Full text of DOI:10.1007/s13738-018-1337-8

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1337-8
ORIGINAL PAPER
Synthesis of some quinazolinone derivatives using magnetic
nanoparticles‑supported tungstic acid as antimicrobial agents
Masoumeh Divar1 · Kamiar Zomorodian2 · Sorayya Bastan1 · Somayeh Yazdanpanah2 · Soghra Khabnadideh1
Received: 21 October 2017 / Accepted: 19 February 2018
© Iranian Chemical Society 2018
Abstract
Quinazolinones are appealing materials because of their precious biological efects. In this study 10 new quinazolinone
derivatives (4a–4j) were synthesized via an efcient three-component condensation reaction between anthranilic acid, acetic
anhydride and diferent amines. This process was carried out for the frst time in the presence of catalytic amount of magnetic
nanoparticle supported tungstic acid, under solvent-free condition. The acidic catalyst can be easily reusing by an outward
magnetic feld after completion the reaction without any uncleanness. Chemical structures of the products were confrmed
by spectroscopic methods such as: 1HNMR and 13CNMR, IR and elemental analysis. Antifungal and antibacterial activities
were evaluated against diferent species of microorganisms including gram positive and gram negative bacteria as well as
fungi. Broth microdilution method as recommended by clinical and laboratory standard institute was used for this purpose.
The results show compounds 4h had the best antibacterial and antifungal activity against the examined bacteria and fungi.
Compounds 4a–d and 4f also showed good activity against some species.
Graphical Abstract
Synthesis of quinazoline derivatives as antimicrobial agents in the presence of MNP-TA
O
Si
O W OH
O
MNP
O
NH2
R
O
O
(0.1 g, 5 mol%)
N
NH2
R
+
+
O
Solvent free, 80oC
COOH
N
4a-4j
Keywords Quinazolinone · Synthesis · Antimicrobial · Antifungal
Introduction
Quinazolinones are remarkable in medicinal chemistry,
because of their wide range of biological activity for exam-
ple hypnotic, sedative, anti-convulsant, anti-tussive, anti-dia-
betic, anti-tumor, antibacterial, antifungal, antiinfammatory,
antimalarial and antiviral [1–6].
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-018-1337-8) contains
supplementary material, which is available to authorized users.
* Soghra Khabnadideh
khabns@sums.ac.ir
Numerous bioactive natural products such as Febrifugine
has quinazolinone moieties with potential biological activity
[7]. Febrifugine is the active principle extracted from a Chi-
nese medicinal plant, chang shan (Dichroa febrifuga Lour),
that has been prescribed in traditional Chinese medicine as
an antimalarial agent [8]. Febrifugine halogenated derivative
1
Pharmaceutical Sciences Research Center, Shiraz University
of Medical Sciences, Shiraz, Iran
2
Department of Parasitology and Mycology, Faculty
of Medicine, Shiraz University of Medical Sciences, Shiraz,
Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
(Halofuginone) is also specifcally shown to be an efective
drug in malaria, cancer, fbrosis and infammatory disease
(Fig. 1) [9].
and still the catalyst stay in it in some cases. We introduced
Tungstic acid (TA) onto solid supports as an efcient catalyst
for MCRs in our previous report [22]. It is rational to accept
that by decreasing the size of the support, reactivity can be
increased and nanoparticles are practical potential candidate
supports. However, when the size of support is decreased, a
new problem arises, i.e., catalyst recapture, because a sim-
ple fltration method cannot overcome the great trouble of
catalyst separation from the reaction media. Recently mag-
netic nanocatalysts have attracted considerable attentions for
organic synthesis. The stability of magnetic nanocatalysts
and their ease of recovery and reusability make them suit-
able for applications in green synthesis [26]. In our previ-
ous procedure by using of magnetic nanoparticles (MNPs)
as supports, both reactivity and reusability of catalyst were
improved [22]. Supported magnetic metal nanoparticles have
high specifc surface area and emerged as a new class of
nanocatalysts [27]. Tungstic acid is known as an efcient
catalyst in organic synthesis and has been made even greener
by immobilization onto solid supports. The dispersibility of
nanoparticles in solution leads to the formation of an emul-
sion with further difusion rate. By immobilization of TA
on MNPs, it is possible to prepare a highly efcient solid
acid for application in organic synthesis. In this study, the
application of the magnetic nanoparticle supported tungstic
acid (MNP-TA) catalyst was investigated for the one-pot
synthesis of spirooxindole analogs.
The quinazoline skeleton is also a building block of natu-
ral purine bases, plant alkaloids and several approved drugs
such as Prazosin, Alfuzosin, Erlotinib, Geftinib [10–17].
Hence, extensive eforts have been made to discover new
simple and direct approaches toward the structure of quina-
zolinone frames [18, 19].
Several major adjustments have been ended to the het-
erocyclic moiety leading to quinazolinone derivatives. A
highly working method for quinazolinone production is
founded on acylation of anthranilic acid with acyl chloride.
Following ring closing with acetic anhydride aford parallel
benzoxazinone which will be treated with diferent amines
to give quinazolinone derivatives [20]. Several carbonyla-
tive procedures for quinazolinones synthesis also have been
realized by other chemists. The carbonylation procedure
can be continuing in good yields of the desired products in
the company of palladium catalyst [21]. However, the dis-
cussed procedures are all homogeneous palladium catalyst
based, which have disadvantages include phosphine ligands
relied and not recyclable. Nevertheless, most of the reported
methods sufer from boring ways and often from low yields.
Therefore, simpler and high yield attitudes to this valuable
nucleus are much desirable [18–21].
Multicomponent reactions (MCRs) represent useful pro-
cedures for this goal as well. By this technique changing the
starting material simply lead to variation in the products
which can be optimized conveniently. Besides, in MCRs
approaches, products are synthesized from freely avail-
able starting materials in a single step process. Accord-
ingly MCRs have developed as green and powerful tools in
organic synthesis [22]. Synthesis of quinazolinone deriva-
tives by this method commonly needs to an acid catalyst
system. In most cases, mineral and organic acids such as sul-
furic acid, p-toluene sulfonic acid and heteropoly acids have
been used to synthesis this class of compounds [23–25]. But,
to remove the residual catalyst from the product it need to
wash the product with large amount of chloroform and water
Here, we decided to use a magnetic reusable acidic cata-
lyst to carry out the reaction under mild and heterogene-
ous conditions. In this study, we are going to use MNP-TA
for synthesis of some novel quinazolinone derivatives. Our
catalyst can be recycling by an external magnetic feld after
completion the reaction. Therefore, in continuation of our
previous work on the synthesis of biologically active com-
pounds [28, 29] and using of MCRs strategy, [30, 31] now
we wish to report an efcient one-pot procedure for synthe-
sis of some novel 3-substituted 2-methylquinazoline-4-(3H)-
one derivatives as antimicrobial agents. We run our reactions
in the presence of MNP-TA under solvent-free condition and
evaluated our new compounds in the point of antifungal and
antibacterial activities.
Materials and methods
The chemicals were purchased from Merck and used without
any additional purifcation. The products were characterized
by FT-IR (ATR), 1H-NMR, and a comparison of their physi-
cal properties with those reported in the literature. FT-IR
(ATR) spectra were acquired on a Bruker, Eqinox 55 spec-
trometer. A Bruker (NMR-300 MHz Spectrometry) NMR
was used to record the 1H NMR spectra. Spectrophotometer
(UV/Vis biotek model UVIKONXL), Melting points were
Febrifugine
Halofunginone
Fig. 1 Some bioactive quinazolinone derivatives
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Journal of the Iranian Chemical Society
determined by using an Electrothermal 9100 digital melt-
ing point apparatus (Electrothermal, Essex, UK). The reac-
tion progress and purity of the synthesized compounds were
checked on Merck aluminum plates precoated with silica
gel 60 F-254. UV radiation and/or iodine were used as the
visualizing agents. Silica gel column chromatography was
performed with Silica gel 60G. The acidic catalyst which
is used in this study was our previously reported MNP-TA
which is consisting of tungstic acid supported on silica
coated magnetic nanoparticles [22, 32]. The chemical struc-
ture of the MNP-TA catalyst is shown in Fig. 2. Our catalyst
was characterized by using conventional techniques such as
TEM, SEM, XRD, EDX and FT-IR analyses. All data were
confrmed the chemical structure of the catalyst and were
enclosed in the supporting fle.
3‑(4‑chlorophenyl)‑2‑methylquinazolin‑4(3H)‑one (4a)
White solid (yield: 94%, 0.25 g); mp: 157–158 °C. IR
(KBr, cm−1): 3305, 2922, 2456, 1673, 1540, 827 cm−1. 1H
NMR (300 MHz, CDCl3): δ (ppm) = 2.19 (s, 3H, CH3),
7.28–7.48 (m, 8 arom. H). 13C NMR (125 MHz, CDCl3):
δ (ppm) = 24.5, 119.8, 121.0, 127.9, 128.7, 129.0, 129.3,
130.5, 133.8, 136.3, 145.4, 153.7, 168.2. MS (EI, 70 eV) m/z
(%): 271.3 [M + H]+. Anal.Calcd for C15H11ClN2O (270.72):
C, 66.55; H, 4.10; N, 10.35. Found: C, 66.65; H, 4.07; N,
10.46.
3‑(5‑chloro‑2‑methoxyphenyl)‑2‑methylquinazo‑
lin‑4(3H)‑one (4b)
White solid (yield: 86%, 0.25 g); mp: 179–181 °C. IR (KBr,
cm−1): 3280, 2965, 2527, 1668, 1594, 804 cm−1. 1H NMR
(300 MHz, CDCl3): δ (ppm) = 2.12 (s, 3H, CH3), 3.79 (s,
3H, OCH3), 6.68–7.66 (m, 6 arom. H), 8.35 (d, J = 1.5 Hz,
1H, CH). 13C NMR (125 MHz, CDCl3): δ (ppm) = 24.8,
55.9, 110.5, 117.9, 119.2, 119.6, 121.4, 122.9, 123.5, 125.2,
126.1, 128.5, 139.5, 141.45, 146.1, 168.1. MS (EI, 70 eV)
m/z (%): 301.04 [M + H]+. Anal.Calcd for C16H13ClN2O2
(300.74): C, 63.90; H, 4.36; N, 9.31. Found: C, 63.95; H,
4.30; N, 9.42.
General procedure for preparation of 3‑substituted
2‑methylquinazoline‑4‑(3H)‑one derivatives
We run multicomponent reaction between antranilic acids,
acetic anhydride and primary amines in the present of MNP-
TA for synthesis of 3-substituted 2-methylquinazoline-
4-(3H)-one derivatives (Scheme 1).
Into a canonical fask (25 ml), a mixture of anthranilic
acid (1 mmol), acetic anhydride (1.2 mmol) with selected
aromatic amines (1 mmol) and MNP-TA (0.058 g, 5 mol%)
was heated at 80 °C for 4–12 h. After completion the reac-
tion, monitored by TLC, the catalyst was separated by exter-
nal magnet. The precipitated solid was fltered. Then, the
pure product was obtained by its recrystallization in dichlo-
romethane/petroleum ether solvent system and compounds
that did not reach this level were purifed by column chroma-
tography on silica gel using petroleum ether/ethyl acetate as
elution aforded the pure 3-substituted 2-methylquinazoline-
4(3H)-one derivatives (Fig. 3).
3‑(2,4‑difuorophenyl)‑2‑methylquinazolin‑4(3H)‑one (4c)
White solid (yield: 82%, 0.22 g); mp: 120–122 °C. IR
(KBr, cm−1): 3264, 3037, 2552, 1666, 1550, 811 cm−1. 1H
NMR (300 MHz, CDCl3): δ (ppm) = 2.23 (s, 3H, CH3),
6.84–8.25 (m, 7 arom. H). 13C NMR (125 MHz, CDCl3):
δ (ppm) = 24.4, 103.1, 103.4, 103.5, 103.8, 111.0, 111.1,
122.8, 122.9, 123.0, 150.7, 154.1, 156.8, 160.1, 168.2.
MS (EI, 70 eV) m/z (%): 273.14 [M + H]+. Anal.Calcd for
C15H10F2N2O (272.25): C, 66.18; H, 3.70; N, 10.29. Found:
C, 66.25; H, 3.62; N, 10.46.
3‑(5‑chloro‑2‑methylphenyl)‑2‑methylquinazo‑
lin‑4(3H)‑one (4d)
White solid (Yield: 85%, 0.24 g); mp: 114–116 °C. IR (KBr,
cm−1): 3440, 3076, 2436, 1666, 15840, 817 cm−1. 1H NMR
(300 MHz, CDCl3): δ (ppm) = 2.25 (s, 3H, CH3), 2.57 (s,
Fig. 2 The chemical structure of MNP-TA
Fig. 3 Synthesis of quinazoline
O
derivatives
Si
O W OH
O
MNP
O
NH2
O
R
O
(0.1 g, 5 mol%)
N
NH2
R
+
+
O
Solvent free, 80oC
COOH
N
4a-4j
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Journal of the Iranian Chemical Society
3H, CH3), 7.24–7.57 (m, 6 arom. H), 8.34 (d, J = 9 Hz, 1H,
CH). 13C NMR (125 MHz, CDCl3): δ (ppm) = 16.6, 24.8,
122.28, 122.9, 124.0, 127.0, 127.9, 128.6, 129.0, 130.1,
131.4, 133.3, 135.2, 140.6, 168.1. MS (EI, 70 eV) m/z (%):
285.58 [M + H]+. Anal.Calcd for C16H13ClN2O (284.74): C,
67.49; H, 4.60; N, 9.84. Found: C, 67.69; H, 4.53; N, 9.91.
3H, CH3), 6.73–8.22 (m, 5 arom. H). 13C NMR (125 MHz,
CDCl3): δ (ppm) = 24.7, 29.69, 117.3, 119.1, 122.5, 123.2,
126.4, 127.8, 128.6, 129.3, 129.8, 131.6, 133.1, 134.6,
135.8, 168.4. MS (EI, 70 eV) m/z (%): 354.55 [M + H]+.
Anal.Calcd for C16H11Cl3N2O (353.63): C, 54.34; H, 3.14;
N, 7.92. Found: C, 54.42; H, 3.07; N, 7.98.
5,7‑dichloro‑3‑(5‑chloro‑2‑methoxyphenyl)‑2‑meth‑
5,7‑dichloro‑3‑(1,5‑dimethyl‑3‑oxo‑2‑phenyl‑2,3‑dihy‑
ylquinazolin‑4(3H)‑one (4e)
dro‑1H‑pyrazol‑4‑yl)‑2‑methylquinazolin‑4(3H)‑one (4i)
White solid (yield: 88%, 0.29 g); mp: 119–121 °C. IR (KBr,
cm−1): 3314, 2964, 2572, 1671, 1596, 801 cm−1. 1H NMR
(300 MHz, CDCl3): δ (ppm) = 2.12 (s, 3H, CH3), 3.79 (s,
3H, OCH3), 6.67–7.68 (m, 4 arom. H), 8.34 (d, J = 3 Hz,
1H, CH). 13C NMR (125 MHz, CDCl3): δ (ppm) = 23.8,
54.91, 109.6, 115.6, 119.6, 122.0, 123.3, 125.1, 127.4,
131.4, 145.1, 153.4, 160.6, 167.2. MS (EI, 70 eV) m/z (%):
370.49 [M + H]+. Anal.Calcd for C16H11Cl3N2O2 (369.63):
C, 51.99; H, 3.00; N, 7.58. Found: C, 52.03; H, 2.97; N,
7.65.
Yellow solid (yield: 80%, 033 g); mp: 189–191 °C. IR
(KBr, cm−1): 3305, 2922, 2456, 1673, 1540, 827 cm−1. 1H
NMR (300 MHz, CDCl3): δ (ppm) = 2.05 (s, 3H, CH3),
2.20 (s, 3H, CH3), 3.09 (s, 3H, N-CH3), 7.28–7.449 (m, 9
arom. H). 13C NMR (62.9 MHz, CDCl3): δ (ppm) = 12.0,
22.6, 35.7108.5, 113.0, 124.7, 127.2, 129.3, 134.4, 150.3,
155.7, 159.9, 162.2, 170.2. MS (EI, 70 eV) m/z (%): 416.30
[M + H]+. Anal.Calcd for C20H18N4O2 (415.27): C, 57.58;
H, 3.88; N, 13.49. Found: C, 57.63; H, 3.76; N, 13.52.
(4‑(5,7‑dichloro‑2‑methyl‑4‑oxoquinazolin‑3(4H)‑yl)ben‑
5,7‑dichloro‑3‑(4‑chlorophenyl)‑2‑methylquinazo‑
zoyl)glycine (4j)
lin‑4(3H)‑one (4f)
White solid (yield: 87%, 0.35 g); mp: 247–249 °C. IR
(KBr, cm−1): 3364, 2778, 1714, 1686, 1631, 791 cm−1. 1H
NMR (300 MHz, CDCl3): δ (ppm) = 2.19 (s, 3H, CH3),
7.28–7.48 (m, 8 arom. H). 13C NMR (62.9 MHz, CDCl3):
δ (ppm) = 24.5, 119.8, 121.0, 127.9, 128.7, 129.0, 129.3,
130.5, 133.8, 136.3, 145.4, 153.7, 168.2. MS (EI, 70 eV) m/z
(%): 407.13 [M + H]+. Anal.Calcd for C18H15N3O4 (406.22):
C, 53.22; H, 3.23; N, 10.34. Found: C, 53.46; H, 3.17; N,
10.36.
White solid (yield: 88%, 0.28 g); mp: 139–141 °C. IR
(KBr, cm−1): 3320, 2985, 2586, 1680, 1611, 795 cm−1. 1H
NMR (300 MHz, CDCl3): δ (ppm) = 2.03 (s, 3H, CH3),
6.54–7.62 (m, 4 arom. H). 13C NMR (125 MHz, CDCl3):
δ (ppm) = 24.3, 116.3, 117.1, 119.9, 120.9, 121.0, 126.9,
128.9, 130.6, 132.4, 138.5, 138.6, 155.6, 162.5, 169.0.
MS (EI, 70 eV) m/z (%): 340.19 [M + H]+. Anal.Calcd for
C15H9Cl3N2O (339.60): C, 52.81; H, 2.36; N, 8.21. Found:
C, 52.90; H, 2.29; N, 8.35.
Antimicrobial susceptibility testing
5,7‑dichloro‑3‑(2,4‑difuorophenyl)‑2‑methylquinazo‑
lin‑4(3H)‑one (4g)
Microorganisms
White solid (yield: 90%, 0.30 g); mp: 92–94 °C. IR (KBr,
Antifungal activities of the synthetic compounds against
nine American Type Culture Collection (ATCC) strains of
fungi, including Candida albicans (ATCC 10261), Can-
dida tropicalis (ATCC 750), Candida krusei (ATCC 6258),
Candida glabrata (ATCC 90030), Candida parapsilosis
(ATCC 4344), Candida dubliniensis (CBS 8501), Cryp-
tococcus neoformans (ATCC 9011), Aspergillus terreuss,
Aspergillus favus (ATCC 64025), Aspergillus fumigatus
(ATCC 14110), Exophiala dermatitidis (ATCC 109136) and
Pseudallescheria boydii were determined. The antibacterial
activities of the fnal compounds against standard species
of Staphylococcus aureus (ATCC 25923), Enterococcus
faecalis (ATCC 51299), Escherichia coli (ATCC 25922)
and Pseudomonas aeruginosa were also determined in this
study. In addition, the antifungal activities of the compounds
were tested against some clinical isolates of yeasts identifed
1
cm−1): 3290, 2998, 2830, 1682, 1620, 802 cm−1. H
NMR (300 MHz, CDCl3): δ (ppm) = 2.25 (s, 3H, CH3),
6.84–8.25 (m, 5 arom. H). 13C NMR (125 MHz, CDCl3):
δ (ppm) = 24.3, 117.6, 119.3, 123.1, 123.3, 130.7, 136.4,
151.03, 154.1, 157.0, 157.1, 160.4, 162.1, 168.8. MS
(EI, 70 eV) m/z (%): 342.15 [M + H]+. Anal.Calcd for
C15H8Cl2F2N2O (341.14): C, 52.81; H, 2.36; N, 8.21. Found:
C, 52.95; H, 2.29; N, 8.34.
5,7‑dichloro‑3‑(5‑chloro‑2‑methylphenyl)‑2‑methylquina‑
zolin‑4(3H)‑one (4h)
White solid (yield: 85%, 0.3 g); mp: 144–146 °C. IR (KBr,
cm−1): 3250, 3015, 2772, 1692, 1615, 793 cm−1. 1H NMR
(300 MHz, CDCl3): δ (ppm) = 2.16 (s, 3H, CH3), 2.74 (s,
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Journal of the Iranian Chemical Society
Table 1 One-pot synthesis of quinazolinone derivatives in diferent conditions
O
Si
O W OH
O
Cl
MNP
NH2
O
NH2
O
O
(0.1 g, 5 mol%)
+
N
+
O
COOH
o
Solvent free, 80 C
N
Cl
(3a)
(2)
(1a)
(4a)
Entry
Catalyst
Fe3O4@SiO2
Fe3O4@SiO2
TA
Solvent
EtOH
none
Catalyst (mol %)
Temp (◦C)
Reflux
Reflux
Reflux
Reflux
Reflux
80
Time (h)
Yield (%)a
1
10
10
20
3
24
24
24
4
Trace
15
2
3
EtOH
EtOH
EtOH
none
45
4
MNP-TA
MNP-TA
MNP-TA
MNP-TA
MNP-TA
55
5
5
4
70
6
5
4
91
7
none
5
100
4
91
8
none
5
120
4
91
a: isolated yield
by polymerase chain reaction–restriction fragment length
polymorphism (PCR–RFLP). This species include Azole-
resistant C. albicans 634, Azole-resistant C. albicans 2303,
Azole-resistant C. albicans 625, Azole-Sensitive C. albicans
3086, Azole-Sensitive C. albicans 537 and Azole-Sensitive
C. albicans 615. The susceptibility of all clinical isolates of
fungi against select compounds was examined by microdilu-
tion and disk difusion methods [33, 34].
with Tween-20. The collected conidia were moved in sterile
saline and their turbidity was adjusted to OD = 0.09–0.11
that yields 0.4–5 × 106 conidia/mL. Working suspension
was prepared by production a 1/50 and 1/1000 dilution with
RPMI of the stock suspension for molds and yeasts, respec-
tively. Working inoculums (0.1 mL) were added to the micr-
otiter plates, which were protected in a humid atmosphere
at 30 °C for 24–48 h. Uninoculated medium (200 μL) was
included as a sterility control (blank). In addition, growth
controls (medium with inoculums but without antibiotics or
the synthetic compounds) were also included. The growth in
each well was compared with that of the growth in the con-
trol well. MICs were visually determined and defned as the
lowermost concentration of the compounds produced ≥ 95%
growth reduction matched with the growth in the control
well. Each experiment was performed in triplicate. In addi-
tion, media from the wells with fungi showing no visible
growth were further cultured on Sabouraud dextrose agar
(Merck, Darmstadt, Germany) to determine the minimum
fungicidal concentration (MFC). MFCs were determined as
the lowest concentration yielding no more than 4 colonies,
which corresponds to a mortality of 98% of the microbes in
the initial inoculums.
The reference antifungal compounds fuconazole (Sigma,
St. Louis, MO, USA), for yeasts and Aspergillus species was
used as standard drugs.
Determination of minimum inhibitory concentration (MIC)
MICs were resolute by the Broth microdilution method
suggested by the clinical and laboratory standard institute
(CLSI) with some alterations [34, 35]. In brief, for deter-
mination of antimicrobial activities against fungi, serial
dilutions of the synthetic compounds (1–1024 μg/mL) were
arranged in 96-well microtiter plates using Rawell Park
Memorial Institute (RPMI-1640 medium) (Sigma, St. Louis,
MO, USA) bufered with morpholine propane sulfonic acid
(MOPS) (Sigma). Stock inoculums were prepared by hang-
ing three colonies of the perused yeast in 5 mL sterile 0.85%
NaCl, and regulating the turbidity of the inoculums to 0.5
McFarland standards at 530 nm wavelengths (this yields
stock suspension of 1–5 × 106 cells/mL). For molds (Asper-
gillus spp.), conidia were improved from the 7-day old cul-
tures grown on potato dextrose agar by a moistening loop
To determine the antibacterial activities, serial dilutions
of the synthetic compounds (1.0–512.0 µg/ml) were pre-
pared in Muller-Hinton Broth media (Merck, Darmstadt,
Germany). Test bacteria strains were suspended in the
media and the cell densities were adjusted to 0.5 McFarland
standards at 530 nm wavelengths using a spectrophotometric
method (this yields stock suspension of 1–5 × 106 cells/ml
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Journal of the Iranian Chemical Society
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Journal of the Iranian Chemical Society
for yeast and 1–1.5 × 108 cells/ml for bacteria). One hun-
dred microliter of the employed inoculums was added to the
microliter plates which were incubated in a damp atmos-
phere at 30 °C for 24–48 h (fungi) or at 37 °C for 24 h (bac-
teria). Two hundred microliter of the inoculated medium was
included as a sterility control (blank). In addition, growth
controls (medium with inoculums but without drugs) were
also included. The growth in each well was compared with
that of the growth control well. MICs were visually deter-
mined and defned as the lowest concentration of the syn-
thetic compounds or drugs produced no visible growth. Each
experiment was performed in triplicate.
To estimate catalytic performance, the MNP-TA catalyst
was applied in the multicomponent reaction of anthranilic
acid, acetic anhydride and aromatic amines. Therefore, the
reaction between anthranilic acid (1a), acetic anhydride (2)
and 4-chloroaniline (3a) was chosen as a simple model reac-
tion, and the results of optimization studies are shown in
Table 1.
In our initial selection, we used Fe3O4@SiO2 as a catalyst
in EtOH, and a trace amount of 4a was isolated (entry 1).
In another attempt, when Fe3O4@SiO2 was used in solvent-
free condition, the isolated yield of product was 15% (entry
2). It was seen that the yield of desired product increased
to 45% when TA was used as a catalyst (entry 3). Then,
we used MNP-TA 3 mol% in EtOH and the yield of the
product increased up to 55% interestingly after 24 h (entry
4). Moreover, by increasing the amount of catalyst up to
5 mol%, the yield of the reaction increased to 70% (entry 5).
Also, the yield of the reaction increased to 91% in solvent-
free condition (entry 6). The yield of the desired product did
not change considerably when the temperature was enhanced
to 100 °C and 120 °C (entry 7, 8). Experiments confrmed
that the MNP-TA catalyst is more capable than TA in this
reaction. Thus, MNP-TA was found to be an efcient, mag-
netic, and recyclable catalyst for the one-pot synthesis of
quinazolinone derivatives. Therefore, we synthesized 10 new
derivatives of quinazolinone compounds by this procedure
(Table 2).
Results and discussion
Synthesis of quinazolinone derivatives in the pres‑
ence of MNP‑TA catalyst
The acidic catalytic site of MNP-TA catalyst is tungstic acid
(TA) which has been previously used in many organic reac-
tions [36, 37]. The immobilization of this acidic part on
diferent supports for synthesis of heterogeneous catalyst
systems has been considered, and several acid catalyst sys-
tem based on TA has been prepared and applied in organic
transformations [36–39].
As shown in Table 2, it is possible to synthesis a range of
quinazolinones, using MNP-TA as a heterogeneous acidic
catalyst in desirable yields. However, using anthranilic acid,
acetic anhydride and diferent amines in the presence of
MNP-TA lead to synthesis a variety of 3-substituted 2-meth-
ylquinazoline-4-(3H)-one compounds. After that, MNP-TA
catalyst was easily separated from the reaction mixture using
an external magnetic feld. This method provides an easy
handling workup process for clean and efcient synthesis
of this class of compounds [40, 41]. The recyclability of
Table 3 Reusability of the
Run Yield of
product
Recovery of
catalyst (%)
MNP-TA catalyst in the
synthesis of 4a under optimized
condition
(%)
1
2
3
4
5
91
88
87
85
80
99
98
96.5
96
95
Table 4 MIC values (μg/mL)
for tested compounds against
diferent bacteria
Microorganisms
Compounds
E. coli
S. aureus
E. faecalis
P. aeruginosa
MIC90
MBC
MIC90
MBC
MIC90
MBC
MIC90
MBC
4a
4b
4c
4d
4e
4f
4g
4h
G
G
G
G
G
G
G
128
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
128
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
128
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
0.5
G
G
G
G
G
G
G
G
G
G
G
4i
4j
G
0.25
G
0.5
G
0.5
Ciprofoxacin
1 3

Journal of the Iranian Chemical Society
Table 5 MIC values (μg/mL)
for tested compounds against
diferent flaments fungi
Microorganisms A. terreuss
A. favus
A. fumigatus
E. dermatitidis P. boydii
Compounds
MIC90 MBC MIC90 MBC MIC90 MBC MIC90 MBC MIC90 MBC
4a
4b
4c
4d
4e
4f
4g
4h
G
G
G
G
G
G
G
G
G
G
4
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
1
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
4
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
16
G
G
G
G
G
G
G
G
G
G
32
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
4i
4j
Griseofulvin
MNP-TA catalyst for this protocol has also been investigated.
Our results showed that the MNP-TA catalyst is recovered
by simple external magnetic attraction. Moreover, there was
no remarkable loss in its catalytic activity after fve cycles
of reusability (Table 3).
Compounds 4b and 4c displayed desired antifungal activi-
ties against C. neoformans and C. tropicalis, respectively, at
concentration 256 µg/mL.
Compound 4d demonstrated appropriate antifungal activ-
ities against C. albicans, C. dubliniensis at concentration of
256 µg/mL and against C. tropicalis and C. neoformans at
concentration of 125 µg/mL.
Antimicrobial activities of the synthetic derivatives
Compounds 4f presented necessary antifungal activi-
ties against C. albicans and C. neoformans at concentration
256 µg/mL.
Antibacterial activities of the synthetic derivatives are
shown in Table 4. Among the tested compounds, 4h inhib-
ited the growth of tested bacteria except P. aeruginosa at
concentration 128 µg/mL. Our other compounds did not
exhibit signifcant bactericidal activities at concentration
up to 256 µg/mL.
Conclusions
In conclusion, we have synthesized some new quina-
zolinone derivatives via multicomponent reaction involv-
ing anthranilic acids, acetic anhydride and different
amines in the presence of MNP-TA as a magnetic reus-
able acidic catalyst, with the hope of discovering new
structure leads serving as potent antimicrobial agents. Our
catalyst was successfully used for the one-pot synthesis of
According to our results, compound 4h exhibited consid-
erable antifungal activities against most of the tested Can-
dida species at concentration of 64–256 µg/mL.
Compounds 4a showed desirable antifungal activities
against C. albicans, C. dubliniensis and C. neoformans at
concentration 256 µg/mL (Tables 5, 6, 7).
Table 6 MIC values (μg/mL) for tested compounds against diferent candida
Microorganisms C. albicans
C. dubliniensis C. glabrata
C. krusei
C. parapsilosis C. tropicalis
C. neoformans
Compounds
MIC90 MBC MIC90 MBC MIC90 MBC MIC90 MBC MIC90 MBC MIC90 MBC MIC90 MBC
4a
4b
4c
4d
4e
4f
4g
4h
256
G
G
256
G
256
G
256
G
G
G
G
G
G
G
G
G
G
G
G
G
256
G
G
G
G
G
G
64
G
G
G
G
G
G
G
G
G
256
G
G
G
G
G
G
G
G
G
G
64
G
G
4
G
G
G
G
G
G
G
128
G
G
G
G
G
G
G
G
G
G
128
G
G
G
G
G
G
G
G
256
G
G
G
G
G
G
G
G
256
G
G
G
G
G
G
G
G
G
G
G
G
G
256
128
G
G
G
64
G
G
G
G
G
G
G
G
G
256
G
256
256
G
128
G
256
G
128
G
G
G
G
G
G
G
G
256
G
4i
4j
G
16
G
32
G
G
G
G
Fluconazole
4
1
1 3

Journal of the Iranian Chemical Society
Table 7 MIC values (μg/mL) for tested compounds against diferent clinical isolates of yeasts
Microorganisms
Azole-resistant C. Azole-resistant C. Azole-resistant C. Azole-sensitive C. Azole- sensitive C. Azole- sensitive
albicans 634 albicans 2303 albicans 625 albicans 3086 albicans 537 C. albicans 615
Compounds
MIC90
MBC
MIC90
MBC
MIC90
MBC
MIC90
MBC
MIC90
MBC
MIC90
MBC
4a
4b
4c
4d
4e
4f
4g
4h
G
G
G
256
G
G
G
G
G
G
4
G
G
G
256
G
G
G
G
G
G
G
G
G
256
G
G
G
G
G
G
1
G
G
G
G
G
G
G
G
G
G
G
256
G
G
256
G
256
G
G
G
G
4
256
G
G
256
G
256
G
G
G
G
G
256
G
G
256
G
256
G
G
G
G
16
256
G
G
256
G
256
G
G
G
G
32
G
G
G
256
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
256
G
G
G
G
G
G
G
G
G
256
G
G
G
G
G
G
4i
4j
Fluconazole
G
spirooxindoles via the multicomponent reaction of isatins
and dicarbonyl compounds. The results revealed that this
new catalyst showed high catalytic activity in this pro-
tocol. This new catalyst easily dispersed in solution to
produce a pseudohomogeneous system to generate a reac-
tive catalyst sites. Reusability and easy workup are other
advantages as well. Additionally, the MNP-TA catalyst
provides great promise toward further useful applications
in other acid-catalyzed transformations in future. It could
be suggested that the following mechanism by with MNP-
TA progresses the reaction (Fig. 2). In this mechanism,
MNP-TA as an acidic catalyst provides a proton to anhy-
dride and sort it tolerable for nucleophilic attack by nitro-
gen lone pair electron of anthranilic acid. In the next step
after cyclization and preparation of a cyclic intermediate,
amine derivative attacks to carbonyl group in this unstable
intermediate via nitrogen lone pair. Finally, intramolecular
nucleophilic attack and dehydration led to cyclization and
preparation of the quinazolinone ring (Fig. 4).
Comparison of MIC values of 4h and 4d showed that
substitution of 2 chlorine atoms on quinazolinone ring
enhanced the antimicrobial activities against the tested
microorganisms. Replacement of methyl in corporation
aniline ring in compound 4h with methoxy residue in 4e
reduces its antimicrobial activities. It might be assumed
that presence of methyl in corporation aniline ring together
with chlorine atoms at meta- and ortho-positions of the
quinazoline ring induce the antimicrobial activity against
broad spectrum of microorganisms.
The obtained results showed, of the tested compounds,
4h exhibited optimum antimicrobial activity against the
studied yeasts and bacteria than others.
Acknowledgements Financial assistance from the Shiraz University
of Medical Sciences by way of grant number 94-01-36-9621 is grate-
fully acknowledged.
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