Synthesis and biological evaluation of some 3H-quinazolin-4-one derivatives

Article abstract of DOI:10.1007/s13738-021-02315-8

Starting from 3-phenylquinazoline-2,4(1H,3H)-dithione, some new derivatives of 3H-quinazoline-4-ones were synthesized. The structures of all new compounds were inferred based on the mass spectral, infrared, and NMR spectral data as well as the elemental analytical data. Some compounds were chosen for testing their biological activities as antibacterial, antifungal, and anticancer agents. Graphic abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s13738-021-02315-8

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-021-02315-8
ORIGINAL PAPER
Synthesis and biological evaluation of some 3H‑quinazolin‑4‑one
derivatives
Afrah Sharaf1,2 · Sherif Shaban Ragab3 · Ahmed A. Elbarbary1 · Elkhabiry Shaban4 · Ibrahim El Tantawy El Sayed5
Received: 7 February 2021 / Accepted: 8 June 2021
© Iranian Chemical Society 2021
Abstract
Starting from 3-phenylquinazoline-2,4(1H,3H)-dithione, some new derivatives of 3H-quinazoline-4-ones were synthesized.
The structures of all new compounds were inferred based on the mass spectral, infrared, and NMR spectral data as well as
the elemental analytical data. Some compounds were chosen for testing their biological activities as antibacterial, antifungal,
and anticancer agents.
Graphic abstract
Keywords Quinazolinones · Synthesis · Nucleosides · Biological · Antibacterial
* Sherif Shaban Ragab
she2rifx@yahoo.com
* Ahmed A. Elbarbary
aeelbarbary@hotmail.com
Extended author information available on the last page of the article
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Introduction
Results and discussion
The wide range of pharmacological activities of quina-
zolinones made them a major source of attraction during
the last decades. They are essentially used as analgestic
[1–3], antinfammatory [4, 5], diuretic [6–8], anticonvul-
sants [9–11], potential antispasmolytic [12], long active
sedatives [1, 13], bronchodilators [14], and cholertic
agents [15]. Additionally, 1,2,4-triazoloquinazoline deriv-
atives [16, 17] were found to be promising biologically
active compounds having potent antihypertensive [18, 19],
antihistaminic [20, 21] with negligible sedation [22], and
anticancer activities [23, 24]. Many derivatives of quina-
zolinone are patented and used in the market as potential
drugs for diferent kinds of diseases (Scheme 1).
The starting 3-phenyl-2-thioxo-2,3-dihydro-1H-quinazolin-
4-one 1 was synthesized according to the reported procedure
[28] by refuxing a mixture of 2-aminobenzoic acid and phe-
nyl isothiocyanate and thiation of the produced compound
with phosphorus pentasulphide in boiling anhydrous pyri-
dine to yield 1 in good yield.
Coupling compound 1 with (2,3,4,6-tetra-O-acetyl-α-
D-glucopyranosyl)bromide (ABG) in the presence of Et3N
in DMF at r.t. aforded the corresponding S-nucleoside 2.
Attempt to deblock compound 2 using MeONa at room tem-
perature aforded the starting aglycone 1 [29, 30] instead of
the desired deblocked compound (3) (Scheme 2).
S-Alkylation of compound 1 was achieved by its treat-
ment with some alkylating agents namely: MeI, BzCl, and/
or phenacyl chloride at room temperature that yielded the
corresponding 2-alkylthio derivatives 4a-c, respectively.
On treatment of the S-benzyl derivative (4b) with boiling
NH2NH2 in MeOH aforded the corresponding hydrazino
derivative (5) through SNAr reaction and replacing SBz
Accordingly, all these facts with our previous work
[25–27] directed us to synthesize some new derivatives of
3H-quinazoline-4-ones for testing their biological activi-
ties as antibacterial, antifungal, and anticancer agents.
Scheme 1 Representative
examples of quinazoline
containing-drugs
Scheme 2 Synthesis of S-nucleoside 2 and attempt for deblocking
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Journal of the Iranian Chemical Society
with NH2-NH2 (Scheme 3). Fusion of compound 1 with
ethyl chloroformate and/or ethyl chloroacetate at the boil-
ing point of each of the reactants yielded the corresponding
2-alkylthio derivatives (6a,b). By the same manner, refux-
ing compound 1 with ethyl chloroacetoacetate in MeOH
for 4 h aforded ethyl-3-oxo-2-(3-phenyl-4-thioxo-1,2,3,4-
tetrahydro-quinazolin-2-ylthio) butanoate 7 (Scheme 3).
Refuxing compound 1 with diphenyl diazomethane (pre-
pared according to known method [31]) in anhydrous ben-
zene for 6 h gave 2-(benzhydrylthio)-3-phenylquinazoline-
4(3H)-thione 8 via S–H insertion as the sole product (tlc)
and not 8i (corresponding to SH elimination) or 8ii (cor-
responding to N–H insertion) (Scheme 4). The structures 8i
and 8ii were ruled out based on diferent spectroscopic data.
As the IR and 1H-NMR spectra showed the absence of NH
for 8i or SH for 8ii, while in the 1H-NMR spectrum of 8 there
is a singlet peak centered at 3.51 ppm corresponding to one
proton assigned to S-CH (Scheme 5).
The amino phosphonates (10a-d), which are phosphonic
analogs of naturally occurring α–amino acids, could be syn-
thesized when the starting compound 9 [30] was allowed to
react with a mixture of triethyl- and/or triphenyl-phosphite
and some aromatic aldehydes namely: benzaldehyde and
4-clorobenzaldehyde in boiling glacial AcOH for 4–6 h
to aford the corresponding amino phosphonates (10a-d)
(Scheme 6).
To understand how compounds 10a-d were formed, the
reaction pathway shown in (Scheme 7) was postulated:
Refuxing compound 9 with triethylorthoformate in gla-
cial AcOH for 3 h yielded 11 as the sole product (as evi-
denced from tlc) through the elimination of EtOH without
any formation of the cyclized one 12 (Scheme 8). Structure
Scheme 3 Synthesis of com-
pounds 4–7
Scheme 4 Reaction of 1 with
diphenyl diazomethane
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Journal of the Iranian Chemical Society
Scheme 5 Reaction pathway for
synthesis of compound 8
Scheme 6 Synthesis of amino
phosphonates 10a-d
Scheme 7 Reaction pathway for
synthesis of compound 10
1
12 was ruled out based on the IR and H-NMR spectral
data, where the IR spectrum showed the characteristic NH
stretching at 3448 cm−1. Moreover, the 1HNMR spectrum
revealed the appearance of characteristic protons of ethyl
group (a quartet peak for CH2 at 4.10 ppm, and a triplet
peak at 1.61 ppm for CH3). The microanalytical data gave
an additional evidence for the structure 11.
cyclized one (14). The cyclized structure 14 was ruled out
according to the IR and MS spectral data. Its IR spectrum
showed 2 CO groups at 1610 cm−1 and 1660 cm−1. The
microanalytical data gave an additional proof for this struc-
ture 13 (Scheme 9). While reacting 9 with phenyl isothyo-
cyanate under the same above reaction conditions for 3 h
aforded the cyclized structure 15 as the sole product via
elimination of H2O (Scheme 9).
Treatment of compound 9 with 4-chlorophenyl isocyanate
in boiling pyridine for 5 h aforded the open ring structure
13 as the entire product (tlc) without any formation of the
Reaction of compound
9
with chloroac-
etaldehyde in boiling EtOH for 3 h yielded
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Journal of the Iranian Chemical Society
Scheme 8 Synthesis of com-
pounds 12
Scheme 9 Synthesis of compounds 14–17
2-(3-amino-6,8-dibromo-4-oxo-1,2,3,4-tetrahydroquina-
zolin-2-ylthio)-acetaldehyde (16) as the sole product (tlc)
without any traces of the cyclized structure 17. While fusion
of compound 9 with 1,3-propane- and/or 1,4-butane-sultone
(18a,b) at 180 °C aforded the corresponding sultams 19a,b,
respectively (Scheme 10).
groups have focused on their synthesis and biological
activities over the last 20 years. A considerable number
of amino and/or ester group derivatives were reported
to be antiviral, antibacterial, antifungal, and anticancer
[34–45]. Producing new antimicrobial and anticancer safe
agents is a great concern, and this is due to the increase in
contamination and microbial infection by microorganisms
and cancer diseases in the last few years. The aim of the
present study is to investigate the antitumor activity of
some newly synthesized quinazolinone derivatives.
Biology
Antitumor activity
Quinazolinone derivatives have been found to exhibit a
wide range of biological activities [32, 33]. Many research
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Journal of the Iranian Chemical Society
Scheme 10 Synthesis of compounds 19a,b
Table 1 Efect of compound 7
Conc. (μg/ml) Surviving ratio
on PC3cell line
0.0
5.0
1.00
0.60
12.5
25.0
50
0.584
0.291
0.182
Anticancer activity
Fig. 1 Efect of compound (7) on PC3 cell line (IC50 =16.3 μg/ml)
In vitro potential cytotoxicities of the tested compounds
were determined using the colorimetric method. Cytotoxic
activity of ethyl-3-oxo-2-(3-phenyl-4-thioxo-1,2,3,4-tetrahy-
dro-quinazolin-2-ylthio)butanoate (7) was tested against
cancer cells (5 mg/mL in DMSO), obtaining medium inhibi-
tory concentration (IC50) values in l g/mL, using a dilution
method in a 96-well plate. After 72 h incubation, the absorb-
ance was measured at 546 nm. DMSO was used as negative
control and Doxorubicin (DOX) as positive control, both at
the same concentration as the tested compounds. Compound
7 was dissolved in DMSO and subjected to cytotoxic evalu-
ation against two cancer cell lines namely: CACO and PC3
cell lines.
Table 2 Efect of compound 7
Conc. (μg/ml) Surviving ratio
on CACO cell line
0.0
5.0
12
25.0
50
1.00
0.820
0.568
0.386
0.299
and Fig. 1, the IC50 of compound 7 was 16.3 μg/ml. The
lowest survival ratio was 0.182 and obtained from the high-
est concentration of 7.
Anticancer activity of 7 against PC3 cell line
Anticancer activity of quinazolinones against CACO
cell line
Quinazolinones were reported to possess diverse pharma-
cological activities such as CNS depressant [46, 47], hyp-
notic, antiinfammatory [31, 48], muscle relaxants [49] and
for their antineoplastic activity [50]. In this study, these
compounds and their modifcation clay with Na-MMT were
examined as anticancer PC3 cell line in vitro. Table 1 and
Fig. 1 showed the anticancer activity of (7). From Table 1
Ethyl-3-oxo-2-(3-phenyl-4-thioxo-1,2,3,4-tetrahydro-quina-
zolin-2-ylthio)butanoate (7) was tested against anticancer
CACO cell line in vitro. The IC50 against CACO cell line
was 17.3 μg/ml., c. f. Table 2 and Fig. 2. Its lowest survival
ratio was 0.299 obtained from 50 μg/ml.
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Journal of the Iranian Chemical Society
Determination of minimal inhibitory concentrations (MICs)
MICs of diferent synthetic compounds were determined for
each antimicrobial agent by using agar dilution method [52].
The inhibition zone was measured in triplicates in diferent
concentrations (0.5, 1.0, 2.0 ug/ml), and the mean value of
MICs is tabulated in the following tables.
MICs (µg/ml) of compounds (9, 6b, 7 and 5) were studied
as shown in Table 4. Compounds 9, 6b and 5 showed anti-
bacterial activities, and their MICs of these compounds were
1.0 µg/ml with diferent tested organisms. While, compound
7 did not show any activity against all organisms.
Fig. 2 Efect of compound (7) on CACO cell line (IC50 =17.3 μg/
ml)
Experimental
Antimicrobial Activity
All melting points were uncorrected and performed by
the open capillary melting point apparatus. Microanalyses
were performed by Microanalysis Unit, Central Laboratory,
Tanta University, Tanta, Egypt. IR spectra were recorded
with a PerkinElmer 1720 spectrometer. The NMR spectra
were recorded on a Bruker AC 250 FT NMR spectrometer
Antimicrobial activity of some quinazolinone derivatives
Our earlier work [46] showed that some quinazolinones
did not give any antimicrobial activity with fungicides
(Fusarium solani), and bactericides (Pseudomonos solani).
Surprisingly, in our hands now we found that treatment of
compounds 9, 6b, 7, and 5 against another type of bacteria
like S.areous (MARSA) gave high antimicrobial activity.
The highest inhibition zone (25 mm) caused by compound
9 [51] (Table 3). On the other hand, testing compounds 9,
6b, 7, and 5 as fungicides (fusorium solani), and bacteri-
cides (psedomonos solani) did not show any antimicrobial
activity (Table 3). About 50 ul of streptomycin was used as
antimicrobial standard, and about 50 ul from amphotrcin
was used as standard and for antifungal.
1
at 250 MHz for H and 62.9 MHz for 13C,Varian UNITY
1
500 NMR spectrometer at 500 MHz for H or 125.7 MHz
for 13C, Bruker 200 MHz And Bruker 90 MHz spectrometer
using TMS as an internal standard, DMSO and CHCl3 as
solvents. Chemical shifts (δ) are reported in parts per million
(ppm), and signals are expressed as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet) or br (broad). Mass spec-
tra (MS) were recorded using electron ionization (E.I.) on a
Varian Mat 311A spectrometer.
Synthesis of 3‑phenylquinazoline‑2,4(1H,3H)‑dith‑
ione (1) [28]
Compound 9 showed the highest inhibition zone
(25 mm) with S.areous (MARSA) only. Its containing
amino group which might be the responsible group for
inhibitory effect on growth of S.areous MARSA. The
amino group bind with the organisms cell wall or cell
membrane or cell constituents. While, compound 7 did
not show any activity against all organisms.
To a solution of 2-aminobenzoic acid (40 g., 0.2 mol) with
phenyl isothyocyanate (0.2 mol) in anhydrous pyridine
(25 ml). The reaction mixture was refuxed for 5 h (tlc).
The solvent was evaporated to dryness under vacuum, and
the residual solid was crystallized from methanol and dried
to give 3-phenyl-2-thioxo-2,3-dihydro-1H-quinazolin-4-one
which was refuxed (0.02 mol) for 2 h (tlc) with phosphorus
pentasulphide (0.03 mol) in anhydrous pyridine (15 ml).
Table 3 Antimicrobial activity of 9, 6b, 7 and 5
Comp
Inhibition zone (mm)
Table 4 MICs (µg/ml) of compounds (9, 6b, 7 and 5)
S.areous
MARSA
E. coli
C. albicans
Comp
Inhibition zone (mm)
S. areous MARSA E. coli
C. albicans
9
25
15
−ve
21
26
−ve
−ve
−ve
−ve
21
−ve
−ve
−ve
−ve
20
9
1.0
1.0
–
–
–
–
–
–
–
–
–
6b
6b
7
7
5
5
1.0
Streptomycin
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Journal of the Iranian Chemical Society
The solvent was evaporated till dryness under vacuum. The
residual solid was recrystallized from methanol and dried to
give 1. Yield 79%; m.p. 165–167 ºC [28].
2‑(Benzylthio)‑3‑phenylquinazoline‑4(3H)‑thione
(4b)
To a solution of compound 96 (0.81 g, 0.003 mol) in EtOH
(20 ml), NaOH (0.6 gm), and benzylchloride (0.38 ml,
0.003 mol) was added, and the solution was stirred at r.t.
for 4 h (tlc). The precipitate was fltered of, recrystal-
lized from petroleum ether to aford 99b. Yield 86% m.p.
181–3 °C. IR spectrum, v, cm−1: 1200 (C=Scyclic), 1690
2‑(2,3,4,6‑Tetra‑O‑acetyl‑β‑D‑glucopyranosyl‑thio)‑
3‑phenyl‑2,3‑dihydro‑quinazoline‑4(1H)‑thione (2)
A solution of compound 1 (0.27 g, 0.001 mol) was dissolved
in a mixture of triethyl amine (2 ml) and DMF (15 ml) and
added to a solution of ABG (0.001 mol). The reaction was
complete within for 4 h at room temperature. Pouring onto
cooled water gave a solid that was fltered of, washed with
water, dried, and crystallized from ethanol to afford 2.
Yield 27%; m.p. 181–183 ºC. IR spectrum, v, cm−1: 1227
(C=Scyclic), 1610 (C=N), 1748 (C=O, acetyl), 2925 (CH); 1H
NMR (DMSO-d6), δ, ppm: 1.96 (s, 12H, 4CH3), 4.01–4.30
(s, 2H, CH2), 4.96 (dd, 1H, J=5.63 Hz, H-5`), 5.10 (t, 1H,
J = 3.04 Hz, H-4`), 5.36 (dd, 1H, J= 4.98 Hz, H-3`), 5.58
(dd, 1H, J=3.85 Hz, H-2`), 5.97 (dd, 1H, J` =4.16, H-1`),
7.39 – 8.55 (m, 9H, Har.)ppm.; 13C NMR (DMSO-d6), δC,
ppm: 20.1 (CH3, C´6), 20,3 (CH3, C´4), 20.3 (CH3, C´2),
20.3 (CH3, C´3), 61.6, 67.9, 68.5, 73.0, 75.0, 81.9 (C´6,
C´4, C´2, C´3, C´5, C´1anomeric), 127.1, 128.8, 129.04, 129.8,
130.2 (Car.), 153.5 (C=Ncyclic), 169.0, 169.2, 169.7, 169.8
(C=O, acetyl), 189.0 (C=Scyclic). Found, %: C, 55.77; H, 4.80;
N, 4.49. C28H28N2O9S2. Calculated, %: C 55.99; H 4.70; N
4.66. M 600.
1
(C=N), 2875 (CHaliph.), 3037 (CHar.); H NMR (DMSO-
d6), δ, ppm: 4.51 (s, 2H, CH2), 7.25 – 8.57 (m, 14H, Har.)
ppm; 13C NMR (DMSO-d6), δC, ppm: 39.2 (CH2), 126.8,
127.3, 128.4, 129.0, 129.4, 129.8, 129.9 and 135.4 (Car.),
156.6 (C=Ncyclic), 188.9 (C=S). Found, %: C 69.63; H
4.42; N 7.73. C21H16N2S2. Calculated, %: C 69.97; H 4.47;
N 7.77. M 360.
1‑Phenyl‑2‑(3‑phenyl‑4‑thioxo‑3,4‑dihydroquinazo‑
lin‑2‑ylthio)‑ethanone (4c)
To a solution of compound 1 (0.81 g, 0.003 mol) in anhy-
drous pyridine (15 ml), was added anhydrous K2CO3
(0.8 g, 0.006 mol) followed by the addition of phenacyl
chloride [47] (0.46 g, 0.003 mol). The reaction mixture
was left stirring at r.t. for 5 h (tlc). Filtration of the pre-
cipitate then recrystallization from MeOH aforded 4c.
Yield 82%; m.p. 192–4 °C. IR spectrum, v, cm−1: 1193
(C=S), 1635 (C=Ncyclic), 1728 (C=O Ph), 2979 (CHaliph.),
Deblocking of Compound 2. Two drops of sodium meth-
oxide solution (0.001 N) were added to methanolic solution
of (1.5 g, 0.01 ml), and the reaction mixture was stirred at
r. t. for 4 h (tlc). Vacuum evaporation of the solvent gave a
residual solid which was dissolved in water and then neutral-
ized with dil HCl. Filteration of the formed solid, washing
with water, drying, recrystallization from ethanol produced
the starting material 1 in excellent yield 1.2 g (92%); m.p.
260–262 °C [30].
1
3088 (CHar.); H NMR (DMSO-d6), δ, ppm: 4.76 (s, 2H,
CH2), 7.20– 8.51(m, 14H, Har) ppm.; 13C NMR (DMSO-
d6), δC, ppm: 43.7 (CH2CO), 126,2, 128.2, 128.7, 128.9,
129.9, 130.0, 133.4 and 135.2 (Car.),186.1 (C=Scyclic,),
193.5 (C=OC6H5). Found, %: C 67.92 H 3.93 N 7.05.
C22H16N2OS2.Calculated, %: C 68.01; H 4.15 N 7.21. M
389.
2‑(Methylthio)‑3‑phenylquinazoline‑4(3H)‑thione
(4a)
2‑Hydrazinyl‑3‑phenylquinazoline‑4(3H)‑thione (5)
Compound 1 (0.81 g, 0.003 mol) was dissolved in MeOH
(20 ml) and NaOH (0.5 g). Methyl iodide (0.13 ml,
0.003 mol) was added, and then stirring at r.t. for 5 h (tlc)
gave a solid which was fltered of, recrystallized from meth-
anol to aford 4a.
A mixture of compound 4b (2.16 g, 0.006 mol) and NH2.
NH2 (2 ml, 0.006 mol) in EtOH (20 ml) was refuxed for
5 h (tlc) and then allowed to cool. The solid formed was
collected and recrystallized from ethanol to aford 5. Yield
73%; m.p. 185–187 ºC. IR spectrum, v, cm−1: 1190 (C=S),
Yield 75%, m.p.122–4 °C. IR spectrum, v, cm−1: 1188
1
3362 (NH2 asym), 3498 (NH2 sym). H NMR (DMSO-d6),
1
(C=Scyclic), 1665 (C=N), 2925 (CH); H NMR (DMSO-
δ, ppm: 4.41 (NH2), 5.07 (NH), 7.26–8.64 (m, 9H, Har.)
ppm; 13C NMR (DMSO-d6), δC, ppm: 125.9, 126.0, 127.2,
128.3, 128.4, 129.2, 129.3, 129.4, 137.2 and 147.1(Car.),
156.8 (C=N), 160.6 (C-NH), 185.4 (C=S). Found, %: C
62.51; H 4.38; N 20.73. C14H12N4S. Calculated, %: C,
62.66; H, 4.51; N, 20.88. M 268.
d6), δ, ppm: 2.75 (s, 3H, CH3), 6.88–7.88 (m, 9H, Har.)
ppm; 13C NMR (DMSO-d6), δC, ppm: 14,1 (CH3), 122.0,
124.1, 126.1, 128.9, 136.8, 143.1 and 149.1 (Car.), 163.2
(C=Ncyclic), 179.1 (C=S). Found, %: C, 62.96; H 4.46; N
9.31. C15H12N2S2. Calculated, %: C 63.35; H 4.25; N 9.85.
M 284.
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Journal of the Iranian Chemical Society
Reaction of compound 1 with ethyl chloroformate
and/or ethyl chloroacetate
2‑(Benzhydrylthio)‑3‑phenylquinazo‑
line‑4(3H)‑thione (8)
Compound 1 (0.81 g, 0.003 mol) was fused in ethyl chloro-
formate and / or ethyl chloroacetate (0.003 mol) at 85 °C
for 4–5 h (tlc). The excess of the reagent was evaporated till
dryness under vacuum. The residual solid was crystallized
from petroleum ether (80–100 °C) to give compounds 6a
and/or 6b, respectively.
Compound 1 (0.8 g, 0.003 mol) was refuxed with diphenyl
diazomethane [31] (0.5 ml, 0.004 mol) dissolved in anhy-
drous benzene (30 ml) for 6 h (tlc). The reaction mixture was
cooled to r.t.. The formed solid was fltered of, recrystallized
from methanol, fltered, and dried to aford 8. Yield 85%,
m.p. 196–8 °C; IR spectrum, v, cm−1: 1240 (C=S), 1690
(C=N), 2927 (CHaliph.), 3090 (CHar.). 1H NMR (DMSO-d6),
δ, ppm: 3.51 (s, 1H, SCH), 6.32–8.51 (m, 19H, Har.) ppm;
13C NMR (DMSO-d6), δC, ppm: 55.2 (CH), 127.2, 128.2,
128.5, 128.6, 128.9, 129.5, 129.8 and 140.0 (Car.), 156.1
(C=N), 190.0 (C=S). Found, %: C 73.90; H 4.56; N 6.38.
C27H20N2S2. Calculated, %: C 74.28; H 4.62; N 6.42. M 436.
Ethyl‑2‑(3‑phenyl‑4‑thioxo‑1,2,3,4‑tetrahydroquina‑
zolin‑2‑ylthio)formate (6a)
Yield 87%, m.p. 184–6 °C. IR spectrum, v, cm−1: 1235
(C=S), 1690 (C=N), 1760 (C=O), 2945 (CHaliph.); 1H NMR
(DMSO-d6), δ, ppm: 1.25 (t, 3H, J = 3.61 Hz, CH3), 3.65
(q, 2H, J = 2.96 Hz, CH2), 7.20–8.55 (m,9H, Har.) ppm.;
13C NMR (DMSO-d6), δC, ppm: 22.5 (CH3), 58.1 (CH2),
115.5, 115.9, 125.2, 127.90, 128.0, 128.5, 129.0, 129.2,
131.7, 131.7, 135.2, 125.3 and 135.7 (Car.), 144.1 (C=N),
172.8 (COO), 189.7 (C=S). Found, %: C 59.26; H 4.06;
N 8.13. C17H14N2O2S2. Calculated, %: C 59.63; H 4.12; N
8.18. M 342.
Synthesis of 3‑amino‑6,8‑dibromo‑2‑thioxo‑2,3‑di‑
hydroquina‑zolin‑4(1H)‑one (9)
A mixture of 2-amino-3,5-dibromobenzoic acid hydrazide
(10 g, 0.03 mol), NaOH (1.2 g, 0.03 mol) and CS2 (0.7 ml,
0.03 mol) in ethanol (120 ml) was refuxed for 15 h (tlc).
Evaporation of the solvent gave a solid that was dissolved
in water (100 ml.) and neutralized with dil. HCl (1:1). The
precipitate that formed was fltered of, washed with H2O
(100 ml.) and recrystallized from ethanol to aford 9, yield
50%, m. p. 260 °C, reported m.p. 260–262 [30].
Ethyl‑2‑(3‑phenyl‑4‑thioxo‑1,2,3,4‑tetrahydroquina‑
zolin‑2‑ylthio)acetate (6b)
Yield 89%, m.p. 210–12 °C. IR spectrum, v, cm−1: 1197
(C=S), 1610 (C=N), 1675 (C=O), 2930 (CHaliph.); 1H NMR
(DMSO-d6), δ, ppm: 1.25 (t, 3H, J=4.71 Hz, CH3), 3.57 (d,
2H, J=3.14 Hz, CH2S), 4.21 (q, 2H, J=2.83 Hz, CH2CO),
6.20–7.85 (m, 9H, Har.) ppm; 13C NMR (DMSO-d6), δC,
ppm: 14.0 (CH3), 33.4 (CH2CO), 61.4 (CH2), 110.1, 119.8,
129.8, 130.0, 136.0, 137.9, 139.3, 143.3, 151.0 and 154.3
(Car.), 173.0 (C=N), 179.2 (C=O), 203.9 (C=S). Found, %:
C 60.29; H 4.46 N 7.81. C18H16N2O2S2. Calculated, %: C
60.65; H 4.52; N 7.86. M 356.
Reaction of compound 9 with a mixture of triethyl‑
and/or triphenyl–phosphite and aromatic aldehydes
A mixture of 9 (0.98 g, 0.0028 mol), aromatic alde-
hydes namely: benzaldehyde and 4-chloro-benzalde-
hyde (0,003 mol) and triethyl- and/or triphenylphosphite
(0.003 mol) in glacial AcOH (30 ml) was heated at 100 °C
for 4–6 h (tlc). The reaction mixture was concentrated to 1/4
volume and poured onto ice. Filtration of the formed solid
then washing with petroleum ether followed by recrystal-
lization from MeOH gave the amino phosphonates (10a-d),
respectively.
Ethyl‑3‑oxo‑2‑(3‑phenyl‑4‑thioxo‑1,2,3,4‑tetrahyd‑
roquinazolin‑2‑ylthio)butanoate (7)
To a solution of compound 1 (0.81 g, 0.003 mol) in methanol
(15 ml) and KOH (0.56 g, 0.01 mol), ethyl chloroacetoace-
tate (0.49 g, 0.003 mol) was added. The reaction mixture was
stirred at r. t. for 5 h (tlc). The solid product that separated
was fltered of and recrystallized from EtOH to give 7. Yield
78%. m.p. 190–2 °C. IR spectrum, v, cm−1: 1250 (C=S),
1610 (C=N), 1742,1665 (2C=O) 2940 (CHaliph.); 1H NMR
(DMSO-d6), δ, ppm: 1.64 (t, 3H, J=4.91 Hz,CH3CH2), 2.55
(s, 3H, CH3CO), 3.41 (q, 2H, J=2.53 Hz, CH2), 3.95 (s, 1H,
CH), 7.00–7.9 (m, 9H, H-Ar). Found, %: C 59.95: H 4.49;
N 6.99. C20H18N2O3S2. Calculated, %: C 60.28; H 4.55; N
7.03. M 398.
Diethyl(6,8‑dibromo‑4‑oxo‑2‑thioxo‑1,2‑dihydro‑
quinazolin‑3(4H)‑ylamino)(phenyl)‑methylphospho‑
nate (10a)
Yield 87%. m.p. 215–217 °C. IR spectrum, v, cm−1: 680
(C–Br), 745 (C–Cl), 1050 (P-O-C), 1260 (C=Scyclic), 1310
1
(P=O), 1687 (C=O), 2849 (CH), 3197, 3300 (2NH); H
NMR (DMSO-d6), δ, ppm: 1.22 (t, 6H, 2CH3), 2.52 (s,
1H, NHacyclic), 3.94 (s, 1H, CH), 4.15 (q, 4H, 2CH2),
7.42–8.05 (m, 6H, Har.), 8.55 (s, 1H, NHcyclic) ppm. 13C
NMR (DMSO-d6), δC, ppm: 14.1 (2CH3), 39.2 (CH),
61.1 (2CH2), 126.5, 127.4, 129.0, 129.9, 130.1, 135.50
1 3

Journal of the Iranian Chemical Society
and 139.9 (Car.), 168.2 (C=O), 188.8 (C=S). Found, %: C
37.05; H 3.08; N 6.82. C19H19Br2ClN3O4PS.Calculated,
%: C 37.31; H 6.87; N 3.13. M 611.
Ethyl N‑6,8‑dibromo‑4‑oxo‑2‑thioxo‑1,2‑dihydro‑
quina‑zolin‑3(4H)‑yl‑formimidate (11)
A mixture of compound 9 (0.7 g, 0.002 mol) and triethyl-
orthoformate (0.43 g, 0.003 mol) in glacial AcOH (25 ml)
was refuxed for 3 h (tlc). The reaction mixture was cooled
at r.t. The solid product that formed was fltered of, recrys-
tallized from EtOH and dried to give 11. Yield 76%, m. p.
192 °C. IR spectrum, v, cm−1: 670 (C–Br),1180 (C=Scyclic),
1630 (C=N), 1740 (C=Ocyclic), 2950 (CH), 3498 (NH); 1H
NMR (DMSO-d6), δ, ppm: 1.61 (t, 3H, J=4.11 Hz, CH3),
4.10 (q, 2H, J=2.17 Hz, CH2), 7.41 (s, 1H, CH), 8.23 (d, 2H,
C6H5), 8.91 (s, 1H, NH). 13C NMR (DMSO-d6), δC, ppm:
14.1 (CH3), 61.5 (CH2), 126.5, 127.4, 129.0, 130.1, 135.5
and 140.9 (Car.), 155.6 (C=N), 167.8 (C=O), 186,7 (C=S).
Found, %: C, 32.31; H, 2.14; N,10.17. C11H9Br2N3O2S. Cal-
culated, %: C, 32.45; H, 2.23; N, 10.32. M 407.
Diethyl(4‑chlorophenyl)(5,7‑dibromo‑1‑oxo‑3‑thi‑
oxo‑3,4‑di‑hydroiso‑quinolin‑2(1H)‑ylamino)meth‑
ylphosphonate (10b)
Yield 89%, m.p. 195–17 °C. IR spectrum, v, cm−1: (cm−1)
695 (C–Br), 1172 (C=S), 1050–1030 (P-O-C), 1280
(P=O), 1663 (C=O), 2955 (CHaliph.), 3065 (CHar.), 3231,
1
3410 (2NH); H NMR (DMSO-d6), δ, ppm: 1.20 (t, 6H,
2CH3), 2.51 (s, 1H, NHacyclic), 3.94 (s, 1H, CH), 4.15 (q,
4H, 2CH2), 7.40–8.05 (m, 6H, Har.), 8.55 (s, 1H, NHcyclic
)
ppm.; 13C NMR (DMSO-d6), δC, ppm: 14.6 (2CH3), 39.4
(CH), 62.1 (2CH2), 127.7, 127.8, 129.8, 129.9, 130.2,
131.6, 136.1 and 138.5 (Car.), 167.1 (C=O), 186.1 (C=S).
Found, %: C 39.51; H 3.37; N 5.96. C19H20Br2N3O4PS.
Calculated, %: C 39.53; H 3.49; N 7.28. M 437.
Reaction of compound 9 with 4‑chlorophenyl isocy‑
anate and/or phenyl isothyocyanate
To a solution of compound 9 (0.35 g, 0.001 mol) in anhy-
drous pyridine (25 ml) was added 4-chlorophenyl isocy-
anate and/or phenyl isothyocyanate (0.006 mol). The reac-
tion mixture was refuxed for 4–5 h (tlc). The solvent was
evaporated and to dryness under vacuum, and the solid
formed was recrystallized from MeOH to aford 13 and/or
15, respectively.
Diphenyl(6,8‑dibromo‑4‑oxo‑2‑thioxo‑1,2‑dihydro‑
quinazolin‑3(4H)ylamino)(phenyl)methylphospho‑
nate (10c)
Yield 80%, m.p. 220–22 °C. IR spectrum, v, cm−1: 680
(C–Br), 1120 (C=S), 1190 (P-O-C), 1260 (P=O), 1640
1
(C=O), 2849 (CH), 3321 (NH); H NMR (DMSO-d6), δ,
ppm: 2.50 (s, 1H, NHacyclic), 4.01 (s, 1H, CH), 6.45–8.05
(m, 17H, Har.), 8.55 (s, 1H, NHcyclic)ppm.; 13C NMR
(DMSO-d6), δC, ppm: 53.5 (CH), 125.5, 126.3, 128.2,
129.1, 131.7, 133.9, 134.5 and 140.7 (2Ph, Car.), 154.3
(P-O-C), 169.2 (C=O), 185.9 (C=S). Found, %: C 48.05
H 2.96 N 6.22. C27H20Br2N3O4PS. Calculated, %: C 48.16;
H 2.99; N 6.24. M 673.
1‑(4‑Chlorophenyl)‑3‑(6,8‑dibromo‑4‑oxo‑2‑thi‑
oxo‑1,2‑dihydroquinazolin‑3(4H)‑yl)urea (13)
Yield 57%. m.p. 192–4 °C. IR spectrum, v, cm−1: 1190
(C=Scyclic), 1610 (C=Ocyclic), 1660 (O=C-NH), 2961 (CH),
1
3450 (NH); H NMR (DMSO-d6), δ, ppm: 7.30–8.21 (m,
6H, Har.), 8.81 (s, 1H, NHcyclic.) 11.7 (s, 2H, 2NHacyclic
)
ppm.; 13C NMR (DMSO-d6), δC, ppm: 119.8, 128.6, 128.8,
129.4, 130.9, 137.7, 138.5 and 139.0 (C-Ar), 149.8 (C=O),
161.0 (C=Ocyclic), 179.0 (C=S). Found, %: C 35.60; H 1.78;
N 11.07. C15H9Br2ClN4O2S. Calculated, %: C 35.70; H 1.80;
N 11.10. M 504.
Diphenyl(4‑chlorophenyl)(5,7‑dibromo‑1‑oxo‑3‑thi‑
oxo‑3,4‑dihydroiso‑quinolin‑2(1H)‑ylamino)methyl‑
phosphonate (10d)
Yield 77%, m.p. 189–91 °C. IR spectrum, v, cm−1: 603
7,9‑Dibromo‑2‑(phenylimino)‑2,3dihydro[1,3,4]
thiadiazolo[2,3‑b]quinazolin‑5‑one (15)
(C–Br), 692 (C–Cl), 1185 (C=S), 1195 (P-O-C), 1265
1
(P=O), 1640 (C=O), 2845 (CH), 3321 (NH); H NMR
Yield 71%. m.p. 122–4 °C. IR spectrum, v, cm−1: 678
(DMSO-d6), δ, ppm: 2.53 (s, 1H, NHacyclic), 4.12 (s, 1H,
CH), 6.45–8.05 (m, 16H, Har.), 8.55 (s, 1H, NHcyclic) ppm.;
13C NMR (DMSO-d6), δC, ppm: 53.1 (CH), 127.0, 128.8,
129.3, 129.9, 130.3, 131.9, 136.2 and 138.8 (Car.), 152.1
(P-O-C), 169.4 (C=O), 189.0 (C=S). Found, %: C 45.72;
H 2.68; N 5.92. C27H19Br2ClN3O4PS. Calculated, %: C
45.82; H 2.71; N 5.94. M 707.
1
(C–Br), 1610 (C=N), 1690 (C=O), 3450 (NH); H NMR
(DMSO-d6), δ, ppm: 2.41 (s, 1H, NH), 7.45–8.25 (m, 7H,
Har.)ppm. 13C NMR (DMSO-d6), δC, ppm: 125.9, 126.0,
127.2, 128.3, 129.2, 129.3 and 137.2 (Car.), 147.1 (C=N),
156.8 (C=O), 160.6 (C-S). Found, %: C 39.73; H 1.76; N
12.36. C15H8Br2N4OS. Calculated, %: C 39.85; H 1.78; N
12.39. M 452.
1 3

Journal of the Iranian Chemical Society
gram-negative bacteria, S. aureus MARS as gram-positive
bacteria, and Candida albicans as fungal pathogenes. All
these strains were collected from Botany Department, Fac-
ulty of science, Tanta university and maintained in tempera-
ture freezer at−80 °C. The antimicrobial spectrum of the
prepared quinazolinone derivatives were determined against
the tested organisms on powdered samples on nutrient agar
which contained per liter: 3 g peptone, 5 g NaCl, 5 g beef
extract, and 20 g agar and Sabouraud’s agar for Candida
albicans.
2‑(3‑Amino‑6,8‑dibromo‑4‑oxo‑1,2,3,4‑tetrahydro‑
quinazolin‑2‑ylthio)‑acetaldehyde (16)
A mixture of compound 9 (0.35 g, 0.001 mol) and chlo-
roacetaldehyde (0.15 g, 0.002 mol) in EtOH (20 ml) was
refuxed for 3 h (tlc). The reaction mixture was cooled at r.t.,
The solid product that formed was fltered of, recrystallized
from ethanol and dried to give 16. Yield 88%, m. p. 185 °C.
IR spectrum, v, cm−1: 730 (C–Br), 1560 (C=N), 1620
(C=Ocyclic), 1690 (C=O), 2850 (CHar.), 3300 (NH2 sym), 3490
(NH2 asym); 1H NMR (DMSO-d6), δ, ppm: 2.50 (s, 2H, NH2),
4.43 (s, 2H, CH2), 8.15 – 8.4 (dd, 2H, J=1.95 Hz, Har.) 9.70
(s, 1H, CH). Found, %: 30.46; 1.77; 10.66. C10H7Br2N3O2S.
Calculated, %: C, 30.56; H, 1.80; N, 10.69. M 393.
Conclusion
Some new derivatives of 3H-quinazoline-4-ones were
synthesized from their precursor 3-phenyl-quinazoline-
2,4(1H,3H)-dithione. Characterization and elucidation of
the structures of all new products were inferred based on
the spectral as well as elemental analytical data. Some com-
pounds were chosen for testing their biological activities as
antibacterial, antifungal, and anticancer agents Compound
7 was subjected to cytotoxic evaluation against two cancer
cell lines namely: CACO and PC3 cell lines Compounds
9, 6b and 5 showed antibacterial activities and their MICs
of these compounds were 1.0 µg/ml with diferent tested
organisms. Moreover, compounds 9, 6b, 7, 5 against another
type of bacteria as S.areous (MARSA) gave high antimicro-
bial activity. The highest inhibition zone (25 mm) caused
by compound 9.
6,8‑Dibromo‑2‑thioxo‑2,3‑dihydroquinazolinoylpro‑
pane‑1,3‑sultam (19a)
A mixture of compounds 9 (0.35 g, 0.001 mol) and 1,3-pro-
pane- and/or 1,4-butane-sultone (0.002 mol) was fused in
an oil bath at 180 °C for 4–6 h (tlc) and cooled to r.t. The
residual solid was recrystallized from EtOH and aforded the
corresponding sultams 19a and 19b, respectively.
Yield 61%. m.p. 192–4 °C. IR spectrum, v, cm−1: 685
(C–Br), 1120 (C=S), 1151 and 1360 (SO2), 1710 (C=Ocyclic),
3390 (NH); 1H NMR (DMSO-d6), δ, ppm: 1.20 (s, 2H, CH2),
3.01(d, 2H, J = 2.01 Hz,CH2), 3.20 (d, 2H, J = 2.21 Hz,
CH2), 4.15 (NH), 7.80 – 8.51 (dd, 2H, J = 2.75 Hz, Har.)
ppm.; 13C NMR (DMSO-d6), δC, ppm: 14.1 (CH2), 39.2
(CH2N), 61.1 (CH2SO2), 126.5, 127.4, 129.0, 130.1, 139.9
(Car.), 168.2 (C=O), 188.8 (C=S). Found, %: C 28.94; H
1.97; N 9.20. C11H9Br2N3O3S2. Calculated, %: C 29.03 H
1.99; N 9.23. M 455.
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Authors and Afliations
Afrah Sharaf1,2 · Sherif Shaban Ragab3 · Ahmed A. Elbarbary1 · Elkhabiry Shaban4 · Ibrahim El Tantawy El Sayed5
1
2
3
4
Department of Chemistry, Faculty of Science, Tanta
University, Tanta 31527, Egypt
Dyeing, Printing and Textile Auxiliaries Department, Textile
Research Division, National Research Centre, El behouth
Street, Dokki, Giza 12622, Egypt
Faculty of Science, Jazan University, 2097, Jazan,
Jizan 45142, Saudi Arabia
5
Chemistry Department, Faculty of Science, Menoufa
University, Shebin Elkom, Egypt
Photochemistry Department, Chemical Industries Research
Division, National Research Centre (NRC), El behouth
Street, Dokki, Giza 12622, Egypt
1 3