Synthesis, crystal structure and antimicrobial activity of 2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-yl)oxy)-N-phenylacetamide derivatives against phytopathogens

Article abstract of DOI:10.1007/s11030-018-9896-2

Abstract: A total of eighteen 2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-yl)oxy)-N-phenylacetamide derivatives were designed and synthesized, via hybrid pharmacophore approach. Among these compounds, chemical structure of compound 4a was unambiguously confirmed by means of single-crystal X-ray diffraction analysis. All the compounds were evaluated in vitro for their inhibition activity against several important phytopathogenic bacteria and fungi in agriculture. The obtained results indicated that several compounds demonstrated potent antibacterial activity against Xanthomonas oryzae pv. oryzae (Xoo). For example, compounds 4c, 4g and 4q had EC₅₀ values of 35.0, 36.5 and 32.4 μg/mL toward this bacterium, respectively, around 1.5 times more active than commercial bactericide bismerthiazol (EC₅₀ = 89.8 μg/mL). Additionally, compounds 4j and 4p were found to display comparable antifungal activity against Gloeosporium fructigenum at 50 μg/mL, to commercial fungicide hymexazol. Finally, the relationships between antibacterial activities and molecular structures of this class of compounds were discussed in detail. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11030-018-9896-2

Molecular Diversity
https://doi.org/10.1007/s11030-018-9896-2
ORIGINAL ARTICLE
Synthesis, crystal structure and antimicrobial activity of 2-((2-(4-(1H-
1,2,4-triazol-1-yl)phenyl)quinazolin-4-yl)oxy)-N-phenylacetamide
derivatives against phytopathogens
Zhijiang Fan1 · Jun Shi1 · Na Luo1 · Xiaoping Bao1
Received: 1 August 2018 / Accepted: 20 November 2018
© Springer Nature Switzerland AG 2018
Abstract
A total of eighteen 2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-yl)oxy)-N-phenylacetamide derivatives were
designed and synthesized, via hybrid pharmacophore approach. Among these compounds, chemical structure of compound
4a was unambiguously confirmed by means of single-crystal X-ray diffraction analysis. All the compounds were evalu-
ated in vitro for their inhibition activity against several important phytopathogenic bacteria and fungi in agriculture. The
obtained results indicated that several compounds demonstrated potent antibacterial activity against Xanthomonas oryzae pv.
oryzae (Xoo). For example, compounds 4c, 4g and 4q had EC50 values of 35.0, 36.5 and 32.4 μg/mL toward this bacterium,
respectively, around 1.5 times more active than commercial bactericide bismerthiazol (EC50 ꢀ89.8 μg/mL). Additionally,
compounds 4j and 4p were found to display comparable antifungal activity against Gloeosporium fructigenum at 50 μg/mL,
to commercial fungicide hymexazol. Finally, the relationships between antibacterial activities and molecular structures of this
class of compounds were discussed in detail.
Graphical abstract
Keywords Quinazoline · 1,2,4-Triazole · Amide · Synthesis · Antimicrobial activity
1
State Key Laboratory Breeding Base of Green Pesticide and
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11030-018-9896-2) contains supplementary
material, which is available to authorized users.
Agricultural Bioengineering, Key Laboratory of Green
Pesticide and Agricultural Bioengineering, Ministry of
Education, Center for Research and Development of Fine
Chemicals, Guizhou University, Guiyang 550025, People’s
Republic of China
Xiaoping Bao
baoxp_1980@aliyun.com
B
123

Molecular Diversity
Introduction
varieties and cultural practices) [9], the method of chemical
control still exhibited distinct advantages over others, includ-
ing high efficiency, fast acting, low cost as well as convenient
application. Chemical control of rice bacterial blight started
in the 1950s, by using Bordeaux mixture, some antibiotics
along with mercuric–copper compounds [9]. Although a few
agrobactericides are currently available on the market for
fighting against this bacterial disease, the search for new and
more effective bactericides against Xoo remains an extremely
urgent task facing agricultural chemists, due to some obvi-
ous drawbacks of existing antibacterial agents, including low
efficiency, environmental hazards, especially increasing bac-
terial resistance [12].
On the other hand, the electron-rich aromatic frame-
work of 1,2,4-triazole heterocycle allows it to readily bind
to relevant receptors and/or enzymes by virtue of multiple
non-covalent binding interactions [13], thus exhibiting var-
ious bioactivities, such as antibacterial [14–16], antifungal
[17] and anticancer [18] activities. Many 1,2,4-triazole-based
derivatives have emerged as commercial agents, including
therapeutic fungicides Fluconazole and Albaconazole, viri-
cide Ribavirin as well as anticancer drug Letrozole (Fig. 1).
It has been widely accepted that the combination of differ-
ent pharmacophores into a single molecule (“hybrid pharma-
Natural products have been extensively investigated in the
fields of medicinal and pesticide chemistry, due to their
unique advantages including extraordinary structural diver-
sity, excellent bioactivities as well as biocompatibility with
the natural environment [1]. One of the most important
classes of natural products is quinazoline derivatives [2],
which exhibit a wide range of biological activities, includ-
ing antibacterial [3–5], antifungal [6], antiviral [7], antitumor
activities [8]. Some quinazoline-containing pharmaceuti-
cals and pesticides have been marketed for years, including
anticancer drug Gefitinib, acaricide Fenazaquin and sympa-
tholytic drug Prazosin (Fig. 1).
The pathogenic bacterium of Xanthomonas oryzae pv.
oryzae (Xoo) is a rod-shaped, round-ended Gram-negative
plant pathogen [9], which is responsible for causing rice bac-
terial blight via invading the vascular system and entering
the xylem tissue from the wounds or natural plant openings
[10]. Bacterial blight of rice is one of the most destructive
rice diseases around the world, which seriously affects the
yield of rice and leads to crop loss up to 50% in some cases
[11]. Despite several methods currently available to cope
with this disease (biological control, breeding of resistant
Fig. 1 Chemical structures of some natural compounds, commercial pharmaceutical or pesticide molecules containing either the quinazoline or
1,2,4-triazole ring
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Molecular Diversity
Fig. 2 Design strategy of target
compounds in this work
cophoreapproach”)isaneffective, practicalapproachfordis-
covering new bioactive molecules, due to a potential cooper-
ation effect [19, 20]. Fluquinconazole (Schering Agrochem)
and Albaconazole (Palau Pharma), widely utilized as anti-
fungal agents in agriculture and medicine, respectively, are
two very successful examples of combining quinazolinone
and 1,2,4-triazole moieties together. Recently, we synthe-
sized a family of (E)-2-(4-(1H-1,2,4-triazol-1-yl)styryl)-
4-(alkyl/arylmethyleneoxy)quinazoline derivatives, wherein
several compounds exhibited much better inhibition activ-
ities against the phytopathogenic bacterium Xanthomonas
axonopodis pv. citri (Xac), relative to control agent bis-
merthiazol [21]. However, antibacterial activities of such
compounds against tested bacteria were far from satisfac-
tory as a whole. Many previous studies have shown that the
presence of an amide group in the antimicrobial molecules
is highly favorable, since it can form effective and selec-
tive hydrogen-bonding interactions with anionic substrates
such as DNA and RNA [22]. Moreover, to the best of our
knowledge, quinazoline compounds substituted by a rigid
phenyltriazole moiety remain largely unexplored. Based on
these considerations and in continuation of our efforts to
develop quinazoline-1,2,4-triazole hybrids as antimicrobial
agents in agriculture [21, 23–25], herein we introduced
various phenylamide groups into the 1,2,4-triazolylphenyl-
functionalized quinazoline framework (Fig. 2) and evaluated
them for inhibition activities toward some important agricul-
tural phytopathogenic bacteria and fungi.
500 NMR spectrometer at room temperature using TMS as
an internal standard, and chemical shift (δ) was expressed
in parts per million (ppm). The following abbreviations
were employed in expressing multiplicity: sꢀsinglet, dꢀ
doublet, tꢀtriplet, qꢀquartet, mꢀmultiplet. HRMS-ESI
spectra were measured on a Thermo Scientific Q Exactive
Hybrid Quadrupole-Orbitrap mass spectrometer. The X-ray
crystallographic data were collected using a Bruker Smart
Apex CCD area detector diffractometer (Bruker, Germany)
with Mo-Kα radiation.
Synthesis
Synthesis of 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-
4(3H)-one (2)
Anthranilamide (136 mg, 1.0 mmol) and triazole-substituted
benzaldehyde 1 [26] (173 mg, 1.0 mmol) were dissolved
in DMSO (10 mL). Next, the reaction mixture was stirred
and heated to 120 °C, and the reaction progress was mon-
itored by TLC. After the completion of the reaction, water
was added after the reaction mixture was cooled to room
temperature. The formed precipitate was collected by filtra-
tion and recrystallized from ethanol to give quinazolinone
1
2. Yield: 75%; mp>300 °C; H NMR (500 MHz, DMSO-
d6): δ 12.65 (s, 1H), 9.46 (s, 1H), 8.39 (d, J ꢀ5.0 Hz, 2H),
8.31 (s, 1H), 8.17 (d, J ꢀ10.0 Hz, 1H), 8.08 (d, J ꢀ5.0 Hz,
2H), 7.87–7.84 (m, 1H), 7.77 (d, J ꢀ10.0 Hz, 1H), 7.54 (t,
J ꢀ7.5 Hz, 1H); 13C NMR (125 MHz, DMSO-d6): δ 162.7,
153.3, 151.7, 149.2, 143.3, 139.2, 135.2, 132.2, 129.9, 128.1,
127.3, 126.4, 121.6, 119.6; ESI-HRMS m/z: [M+H]+ calcd
for C16H12N5O: 290.1036; found: 290.1037.
Experimental
General
General procedure for the synthesis of compounds 4a–4r
All the chemicals were purchased from commercial suppliers
and used without further treatment (unless stated otherwise).
Melting points were determined and uncorrected on a XT-4
binocular microscope (Beijing Tech Instrument Co., China).
1H and 13C NMR spectra were obtained using a JEOL-ECX
A mixture of intermediate 2 (194 mg, 0.67 mmol), K2CO3
(185 mg, 1.34 mmol) and the corresponding bromoac-
etamides 3a–3r [23] (0.67 mmol) was added to DMF
(10 mL), which was then stirred and heated to 80 °C for
123

Molecular Diversity
8 h. Next, the reaction mixture was poured into cold water
and the resulted precipitate was filtered, washed with water
and recrystallized from ethanol to afford compounds 4a–4r
in 43–67% yield.
119.7, 116.0 (d, J ꢀ22.3 Hz), 114.9, 66.0. ESI-HRMS
m/z: [M+H]+ calcd for C24H18FN6O2: 441.1470; found:
441.1479.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(2-chlorophenyl)acetamide (4e) Yield 50%;
mp: 229–230 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.23
(s, 1H), 9.43 (s, 1H), 8.67 (d, J ꢀ5.0 Hz, 2H), 8.28 (d, J ꢀ
2.0 Hz, 2H), 8.02 (s, 2H), 8.00 (d, J ꢀ1.8 Hz, 1H), 7.99 (s,
1H), 7.96 (d, J ꢀ10.0 Hz, 1H), 7.68 (t, J ꢀ7.1 Hz, 1H),
7.32–7.30 (m, 1H), 7.13 (t, J ꢀ7.5 Hz, 2H), 5.40 (s, 2H);
13C NMR (125 MHz, DMSO-d6): δ 166.9, 166.3, 158.1,
153.2, 151.8, 143.2, 139.0, 136.7, 135.2, 134.8, 130.1,
130.0, 128.2, 128.1, 128.0, 127.4, 127.2, 126.8, 124.1,
119.6, 114.9, 65.8. ESI-HRMS m/z: [M+H]+ calcd for
C24H18N6O2Cl: 457.1174; found: 457.1193.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-phenylacetamide
(4a) Yield
60%;
mp:
260–262 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.48
(s, 1H), 9.39 (s, 1H), 8.60 (d, J ꢀ10.0 Hz, 2H), 8.26 (d, J
ꢀ5.0 Hz, 2H), 8.01–7.96 (m, 2H), 7.94 (d, J ꢀ5.0 Hz, 2H),
7.71–7.68 (m, 1H), 7.61 (d, J ꢀ10.0 Hz, 2H), 7.30 (t, J ꢀ
7.5 Hz, 2H), 7.04 (t, J ꢀ7.5 Hz, 1H), 5.32 (s, 2H); 13C NMR
(125 MHz, DMSO-d6): δ 166.5, 166.4, 158.1, 153.2, 151.8,
143.2, 139.1, 139.0, 136.8, 135.2, 130.0, 129.4, 128.2,
128.1, 124.2, 124.1, 120.1, 119.6, 114.9, 66.1. ESI-HRMS
m/z: [M+H]+ calcd for C24H19N6O2: 423.1564; found:
423.1574.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(4-chlorophenyl)acetamide (4f) Yield 54%;
mp: 230–231 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.63
(s, 1H), 9.39 (s, 1H), 8.59 (d, J ꢀ10.0 Hz, 2H), 8.27 (d, J ꢀ
5.0 Hz, 2H), 8.01–7.96 (m, 2H), 7.94 (d, J ꢀ10.0 Hz, 2H),
7.71–7.68 (m, 1H), 7.64 (d, J ꢀ10.0 Hz, 2H), 7.36 (d, J ꢀ
10.0 Hz, 2H), 5.31 (s, 2H); 13C NMR (125 MHz, DMSO-
d6): δ 166.7, 166.4, 158.1, 153.2, 151.8, 143.2, 139.0, 138.0,
136.7, 135.3, 130.0, 129.3, 128.2, 128.1, 127.8, 124.1,
121.6, 119.7, 114.9, 66.1. ESI-HRMS m/z: [M+H]+ calcd
for C24H18N6O2Cl: 457.1174; found: 457.1177.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(2-fluorophenyl)acetamide (4b) Yield 61%;
mp: 213–214 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.34
(s, 1H), 9.46 (d, J ꢀ5.0 Hz, 1H), 8.69 (d, J ꢀ10.0 Hz, 2H),
8.33–8.32 (m, 2H), 8.06–8.02 (m, 4H), 7.82 (t, J ꢀ7.5 Hz,
1H), 7.76–7.73 (m, 1H), 7.35–7.31 (m, 1H), 7.22–7.16 (m,
2H), 5.45 (s, 2H); 13C NMR (125 MHz, DMSO-d6): δ 166.9,
166.4, 158.1, 154.6 (d, J ꢀ245.5 Hz), 153.2, 151.9, 143.2,
139.0, 136.8, 135.2, 130.0, 128.2, 128.1, 126.4 (d, J ꢀ
7.1 Hz), 126.0 (d, J ꢀ11.7 Hz), 125.2, 125.0, 124.1, 119.7,
116.2 (d, J ꢀ19.2 Hz), 114.9, 65.8. ESI-HRMS m/z: [M+
H]+ calcd for C24H18FN6O2: 441.1470; found: 441.1486.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(2-(trifluoromethyl)phenyl)acetamide
(4g)
Yield 43%; mp: 221–223 °C; 1H NMR (500 MHz, DMSO-
d6): δ 10.07 (s, 1H), 9.46 (s, 1H), 8.71 (d, J ꢀ10.0 Hz, 2H),
8.32 (d, J ꢀ10.0 Hz, 2H), 8.06–8.00 (m, 4H), 7.78–7.71
(m, 2H), 7.66 (t, J ꢀ7.5 Hz, 1H), 7.51 (d, J ꢀ5.0 Hz, 1H),
7.46 (t, J ꢀ7.5 Hz, 1H), 5.43 (s, 2H); 13C NMR (125 MHz,
DMSO-d6): δ 167.6, 166.3, 158.1, 153.2, 151.9, 143.2,
139.0, 136.8, 135.3, 135.1, 133.6, 130.3, 130.1, 128.2,
128.0, 127.5, 127.3, 126.9, 124.2, 124.1 (q, J ꢀ273.5 Hz),
119.7, 115.0, 65.6. ESI-HRMS m/z: [M+H]+ calcd for
C25H18F3N6O2: 491.1438; found: 491.1448.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(3-fluorophenyl)acetamide (4c) Yield 48%;
mp: 260–261 °C; 1H NMR (500 MHz, DMSO-d6) δ 10.75
(s, 1H), 9.44 (s, 1H), 8.64 (d, J ꢀ10.0 Hz, 2H), 8.32 (d, J ꢀ
10.0 Hz, 2H), 8.07–8.04 (m, 2H), 7.99 (d, J ꢀ10.0 Hz, 2H),
7.77–7.74 (m, 1H), 7.62 (d, J ꢀ10.0 Hz, 1H), 7.42–7.38 (m,
2H), 6.95–6.91 (m, 1H), 5.38 (s, 2H); 13C NMR (125 MHz,
DMSO-d6): δ 166.9, 166.3, 162.7 (d, J ꢀ241.7 Hz), 158.1,
153.2, 151.9, 143.1, 140.8 (d, J ꢀ10.9 Hz), 139.0, 136.7,
135.2, 131.1 (d, J ꢀ9.5 Hz), 130.0, 128.2, 128.1, 124.0,
119.6, 115.8, 114.9, 110.7 (d, J ꢀ21.3 Hz), 106.8 (d,
J ꢀ26.2 Hz), 66.0. ESI-HRMS m/z: [M+H]+ calcd for
C24H18FN6O2: 441.1470; found: 441.1482.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(4-(trifluoromethyl)phenyl)acetamide
(4h)
Yield 52%; mp: 245–246 °C; 1H NMR (500 MHz, DMSO-
d6): δ 10.07 (s, 1H), 9.46 (s, 1H), 8.71 (d, J ꢀ10.0 Hz, 2H),
8.32 (d, J ꢀ10.0 Hz, 2H), 8.06–8.0 (m, 4H), 7.76–7.71 (m,
2H), 7.66 (t, J ꢀ7.5 Hz, 1H), 7.51 (d, J ꢀ5.0 Hz, 1H),
7.46 (t, J ꢀ7.5 Hz, 1H), 5.43 (s, 2H); 13C NMR (125 MHz,
DMSO-d6): δ 167.2, 166.3, 158.0, 153.2, 151.9, 143.2,
142.7, 139.0, 136.7, 135.3, 129.9, 128.2, 128.1, 126.8,
124.8 (q, J ꢀ271.4 Hz), 124.3, 124.0, 119.9, 119.7, 114.9,
66.0. ESI-HRMS m/z: [M+H]+ calcd for C25H18F3N6O2:
491.1438; found: 491.1455.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(4-fluorophenyl)acetamide (4d) Yield 65%;
mp: 231–233 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.56
(s, 1H), 9.43 (s, 1H), 8.64–8.62 (m, 2H), 8.30 (t, J ꢀ5.0 Hz,
2H), 8.05–8.01 (m, 2H), 7.99–7.97 (m, 2H), 7.74–7.72 (m,
1H), 7.66–7.64 (m, 2H), 7.20–7.16 (m, 2H), 5.34 (s, 2H); 13C
NMR (125 MHz, DMSO-d6): δ 166.5, 166.4, 158.1, 156.8
(d, J ꢀ246.4 Hz), 153.1, 151.9, 143.2, 139.0, 136.7, 135.4,
135.2, 130.0, 128.2, 128.1, 124.1, 121.9 (d, J ꢀ7.8 Hz),
123

Molecular Diversity
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(2-nitrophenyl)acetamide (4i) Yield 61%;
mp: 203–205 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.86
(s, 1H), 9.42 (s, 1H), 8.66–8.64 (m, 2H), 8.31 (d, J ꢀ
10.0 Hz, 1H), 8.28 (s, 1H), 8.02–7.99 (m, 4H), 7.98–7.96
(m, 1H), 7.86–7.85 (m, 1H), 7.73–7.70 (m, 2H), 7.36–7.33
(m, 1H), 5.38 (s, 2H); 13C NMR (125 MHz, DMSO-d6):
δ 167.0, 166.1, 158.1, 153.2, 151.9, 143.2, 142.2, 139.0,
136.7, 135.3, 135.0, 131.6, 130.1, 128.2, 128.1, 126.0, 125.7,
125.5, 124.0, 119.7, 114.9, 65.8. ESI-HRMS m/z: [M+H]+
calcd for C24H18N7O4: 468.1415; found: 468.1413.
mp: 249–250 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.62
(s, 1H), 9.39 (d, J=5.0 Hz, 1H), 8.58 (d, J ꢀ10.0 Hz, 2H),
8.26 (d, J ꢀ0.9 Hz, 1H), 8.24 (d, J ꢀ0.6 Hz, 1H), 8.00–7.96
(m, 2H), 7.95–7.94 (m, 1H), 7.92 (s, 1H), 7.69–7.66 (m,
1H), 7.59 (d, J=10.0 Hz, 2H), 7.48 (d, J ꢀ10.0 Hz, 2H),
5.31 (s, 2H); 13C NMR (125 MHz, DMSO-d6): δ 166.7,
166.3, 158.1, 153.2, 151.8, 143.2, 139.0, 138.4, 136.7,
135.2, 132.2, 130.0, 128.2, 128.1, 124.1, 122.0, 119.6,
115.8, 114.9, 66.1. ESI-HRMS m/z: [M+H]+ calcd for
C24H18N6O2Br: 501.0669; found: 501.0672.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(4-methoxyphenyl)acetamide (4n) Yield 66%;
mp: 236–237 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.33
(s, 1H), 9.43 (s, 1H), 8.64 (d, J ꢀ10.0 Hz, 2H), 8.30 (d, J ꢀ
10.0 Hz, 2H), 8.02 (t, J ꢀ7.5 Hz, 2H), 7.99 (d, J ꢀ5.0 Hz,
2H), 7.74–7.71 (m, 1H), 7.53 (d, J ꢀ10.0 Hz, 2H), 6.90
(d, J ꢀ5.0 Hz, 2H), 5.31 (s, 2H), 3.70 (s, 3H); 13C NMR
(125 MHz, DMSO-d6): δ 166.4, 166.0, 158.1, 156.0, 153.2,
151.9, 143.2, 139.0, 136.8, 135.2, 132.1, 130.0, 128.2, 128.1,
124.1, 121.8, 119.7, 115.0, 114.5, 66.1, 55.7. ESI-HRMS
m/z: [M+H]+ calcd for C25H21N6O3: 453.1670; found:
453.1690.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(3-nitrophenyl)acetamide (4j) Yield 62%;
1
mp: 229–231 °C; H NMR (500 MHz, DMSO-d6): δ 9.37
(d, J ꢀ2.6 Hz, 1H), 8.61 (d, J ꢀ2.1 Hz, 1H), 8.59 (d, J ꢀ
2.3 Hz, 1H), 8.54 (d, J ꢀ2.4 Hz, 1H), 8.27 (d, J ꢀ5.0 Hz,
1H), 8.25 (d, J ꢀ5.0 Hz, 1H), 8.00 (s, 2H), 7.97–7.94 (m,
2H), 7.92 (d, J ꢀ10.0 Hz, 1H), 7.89 (d, J ꢀ10.0 Hz, 2H),
7.72–7.69 (m, 1H), 7.63–7.59 (m, 1H), 5.36 (s, 2H); 13C
NMR (125 MHz, DMSO-d6): δ 167.4, 166.4, 158.0, 153.2,
151.9, 148.5, 143.2, 140.5, 139.0, 136.7, 135.3, 130.9, 129.9,
128.2, 128.1, 126.1, 124.1, 119.7, 118.6, 114.9, 114.2, 66.1.
ESI-HRMS m/z: [M+H]+ calcd for C24H18N7O4: 468.1415;
found: 468.1411.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(2,4-difluorophenyl)acetamide (4o) Yield 51%;
mp: 225–227 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.35
(s, 1H), 9.46 (s, 1H), 8.69–8.66 (m, 2H), 8.33–8.31 (m,
2H), 8.04–8.02 (m, 4H), 7.76–7.71 (m, 2H), 7.41–7.39 (m,
1H), 7.10–7.06 (m, 1H), 5.43 (s, 2H); 13C NMR (125 MHz,
DMSO-d6): δ 167.0, 166.3, 158.1, 157.0 (d, J ꢀ243.7 Hz),
155.0 (d, J ꢀ249.6 Hz), 153.2, 151.8, 143.2, 139.0, 136.8,
135.2, 130.0, 128.1 (t, J ꢀ15.2 Hz), 126.8 (d, J ꢀ9.7 Hz),
124.1, 122.5, 122.4, 119.6, 114.92, 111.8 (d, J ꢀ24.9 Hz),
104.9 (t, J ꢀ23.7 Hz), 65.5. ESI-HRMS m/z: [M+H]+ calcd
for C24H17F2N6O2: 459.1376; found: 459.1369.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(m-tolyl)acetamide (4k) Yield 67%; mp:
200–202 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.43
(s, 1H), 9.39 (s, 1H), 8.60 (d, J ꢀ10.0 Hz, 2H), 8.27–8.26
(m, 2H), 8.02–7.98 (m, 2H), 7.97–7.93 (m, 2H), 7.71–7.68
(m, 1H), 7.44 (s, 1H), 7.38 (d, J ꢀ10.0 Hz, 1H), 7.17 (t, J
ꢀ7.5 Hz, 1H), 6.85 (d, J ꢀ10.0 Hz, 1H), 5.30 (s, 2H), 2.23
(s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 166.4, 158.1,
153.2, 151.8, 146.6, 143.1, 142.1, 139.0, 138.6, 136.7,
135.2, 130.0, 129.2, 128.2, 128.1, 124.9, 124.1, 120.6,
119.6, 117.3, 114.9, 65.9, 21.5. ESI-HRMS m/z: [M+H]+
calcd for C25H21N6O2: 437.1721; found: 437.1721.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(2,6-difluorophenyl)acetamide (4p) Yield 47%;
mp: 270–271 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.25
(s, 1H), 9.48 (s, 1H), 8.71 (d, J ꢀ10.0 Hz, 2H), 8.33 (d,
J ꢀ10.0 Hz, 2H), 8.05 (d, J ꢀ5.0 Hz, 2H), 8.04–8.02 (m,
2H), 7.73 (t, J ꢀ7.5 Hz, 1H), 7.39–7.33 (m, 1H), 7.18
(t, J ꢀ10.0 Hz, 2H), 5.44 (s, 2H); 13C NMR (125 MHz,
DMSO-d6): δ 167.1, 166.3, 158.3 (d, J ꢀ249.1 Hz), 158.2,
153.2, 151.8, 143.2, 139.0, 136.7, 135.2, 130.1, 128.8 (t,
J ꢀ10.0 Hz), 128.2, 128.0, 124.2, 119.6, 115.0, 114.4 (t,
J ꢀ16.9 Hz), 112.5 (d, J ꢀ22.9 Hz), 65.6. ESI-HRMS
m/z: [M+H]+ calcd for C24H17F2N6O2: 459.1376; found:
459.1377.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(p-tolyl)acetamide (4l) Yield 49%; mp:
257–258 °C; 1H NMR (500 MHz, DMSO-d6): δ 10.40
(s, 1H), 9.42 (s, 1H), 8.62 (d, J ꢀ5.0 Hz, 2H), 8.29 (d, J
ꢀ5.0 Hz, 2H), 8.03–8.00 (m, 2H), 7.98 (s, 1H), 7.96 (s,
1H), 7.73–7.70 (m, 1H), 7.50 (d, J ꢀ10.0 Hz, 2H), 7.11
(d, J ꢀ10.0 Hz, 2H), 5.32 (s, 2H), 2.23 (s, 3H); 13C NMR
(125 MHz, DMSO-d6): δ 166.4, 166.2, 158.1, 153.2, 151.8,
143.2, 139.0, 136.8, 136.5, 135.2, 133.1, 130.0, 129.8, 128.2,
128.1, 124.1, 120.1, 119.7, 114.9, 66.1, 21.0. ESI-HRMS
m/z: [M+H]+ calcd for C25H21N6O2: 437.1721; found:
437.1721.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(4-bromophenyl)acetamide (4m) Yield 52%;
yl)oxy)-N-(2,4-dichlorophenyl)acetamide
58%; mp: 254–255 °C; H NMR (500 MHz, DMSO-d6):
(4q) Yield
1
123

Molecular Diversity
Scheme 1 Synthetic route of target compounds 4a–4r
δ 10.18 (s, 1H), 9.44 (s, 1H), 8.67 (d, J ꢀ10.0 Hz, 2H),
8.30 (s, 2H), 8.02 (d, J ꢀ10.0 Hz, 4H), 7.73–7.68 (m,
3H), 7.40 (d, Jꢀ10.0 Hz, 1H), 5.44 (s, 2H); 13C NMR
(125 MHz, DMSO-d6): δ 167.1, 166.3, 160.4, 158.1, 153.2,
151.8, 143.2, 139.0, 136.7, 135.3, 134.0, 130.3, 130.0,
129.6, 128.2, 128.1, 127.9, 124.1, 120.0, 119.7, 114.9,
65.8. ESI-HRMS m/z: [M+H]+ calcd for C24H17N6O2Cl2:
491.0785; found: 491.0783.
2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-
yl)oxy)-N-(2,6-dimethylphenyl)acetamide
(4r) Yield
61%; mp: 285–286 °C; 1H NMR (500 MHz, DMSO-d6): δ
9.70 (s, 1H), 9.47 (s, 1H), 8.72 (d, J ꢀ10.0 Hz, 2H), 8.36
(d, J ꢀ5.0 Hz, 1H), 8.32 (s, 1H), 8.07 (d, J ꢀ10.0 Hz, 2H),
8.03 (s, 2H), 7.73 (d, J ꢀ5.0 Hz, 1H), 7.03 (s, 3H), 5.44
(s, 2H), 2.09 (s, 6H); 13C NMR (125 MHz, DMSO-d6):
δ 166.6, 166.3, 158.2, 153.2, 151.8, 143.2, 139.0, 136.7,
135.9, 135.2, 134.9, 130.5, 130.1, 128.2, 127.9, 127.2,
124.5, 119.6, 115.1, 65.7, 18.3. ESI-HRMS m/z: [M+H]+
calcd for C26H23N6O2: 451.1877; found: 451.1867.
Fig. 3 Crystal structure of compound 4a
powder, 10 g of glucose, 1 L of distilled water, pHꢀ7.0−
7.2) containing the bacterium Xoo/Xac/Rs was added to the
mixed solvent system including 4 mL of solvent NB and
1 mL of 0.1% Tween-20 aqueous solution containing tested
compound or BMT. The above test tube was incubated at
30 1 °C and continuously shaken at 180 rpm for 1–3 days.
The bacterial growth was monitored by measuring the optical
Antimicrobial assay
Antibacterial assay
Antibacterial activities of target compounds were determined
against three pathogenic bacteria (Xac, Xoo and Rs/Ralstonia
solanacearum), using the turbidimetric method [23, 27]. The
tested compounds were prepared at two concentrations of
200 and 100 μg/mL. Pure DMSO in sterile distilled water
was utilized as blank control, and commercial agrobacteri-
cides bismerthiazol (BMT) and thiodiazole-copper (TDC)
were used as positive control agents. About 40 μL of sol-
vent NB (3 g of beef extract, 5 g of peptone, 1 g of yeast
density at 600 nm (OD600), given by turbiditycorrected values
ꢀ
ODbacterium −ODno bacterium, I ꢀ(Ctur −Ttur)/Ctur ×100%.
The Ctur represents the corrected turbidity value of bacterial
growth of untreated NB (blank control), and Ttur repre-
sents the corrected turbidity value of bacterial growth of
compound-treated NB. The I represents the inhibition rate
of test compound against the bacterium.
Next, antibacterial activities of target compounds were
further assessed against Xoo under five different concentra-
123

Molecular Diversity
Table 1 Antibacterial activities
of compounds 4a–4r against
pathogenic phytobacteria Xoo,
Xac and Rs
Inhibition rate (%)a
Compd.
Xoo
Xac
Rs
200 μg/mL
100 μg/mL
200 μg/mL
100 μg/mL
200 μg/mL
100 μg/mL
4a
73.5 1.9
67.3 2.0
94.1 1.9
79.1 1.0
68.0 3.9
61.9 1.1
81.5 4.2
67.6 2.8
82.0 4.7
58.5 1.1
53.6 5.1
62.2 3.7
69.2 3.5
71.0 4.2
69.2 2.8
66.9 5.7
96.3 2.2
45.2 1.7
NT
67.2 1.1
48.8 1.2
83.4 0.5
68.7 0.8
44.6 1.0
41.4 1.6
76.5 0.3
54.1 0.4
62.4 2.6
49.7 2.9
41.9 2.1
34.1 3.9
44.6 1.0
62.6 3.3
61.0 0.5
43.6 3.2
84.6 3.4
24.5 3.0
NT
40.8 3.2
32.9 5.4
41.2 0.5
32.3 2.9
19.6 1.6
34.6 0.9
40.2 4.0
52.7 4.7
56.8 2.4
59.6 1.1
19.2 1.6
36.5 3.4
33.5 1.4
51.3 4.9
40.5 0.6
36.7 0.9
45.1 6.5
37.0 1.2
NT
21.4 1.4
16.6 3.3
29.9 2.2
24.0 1.8
6.5 3.4
29.5 1.8
8.7 0.5
41.9 3.1
39.2 1.6
47.6 3.1
6.5 1.3
12.0 1.2
25.4 1.9
32.6 3.7
32.0 1.7
19.2 2.4
32.8 2.2
20.0 2.1
NT
42.6 3.8
19.3 4.6
29.1 2.7
15.7 1.6
21.3 1.5
21.5 0.7
22.0 1.3
16.4 1.1
38.1 2.4
40.2 2.3
13.4 1.2
23.7 1.7
5.8 0.9
30.1 0.8
28.3 2.3
19.4 1.6
27.0 0.5
26.1 0.3
52.3 4.8
NT
17.4 2.2
2.8 1.3
11.3 2.1
13.4 2.0
14.2 1.7
9.7 1.4
19.8 1.9
11.5 2.3
21.7 1.5
25.6 3.4
4.6 2.1
11.3 2.3
2.5 1.0
20.9 1.8
24.7 1.3
3.0 1.1
3.3 1.8
3.5 1.7
21.2 3.5
NT
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
TDCb
BMTb
79.0 1.7
57.1 3.7
83.6 1.2
62.4 4.5
NT = not tested
aThe average of three trials
bCommercial agrobactericides bismerthiazol (BMT) and thiodiazole-copper (TDC) were used as positive
control agents
tions (200, 100, 50, 25 and 12.5 μg/mL) to obtain their EC50
values, which were statistically determined by Probit analy-
sis using the software package SPSS 17.0.
In this formula, the C represents the average mycelial
diameter of negative control and T represents the average
mycelial diameter of test compound-treated PDA.
Antifungal assay
Results and discussion
Mycelial growth rate method [28] was utilized to evaluate
antifungal activities of target compounds against six phy-
topathogenic fungi. DMSO solution of the tested compound
was added into sterilized Petri dishes, which contained about
10 mL molten potato dextrose agar (PDA). Subsequently, a
4-mm-diameter mycelial plug was cut from the fungal colony
and placed at the center of PDA plate at 28 1 °C for 4 days.
Antifungal assays were conducted in triplicate for each com-
pound. Additionally, pure DMSO and commercial fungicide
(Hymexazol) were utilized as negative and positive controls,
respectively.
Synthesis
The synthetic procedures of target compounds 4a–4r
are summarized in Scheme 1. In brief, 1,2,4-triazole-
substituted benzaldehyde 1 was reacted with anthranilamide
in hot DMSO to furnish the intermediate quinazolinone
2, which was then treated with N-(substituted phenyl)-2-
bromoacetamide 3a–3r in hot DMF containing anhydrous
K2CO3 as catalyst to afford target compounds 4a–4r in
43–67%yield. Allthetargetcompoundswerefullycharacter-
ized by 1H NMR, 13C NMR and HRMS spectra, which were
in good accordance with the proposed structures in Scheme 1.
The inhibition rate (I) of the tested compound was deter-
mined based on the following formula:
I ꢀ (C − T )/(C − 0.4) × 100%
123

Molecular Diversity
Table 2 EC50 values of compounds 4a–4r against Xoo
Crystal structure
Compd. Toxic regression
equation
Correlation
coefficient (r)
ECa50 SD
(μg/mL)
A single crystal of compound 4a suitable for X-ray diffrac-
tion analysis was obtained by slow evaporation of 4a in a
CH2Cl2-EtOH (5/1, v/v) solution at room temperature. As
shown in Fig. 3, the acetamide group was directly attached
to 4-position oxygen atom of quinazoline nucleus, rather
than 3-position of nitrogen atom. Crystallographic data for
4a: colorless crystal, C24H18N6O2, Mr=422.43, triclinic,
space group P-1; a ꢀ4.6875(9) Å, b ꢀ19.043(4) Å, c ꢀ
22.820(5) Å; α ꢀ99.38(3)°, β ꢀ90.00(3)°, γ ꢀ90.00(3)°,
V ꢀ2009.8(7) Å3, T ꢀ293 K, Z ꢀ4, Dc ꢀ1.393 g/cm3,
F(000)ꢀ876.0, reflections collected/independent reflec-
tionsꢀ9776/3657, goodness-of-fit on F2 ꢀ1.031, R1ꢀ
0.13, wR2=0.2653. CCDC 1573558.
4a
4b
4c
y ꢀ1.3010x +2.7296 0.9919
y ꢀ1.3381x +2.3536 0.9972
55.6 3.2
95.0 3.5
35.0 2.0
53.2 3.5
110.6 5.2
128.4 3.2
36.5 1.8
100.5 4.1
72.0 2.5
110.9 4.8
138.5 3.1
158.9 8.1
102.2 6.4
54.4 3.6
79.6 3.5
119.3 7.5
32.4 2.2
240.7 3.2
89.8 1.8
y ꢀ2.3456x +1.3783 0.9969
y ꢀ1.5035x +2.4050 0.9963
y ꢀ1.9568x +1.0010 0.9856
y ꢀ1.5323x +1.7691 0.9983
y ꢀ1.3058x +2.9602 0.9904
y ꢀ1.8485x +1.2993 0.9954
y ꢀ2.0656x +1.1635 0.9948
y ꢀ1.3564x +2.2261 0.9796
y ꢀ1.5009x +1.7858 0.9988
y ꢀ1.7944x +1.0503 0.9846
y ꢀ2.2084x +0.5627 0.9919
y ꢀ1.0030x +3.2595 0.9966
y ꢀ1.6493x +1.8650 0.9796
y ꢀ1.8201x +1.2201 0.9995
y ꢀ2.1648x +1.7293 0.9981
y ꢀ1.7696x +0.7858 0.9988
y ꢀ2.1405x +0.8190 0.9908
4d
4e
4f
4g
4h
4i
4j
4k
4l
Antibacterial activity
4m
4n
4o
4p
4q
4r
Antibacterial activity of compounds 4a–4r against three
pathogenic bacteria (Xoo, Xac and Rs) was firstly assessed
in vitro at 200 and 100 μg/mL, using a turbidimetric method.
As shown in Table 1, nearly half of this class of compounds
demonstrated stronger inhibition activities against Xoo than
control bismerthiazol at 100 μg/mL, with compounds 4q and
4c being the two most effective (having the inhibition rates
of 84.6% and 83.4%, respectively). Significantly improved
antibacterial activity towardXoo was observed for these com-
pounds, compared with recently reported quinazolinylether
derivatives having a 1,2,4-triazolylstyryl moiety [21]. Fur-
thermore, a few compounds also demonstrated moderate
antibacterial activity against Xac. For example, compounds
4h, 4i, 4j, 4n, 4o and 4q possessed inhibition rates of 41.9%,
39.2%, 47.6%, 32.6%, 32.0% and 32.8% at 100 μg/mL,
respectively. As for the bacterium Rs, only compounds 4a,
4i and 4j were found to display modest inhibition activi-
ties against this pathogen under a higher concentration of
200 μg/mL.
BMTb
aThe average of three trials
bCommercial agrobactericide bismerthiazol (BMT) was used as control
agent
(compounds 4k, 4l and 4r) exhibited a poor antibacterial
activity, with compound 4r (having a bulky 2,6-di-CH3-Ph
group) being the worst (EC50 ꢀ240.7 μg/mL); (3) The posi-
tion effect of certain substitutions on the benzene ring exerted
a pronounced influence on the antibacterial activity, such as
compounds 4c (3-F-Ph) vs 4b (2-F-Ph) as well as 4g (2-CF3-
Ph) vs 4h (4-CF3-Ph), displaying approximately threefold
differences in the antibacterial activity.
Antifungal activity
To better evaluate antibacterial activities of these com-
pounds against Xoo, their EC50 values were then determined
using serial dilution method. As summarized in Table 2,
compounds 4a, 4c, 4d, 4g, 4i, 4n, 4o and 4q were found
to have EC50 values of 55.6, 35.0, 53.2, 36.5, 72.0, 54.4,
79.6 and 32.4 μg/mL against this pathogen, respectively,
which were indeed superior to the control bismerthiazol
(EC50 ꢀ89.8 μg/mL). In particular, the efficacy of com-
pounds 4c, 4g and 4q was nearly 1.5 times more active than
commercial bactericide bismerthiazol. A preliminary struc-
ture–activity relationship analysis was performed, and some
tentativeconclusionscouldbedrawnasfollows:(1)Thethree
most effective compounds (namely compounds 4c, 4g and
4q) included halogen substitutions, which favored the bind-
ing interactions between small molecules and proteins [29];
(2) Among these compounds, methyl-substituted compounds
Antifungal activities of compounds 4a–4r against six phy-
topathogenic fungi were tested in vitro at 50 μg/mL, using
mycelial growth rate method. As listed in Table 3, all the
compounds displayed moderate to good antifungal activity
against Gloeosporium fructigenum. It is worth mentioning
that inhibition rates of compounds 4j and 4p were determined
to be 44.4% and 44.0% against this pathogen, respectively,
close to commercial fungicide Hymexazol (49.8%).
Conclusions
In conclusion, a series of 2-((2-(4-(1H-1,2,4-triazol-1-
yl)phenyl)quinazolin-4-yl) oxy)-N-phenyl acetamide deriva-
123

Molecular Diversity
Table 3 Antifungal activities of
compounds 4a–4r at 50 μg/mL
Compd.
Inhibition rate (%)a
GF
VD
PI
FO
9.6 2.8
PS
CM
4a
39.4 1.1
36.1 1.7
36.5 2.4
36.1 4.0
35.7 1.3
29.1 2.4
31.1 1.7
39.0 2.6
41.9 2.5
44.4 2.1
27.1 1.4
36.4 2.1
39.4 2.0
38.5 2.5
35.7 2.7
44.0 0.7
37.3 0.8
35.3 4.3
49.8 2.4
12.3 1.8
6.9 0.6
8.7 1.3
12.3 1.8
6.0 0.4
12.9 0.4
15.4 0.8
0
10.3 1.5
14.8 2.6
16.6 5.7
16.0 1.9
12.2 2.4
13.9 2.6
14.5 2.1
13.4 1.0
14.2 0.7
15.7 2.5
14.5 1.5
14.5 2.1
13.6 1.5
13.3 1.6
14.5 2.1
16.3 2.0
12.4 1.2
16.3 2.0
64.9 3.2
30.1 3.3
26.8 6.7
32.4 1.3
28.1 4.9
20.8 2.4
25.3 3.2
17.9 2.4
18.4 4.6
16.8 3.1
30.0 4.0
16.9 1.9
16.1 3.1
19.2 4.5
27.3 3.6
20.8 1.1
27.3 0.7
19.6 3.4
22.9 4.1
74.5 3.2
24.6 8.6
14.1 7.2
23.5 6.7
21.7 5.6
19.4 3.8
20.1 5.9
21.4 2.4
21.3 4.3
17.5 4.6
18.0 2.6
17.1 4.9
23.5 6.8
18.2 6.0
27.3 3.4
0
4b
11.4 0.6
8.6 3.9
8.2 1.6
9.6 1.0
9.3 2.7
7.9 0.6
13.2 1.2
12.9 1.8
24.3 1.2
13.6 2.4
17.1 1.0
17.5 0.7
12.8 2.1
9.3 1.3
8.9 2.5
10.4 0.6
12.1 0.7
72.7 1.4
4c
4d
4e
4f
4g
4h
4i
16.3 1.4
34.7 1.6
12.6 4.4
12.6 0.9
10.8 2.6
14.7 3.2
16.3 1.7
15.3 2.2
16.5 2.5
18.4 1.6
84.7 0.8
4j
4k
4l
4m
4n
4o
4p
18.6 5.4
19.0 8.9
21.4 2.2
66.2 0.1
4q
4r
Hymexazolb
GF Gloeosporium fructigenum, VD Verticillium dahliae, PI Phytophthora infestans, FO Fusarium oxysporum,
PS Pellicularia sasakii, CM Cytospora mandshurica
aThe average of three trials
bCommercial agrofungicide Hymexazol was used as control agent
tives were synthesized and evaluated for their antimicrobial
activity against the phytopathogenic bacteria and fungi in
agriculture. The work presented herein demonstrated the
potential of this new molecular framework for being a useful
molecular platform for developing more efficient agrobacte-
ricides against the pathogen Xoo.
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Top-Notch Talent Support Program of Guizhou Provincial Education
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