 (t, 1H, J6(5,7) = 7.2 Hz, H-6), 7.47 (t, 1H, J4′(3′,5′)
=
7.8 Hz, H-4′), 7.01 (m, 2H, H-5′, H-3′); EI-MS: m/z (rel. abund. %), 238 (M+, 100), 119
(77.5). Anal. Calcd for C14H10N2O2: C, 70.58; H, 4.23; N, 11.76; O, 13.43; Found: C, 70.57;
H, 4.22; N, 11.78.
4.4.22. 2-[2′-Hydroxy-5′-(methyloxy)phenyl]quinazolin-4(3H)-one (22)
1
Yield: 82%; H-NMR: (400 MHz, DMSO-d6): δH 13.42 (s, 1H, NH), 12.55 (s, 1H, 2′-OH),
8.15 (d, 1H, J5,6 = 7.6 Hz, H-5), 7.84 (m, 3H, H-7, H-8, H-6), 7.53 (s, 1H, H-6′), 7.05 (s, 1H,
H-4′), 6.94 (d, 1H, J3′,4′ = 7.6 Hz, H-3′), 3.78 (s, 3H, 5′-OCH3); EI-MS: m/z (rel. abund. %),
268 (M+, 76.9), 253 (100), 119 (3.8). Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; N,
10.44; O, 17.89; Found: C, 67.15; H, 4.53; N, 10.43
4.4.23. 2-(2′-Chlorophenyl)quinazolin-4(3H)-one (23)
Yield: 98 %; 1H-NMR: (300 MHz, DMSO-d6): δH 12.62 (s, 1H, NH), 8.17 (d, 1H, J5,6 = 7.2
Hz, H-5), 7.84 (s, 1H, H-6′), 7.71 (m, 6H, H-7, H-8, H-6, H-3′, H-4′, H-5′); EI-MS: m/z (rel.
abund. %), 258 (M++2, 27.0), 256 (M+, 75.5), 239 (6.9), 221 (8.4), 119 (100). Anal. Calcd for
C14H9ClN2O: C, 65.51; H, 3.53; Cl, 13.81; N, 10.91; O, 6.23; Found: C, 65.49; H, 3.54; N,
10.91.
4.4.24. 2-(2′-Bromo-6′-hydroxyphenyl)quinazolin-4(3H)-one (24)
1
Yield: 76%; H-NMR: (300 MHz, DMSO-d6): δH 13.81 (s, 1H, NH), 12.57 (s, 1H, 6′-OH),
8.45 (s, 1H, H-5), 8.16 (d, 1H, J8,7 = 6.7 Hz, H-8), 7.86 (m, 2H, H-7, H-6), 7.57 (m, 2H, H-3′,
H-4′), 6.98 (d, 1H, J5′,4′ = 6.6 Hz, H-5′); EI-MS: m/z (rel. abund. %), 318 (M++2, 100), 316
(M+, 100), 238 (3.7), 145 (3.8), 119 (47.2). Anal. Calcd for C14H9BrN2O2: C, 53.02; H, 2.86;
Br, 25.20; N, 8.83; O, 10.09; Found: C, 53.04; H, 2.84; N, 8.85.
11

4.4.25. 2-[4′-(Ethyloxy)phenyl]quinazolin-4(3H)-one (25)
1
Yield: 98%; H-NMR: (400 MHz, DMSO-d6): δH 12.39 (s, 1H, NH), 8.18 (d, 1H, J5,6 = 8.7
Hz, H-5), 8.13 (d, 2H, J2′,3′ = J6′,5′ = 8.1 Hz, H-2′, H-6′), 7.82 (t, 1H, J7(6,8) = 7.2 Hz, H-7), 7.70
(d, 1H, J8,7 = 8.1 Hz, H-8), 7.49 (t, 1H, J6(5,7) = 7.2 Hz, H-6), 7.07 (d, 2H, J3′,2′ = J5′,6′ = 8.7
Hz, H-3′, H-5′), 4.13 (q, 2H, J(CH2,CH3) = 6.9 Hz, CH2), 1.37 (t, 3H, J(CH3,CH2) = 6.9 Hz, CH3);
EI-MS: m/z (rel. abund. %), 266 (M+, 100), 238 (23.1), 221 (3.7), 119 (57.2). Anal. Calcd for
C16H14N2O2: C, 72.16; H, 5.30; N, 10.52; O, 12.02; Found: C, 72.18; H, 5.33; N, 10.51.
Acknowledgements: The authors are thankful to the Organisation for the Prohibition of
Chemical Weapons (OPCW), The Netherlands, for their financial support for project No.
L/ICA/ICB/173681/12.
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14

Captions of all figures and tables:
Table-1: β-Glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-ones, 1-25
Table-2: Cytotoxicity of compounds 1-25 for cytotoxicity against PC-3 cells in vitro
Scheme-1: General procedure for the synthesis of compounds 1–25
15

4.2. General procedure for the synthesis of compounds 1–25
16

Table-1: β-Glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-ones, 1-25
Compound
No.
Ar
Yield; %
IC50 SEMa [µM]
2'
5'
1'
3'
4'
90
20.1 0.92
1
2
3
4
5
6
7
6'
NO2
94
99
84
89
88
64
39.8 2.88
22.2 0.31
1.1 0.05
2'
5'
1'
3'
4'
6'
OMe
172.7 4.84
198.2 2.88
50.4 1.40
17

2'
5'
OH
1'
3'
4'
100
96
2.8 0.05
8
9
6'
OMe
37.7 1.21
2'
OMe
OMe
1'
3'
4'
99
120.5 2.54
10
6'
5'
OMe
99
98
5.5 0.14
1.17 0.12
0.6 0.45
11
12
13
100
NO2
2'
1'
3'
4'
92
96
99
1.5 0.05
2.1 0.06
14
15
16
6'
5'
2'
OH
OH
1'
3'
4'
6'
5'
61.03 6.26
95
3.2 0.11
17
18

100
30.9 2.64
18
97
97
58
0.7 0.01
177.0 5.04
10.0 0.54
19
20
21
OH
2'
1'
3'
4'
6'
5'
82
98
1.8 0.11
22
23
1.8 0.02
OH
6'
1'
76
98
44.0 3.12
5'
4'
24
25
2'
Br
3'
2.1 0.07
aSEM is the standard error of the mean.
Standard: D-Saccharic acid 1,4-lactone, IC50 SEM = 45.75 2.16 µM
19

Table-2: Cytotoxicity of compounds 1-25 for cytotoxicity against PC-3 cells in vitro
Compounds
1
IC50 (µM) SEM
Compounds
14
IC50 (µM) SEM
>30
>30
2
3
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
15
>30
>30
16
>30
4
17
>30
5
18
>30
6
19
>30
7
20
>30
8
21
>30
9
22
>30
10
11
12
13
23
>30
24
25
>30
Doxorubicin Std.
0.912 0.12
20

Synthesis and -glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-ones
β
Khalid Mohammed Khan,*a Syed Muhammad Saad,a Nimra Naveed Shaikh,a Shafqat Hussain,a Muhammad Imran Fakhri,a
Shahnaz Perveen,b Muhammad Iqbal Choudharya,c
aH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi,
Karachi-75270, Pakistan.
bPCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi-75280, Pakistan.
cDepartment of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah-22254, Saudi Arabia.
O
O
O
CuCl2.2H2O
NH2
NH2
NH
Ar
+
H
Ar
EtOH; ∆
N
Twenty-five 2-arylquinazolin-4(3H)-one derivatives 1-25 were synthesized by reacting anthranilamide with various
benzaldehydes using CuCl2.2H2O as a catalyst in ethanol under reflux for 16 h. Synthetic 2-arylquinazolin-4(3H)-ones
1 25
-
were evaluated for their β-glucuronidase inhibitory potential.