2
J. Zhang et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
Optimization of reaction conditions and quantity of catalysts for the synthesis of
compound 4aaa
Entry
Catalyst
Solvent
Catalyst loading
(mol %)
Time
(h)
Yieldsb
(%)
1
2
3
4
5
6
7
8
nano CeO2
nano CuO
nano Fe3O4
nano CeO2
nano CeO2
nano CeO2
nano CeO2
nano CeO2
nano CeO2
nano CeO2
nano CeO2
nano CeO2
CeO2
EtOH
EtOH
EtOH
DMF
Acetonitrile
DMSO
MeOH
H2O
EtOH
EtOH
10
10
10
10
10
10
10
10
—
8
5
3
10
6
6
6
10
10
10
6
6
10
5
5
5
82
63c
40d
Trace
Trace
Trace
70
51
Trace
82
9
10
11
12
13
EtOH
EtOH
EtOH
82
Figure 1. Reported quinazolinone antifungal agents form natural or synthesis and
designed target compounds.
57
8
20e
a
for the broad antifungal activities of synthesized compounds. It was
one of the important enzymes for degrading chitin (polymer of
b-(1,4)-linked N-acetylglucosamine) involved in the essential life
cycles of pathogenic fungi. Chitin was a major structural component
of fungi cell walls and insect cuticles, and it also cannot be found in
higher plants and mammals.12,39 The chitinase inhibitors are
potential fungicides and have attracted much attention for the
low toxicity to non-target organisms and safe to the ecological
environment.31,40 The binding modes of the allosamidin and
All reactions were carried out with 1.5 mmol of isatoic anhydride, 1.6 mmol of
benzhydrazide, and 1.6 mmol of benzaldehyde in the presence of catalyst in solvent
(5 mL) at refluxing temperature.
b
Isolated yields.
c
CuO nanoparticles (Outside Diameter(OD) 40 nm) as catalyst.
Fe3O4 nanoparticles (OD 40 nm) as catalyst.
CeO2 powder as catalyst.
d
e
in satisfied yield and listed in Table 2. The substrates with
electron-donating groups on the B or C ring, such as OH, OMe,
Me, N(CH3)2 and CH(CH3)2, exhibited good reactivity(4ab–4ah,
4bb–4bd, 4ca–4cb, 4da–4de, 4eb–4ed). The strong electron-
withdrawing group, NO2 or CHO, led to the corresponding products
4ai–4ak, 4be and 4cc with slightly lower yields. It was notable
that heterocyclic aldehydes, such as 3-pyridinecarboxaldehyde,
4-pyridinecarboxaldehyde, and furfural, were also found to be
suitable for the reaction and gave the corresponding products in
satisfactory yields (Table 2, 4al–4an, 4bf, 4cd, 4ce). In addition,
isobutyraldehyde and cyclohexanone also furnished the desired
products 4ao, 4ap, 4cf, 4df, 4ee. The structures of all compounds
were confirmed by analytical and spectral data. In particular, 17
compounds (4ak, 4am, 4ba–4bf, 4cb–4ce, 4da–4dd, 4df) were first
synthesized.
N-acetyl-
previously determined by X-ray crystallography (PDB:2A3E).41 Due
to allosamidin and N-acetyl-
-allosamine42 restricted in use for their
D-allosamine natural origin to family 18 chitinase were
D
high cost and limited availability, the development of new antifungal
agents to the same active site inchitinase was crucial. The synthesized
compounds contained the analogous nitrogen heterocycle and amide
moiety just like the original inhibitors. Thus, we chose family 18 chiti-
nase as the target for the docking study and the result was satisfied
with vitro antifungal activities. The structure of 3-acrylaminoquina-
zolinone was verified to be active toward the target. The docking
simulation was performed and explained the special structure played
an important role in increasing the binding interaction. In addition,
the synthetic method we developed was convenient and efficient
for industrial production.
Our efforts to synthesize the functionalized quinazolinone
derivatives bearing acylamino motif began by exploring the
one-pot process of isatoic anhydride, benzhydrazide, and
benzaldehyde. Compound 4aa was obtained in yields of 82%, 63%,
and 40% by using CeO2 nanoparticles, CuO nanoparticles, and
Fe3O4 nanoparticles as the catalyst, respectively (Table 1, entries
1–3). CeO2 nanoparticles appeared more efficient than other
nanoparticles. Studies were continued to improve the yields by
conducting the reaction in different solvents and catalysed
loadings. Aprotic solvents dimethyl formamide(DMF), acetonitrile
and dimethylsulfoxide (DMSO) failed to provide the desired
products (Table 1, entries 4–6), while methanol and water gave
the desired product in moderate yields (Table 1, entries 7, 8). Ethanol
was found to be the superior choice for the reaction (Table 1, entry
11). The effect of the amount of catalyst was also investigated
(Table 1, entries 9–12). The yield was increased from 57% to 82% by
the increasing of the loading amount of CeO2 nanoparticles from
3 mol % to 5 mol %. When the concentration of CeO2 nanoparticles
was increased above 5 mol %, the yield was no further improved.
Compared with CeO2 powder (Table 1, entry 13), CeO2 nanoparticles
provided the higher yield. The best yield (82%) (Table 1, entry 11) was
obtained under the optimal condition of refluxing with 5 mol % CeO2
nanoparticles in ethanol.
A possible formation mechanism of 4 was shown in Scheme 2.
CeO2 nanoparticles activate the isatoic anhydride in the protic
solvent, followed by nucleophilic attack of phenylhydrazine or
benzhydrazide. CO2 was then eliminated, resulting in intermediate
I. In the presence of CeO2 nanoparticles, intermediate I was subject
to a nucleophilic attack by an aldehyde to form intermediate II.
Intermolecular cyclization produced intermediate III, and a 1,5-H
shift transforms intermediate III into the final product.
All the synthesized compounds were screened for their in vitro
antifungal activity against four phytopathogenic fungi (P. capsici,
C. gloeosporioides, V. mali, A. alternate). The results showed all the
compounds displayed the activity in varying degrees against each
of the test fungi (Table 2). Most compounds represented mild
activity against each of the fungi at 128 lg/mL. Part of the
synthesized compounds appeared the same active with the
positive control ketoconazole. Compounds 4ab, 4ac, 4ae, 4bc and
4cb exhibited the highest antifungal activity against P. capsici at
32
4cc and 4de showed the same activity with the positive control
at 32 g/mL against C. gloeosporioides. Compounds 4af, 4ag, 4bb,
4bf, 4ee appeared the best activities at 32 g/mL against V. mali
lg/mL, and compounds 4ad, 4ag, 4ak, 4al, 4bb–4bd, 4bf, 4cb,
l
l
which were slightly lower than the positive control. The tested
results of compounds 4aa, 4ab, 4ad, 4ag, 4aj, 4am, 4bb, 4bc,
4cd, 4da, 4dc and 4de were as the same MIC values as the positive
With the optimal conditions, a wide range of functional groups
such as electron donating and electron withdrawing group on ring
control at 64 lg/mL against A. alternate. In general, compounds
B
and ring
C were well tolerated (Scheme 1). Thirty-nine
4ag, 4bb and 4bc presented a broad-spectrum antifungal activity
3-acylaminoquinazolinone derivatives (4aa–4ee) were synthesized
against at least three fungi.