Synthesis, antibacterial evaluation and molecular docking studies of novel series of acridone- 1,2,3-triazole derivatives

Article abstract of DOI:10.1007/s11224-020-01512-0

Development of new drugs with antibacterial potency is an important solution to overcome drug-resistance problems. In the goal to develop novel structure with antibacterial potency, we designed and synthesized novel acridone derivatives bearing triazole nucleus. The novel synthesized compounds were tested for their in vitro antibacterial activity against four bacterial human pathogenic strains. The compound 4h displayed significant antibacterial activities against Staphylcoccus aureus (MRSA) with MIC = 19.6?μg/mL. The synthesized compounds were subjected for docking study to understand the interaction of our compounds and the dihydropteroate synthase (DHPS) in methicillin-resistant Staphylcoccus aureus (MRSA).

Full text of DOI:10.1007/s11224-020-01512-0

Structural Chemistry
https://doi.org/10.1007/s11224-020-01512-0
ORIGINAL RESEARCH
Synthesis, antibacterial evaluation and molecular docking studies
of novel series of acridone- 1,2,3-triazole derivatives
1
1
2
3
1
Mohammed Aarjane & Siham Slassi & Bouchra Tazi & Mohamed Maouloua & Amina Amine
Received: 29 May 2019 /Accepted: 21 February 2020
#
Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
Development of new drugs with antibacterial potency is an important solution to overcome drug-resistance problems.
In the goal to develop novel structure with antibacterial potency, we designed and synthesized novel acridone
derivatives bearing triazole nucleus. The novel synthesized compounds were tested for their in vitro antibacterial
activity against four bacterial human pathogenic strains. The compound 4h displayed significant antibacterial activ-
ities against Staphylcoccus aureus (MRSA) with MIC = 19.6 μg/mL. The synthesized compounds were subjected for
docking study to understand the interaction of our compounds and the dihydropteroate synthase (DHPS) in
methicillin-resistant Staphylcoccus aureus (MRSA).
.
.
.
.
Keywords Synthesis Acridone Triazole Antibacterial activity Docking
Introduction
attractive for synthesis since they possess diverse pharma-
cological properties such as antifungal [4], antibacterial
[5], anti-malarial [6], antiviral [7], antitumoral [8], and
anti-inflammatory [9] activities. Moreover, the synthesis
of 1,2,3-triazole via click chemistry by 1,3-dipolar cyclo-
addition of substituted azides and alkynes in the presence
of Cu(I) gives regioselective 1,4-disubstituted 1,2,3-tri-
azole with good yields.
On the other hand, acridone and acridine derivatives are
known for many years for their biological activities such as
antitumor [10], antiviral [11], anti-inflammatory [12], antima-
larial [13], and antimicrobial bioactivity [14] . Numerous
acridone compounds that have antibacterial activity have been
developed, including some heterocyclic such as triazole, thia-
zole, and 1,3,4-oxadiazole nucleus [15–17] . Several methods
are reported for the preparation of the acridone ring, among
them are Ullmann reaction which was considered as the most
efficient [18]; it consist the condensation of o-halobenzoic
acid with aromatic amine in the presence of Cu followed by
intramolecular cyclization using sulfuric acid.
Antibiotic resistance is currently considered as major
public health problem [1]. Therefore, the development
of new compounds with antimicrobial activity is impor-
tant errands of this century. One of the researched ther-
apeutic targets in the field of antibacterial discovery is
dihydrofolate reductase (DHFR), an essential enzyme
whose role is to regenerate folic acid into its reduced
form tetrahydrofolate; this enzyme represents an attrac-
tive antibacterial target [2].
Triazole is an important heterocyclic skeleton with
large biological activity. 1,2,3-triazoles are important class
in the triazoles series [3]; these compounds continue to be
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11224-020-01512-0) contains supplementary
material, which is available to authorized users.
*
Mohammed Aarjane
aarjane.mohammed@gmail.com
In a view of the significant bio-potential of 1,2,3-triazole
and acridone nucleus and in order to develop novel bioactive
therapeutic agents, we focused our work on the preparation
and evaluation of novel acridone bearing 1,2,3-triazole nucle-
us as antibacterial agents against four bacteria. The synthe-
sized compounds had led to some important structure with
interesting antibacterial activity.
1
2
3
LCBAE, Faculty of Science, University Moulay Ismail, Zitoune,
11201 Meknes, Morocco
Department of Basic Sciences, National School of Agriculture,
Meknes, Morocco
Medical Microbiology Laboratory, Mohamed V. Hospital,
Meknes, Morocco

Struct Chem
Materials and methods
Synthesis
Materials
Synthesis of acridone from 2-(phenylamino)benzoic acid
All materials were purchased from commercial suppliers. IR
spectra were recorded using JASCO FT-IR 4100 spectropho-
tometer. Mass spectrometric measurements were recorded
using SHIMADZU 8040 LC/MS/MS. The H, C NMR
spectra was recorded with Bruker Avance 300 at 25 °C.
A mixture of aniline (0.65 g, 7 mmol), o-bromobenzoic acid
(1 g, 5 mmol), anhydrous potassium carbonate (0.82 g,
6 mmol), 0.1 g of copper powder, and 0.04 g of copper oxide
was refluxed for 4 h in 15 mL of amyl alcohol. The amyl
alcohol was evaporated then poured into (100 mL) hot water,
cooled to room temperature, acidification with HCl lead to 1
as a white precipitate which was then recrystallized from eth-
anol. The N-phenylanthranilic acid (1 g, 4.7 mmol) was taken
in 4 mL of concentrated sulfuric acid and heated on water bath
for 3 h. Reaction mixture was added to hot water and the
resulting precipitates were filtered to get acridone. The sample
of acridone 2 was recrystallized from acetic acid. Yield 70%,
1
13
Determination of minimum inhibitory concentration
The synthesized compounds were tested for their antibac-
terial activity by the disk diffusion method; the active
compounds were subjected to the determination of the
MIC, using the broth microdilution method. The micro-
organisms utilized for the test were Escherichia coli,
Staphylococcus aureus, Pseudomonas putida, and
Klebsiella pneumonia. They were collected from clinical
isolates. Bacterial inoculums were prepared by
subculturing microorganisms into MHB at 37 °C for
R 0.71, mp > 330 C. IR (KBr) 3275 (N–H), 3084 (C–H aro-
f
1
matic), 1640 (C=O), 1570 (C=C). H NMR (300 MHz,
[D ]DMSO, 25 °C, TMS): δ 11.74 (s, 1H, NH), 8.23 (dd,
6
J = 8.1, 1.2 Hz, 2H, H -H ), 7.70 (td, J = 8.4, 1.5 Hz, 2H,
1
8
H -H ), 7.53 (d, J = 8.1 Hz, 2H, H -H ), 7.23 (td, J = 8.4,
3
6
4
5
1
3
1.5 Hz, 2H, H -H ). C NMR (75 MHz, [D ]DMSO,
2
7
6
6
−1
1
8 h and were diluted to approximately 10 CFU mL .
25 °C, TMS) δ: 177.29, 141.35, 133.94, 126.46, 121.49,
Initial solution with concentration 0.5 mg/mL of the
compounds (4a-h) were prepared in DMF; further serial
dilutions were made in the microplates, and 100 μl of
MHB containing each test microorganism were added to
the microplate [19–21], then incubated at 36 °C for 24 h.
After incubation, 20 μL of TTC (0.04 mg/mL) were
added to each microplate. The color changes of TTC
from colorless to red were accepted as microbial growth
120.91, 117.80.
Synthesis of 10-(prop-2-yn-1-yl)acridone (3)
To a mixture of acridone 2 (0.5 g, 2.5 mmol), sodium hydride
(45 mg, 3.6 mmol) and TBAB (0.5 g, 2 mmol) in DMF
(3 mL), propargyl bromide (0.38 g, 3.6 mmol) was added
and the mixture was stirred at 85 °C for 3 h. After which, it
was poured into crushed ice and the white yellow formed
precipitate was recrystallized from ethanol-DMF.
[
22]. A negative control was prepared using the inocu-
lum and DMF without derivative, whereas chloramphen-
icol was used as positive control.
White solid; yield 74%, R 0.84, mp = 178 °C. IR (KBr):
f
−
1
1
3
206, 3008, 2913, 1639, 1600, 1495 cm . H NMR
(
300 MHz, [D ]DMSO, 25 °C, TMS): δ 8.34 (d, 2H, H1-
6
Molecular docking studies
H8), 7.85–7.81 (m, 4H, H3-H6-H4-H5), 7.38–7.32 (m, 2H,
H2-H7), 5.34 (s, 2H, CH2), 2.48 (s, 1H, CH); C NMR
1
3
Molecular docking of the compounds (4a-h) into the
S. aureus DHFR complex structure (PDB code, 2W9S)
(75 MHz, [D ]DMSO, 25 °C, TMS) δ 177.08, 141.70,
134.76, 134.46, 127.18, 127.00, 122.37, 122.20, 117.44,
116.35, 79.12, 76.16, 36.
6
[
23] was carried out using Molecular Operating
Environment (MOE-Dock 2015.10) software [24]. The
Discovery Studio (version 4.5) was used for graphical
visualization. The structure of 2W9S in docking study
was downloaded from Protein Data Bank. The 3D struc-
tures of compounds (4a-h) were constructed using
Chem ultra 12.0 software and were energetically mini-
mized, then the 3D structure of compounds (4a-h) was
placed in database. For protein preparation, the hydro-
gen atoms were added; water and impurities were re-
moved. Different types of interactions between protein
and the docked compounds (4a-h) were analyzed using
Discovery Studio.
General procedure for the synthesis
of acridon-1,2,3-triazole derivatives (4a-h)
A mixture of 10-(prop-2-yn-1-yl)acridone (0.1 g, 0.42 mmol),
azide (0.63 mmol), copper sulfate (21 mg, 0.081 mmol), and
sodium ascorbate (33 mg, 0.16 mmol) in DMF (5 mL) was
stirred at room temperature for 12 h. Then the mixture was
diluted with water, poured onto ice, and the precipitate was
filtered off, washed with cold water, and purified by flash
chromatography on silica gel using hexane/diethyl ether
(1:4) to afford desire product.

Struct Chem
Ethyl 2-{4-[(9-oxoacridin-10-yl)methyl]
7.2 Hz, 2H, H1’,H4’), 7.36 (d, J = 7.2 Hz, 4H,
1
3
-
1,2,3-triazol-1-yl}acetate (4a)
H2,H7,H2’,H3’), 5.87 (s, 2H, CH2), 2.36(s, 3H, CH3).
C
NMR (75 MHz, [D ]DMSO, 25 °C, TMS):177.07, 144.10,
6
Yellow solid; yield 80%, R 0.73 (hexane:diethyl ether = 1:6),
142.51, 138.85, 134.61, 130.85, 127.14, 122.42, 121.94,
120.52, 116.74, 42.39, 20.96. MS (ESI) for C H N O
[M + 1] , calcd 367.17, found 367.15.
f
mp > 300 °C. IR (KBr): 3132, 2986, 2914, 1745, 1634, 1600,
2
3
18
4
−1
1
+
1
493, 1227 cm . H NMR (300 MHz, [D ]DMSO, 25 °C,
6
TMS): δ 8.36 (dd, J = 8.1, 1.5 Hz,2H, H1-H8), 8.10 (s, 1H,
triazole), 7,95 (d, J = 8,7 Hz, 2H, H4, H5), 7.80 (td, J = 15.6,
Ethyl 2-{4-[(2-methyl-9-oxoacridin-10-yl)methyl]
-1,2,3-triazol-1-yl}acetate (4e)
6
.9 1.5 Hz, 2H, H3, H6), 7.33 (t, J = 7.5 Hz, 2H, H2,H7), 5.83
(
1
s, 2H, CH2), 5.31(s, 2H, CH2), 4,11 (q, J = 7.2 Hz, 2H, CH2),
,13 (t, J = 7.2 Hz, 3H,CH3). C NMR (75 MHz,
1
3
Yellow solid; yield: 84%, R 0.77 (hexane:diethyl ether = 1:6),
f
[
D ]DMSO, 25 °C, TMS): 177.07, 167.53, 143.01, 142.23,
mp > 300 °C. IR (KBr): 3130, 2981, 1746, 1635, 1602, 1496,
6
−1 1
1
4
3
34.65, 127.13, 125.25, 122.20, 122.00, 116.74, 61.89, 50.86,
1228 cm . H NMR (300 MHz, [D ]DMSO, 25 °C, TMS):
6
+
1.94, 14.34. MS (ESI) for C H N O [M + 1] , calcd
8.34 (d, J = 7.8 Hz,1H, H1), 8.13 (s,1H, H8), 8.05 (s,1H, tri-
azole), 7,93–7.85 (m, 3H, H3,H4, H5), 7.63 (d, J = 8.1 Hz,
2
0
18
4
3
63,13, found 363.14.
1H, H6), 7.30 (t, J = 7.5 Hz, 1H, H2), 5.80 (s, 2H, CH2),
{
(
4-[(9-oxoacridin-10-yl)methyl]-1,2,3-triazol-1-yl}acetic acid
4b)
5.29(s, 2H, CH2), 4,11 (q, J = 7.2 Hz, 2H, CH2), 2.41 (s,3H,
1
3
CH3), 1,13 (t, J = 7.2 Hz, 3H,CH3). C NMR (75 MHz,
D ]DMSO, 25 °C, TMS): 176.91, 167.47, 143.07, 142.09,
[
6
Yellow solid; yield 82%, R 0.62 (hexane:diethyl ether = 1:4),
140.36, 135.92, 134.42, 131.21, 127.15, 126.35, 125.16,
122.13, 121.69, 116.73, 116.55, 61.87, 50.87, 41.87, 20.63,
f
mp > 300 °C. IR (KBr): 3400, 3120, 2970, 1700, 1635, 1601,
−1
1
+
1
497, 1236 cm . H NMR (300 MHz, [D ]DMSO, 25 °C,
14.32. MS (ESI) for C H N O [M + 1] , calcd 377.15,
6
21 20 4 3
TMS): 10.82 (s, 1H, OH), 8.36 (dd, J = 8.0, 1.1 Hz,2H, H1-
H8), 8.11 (s, 1H, triazole), 7,96 (d, J = 8,7 Hz, 2H, H4, H5),
found 377.16.
7
2
.80 (td, J = 15.6, 6.9 1.8 Hz, 2H, H3, H6), 7.33 (t, J = 8.1 Hz,
H, H2,H7), 5.81 (s, 2H, CH2), 5.19(s, 2H, CH2). C NMR
{4-[(2-methyl-9-oxoacridin-10-yl)methyl]
-1,2,3-triazol-1-yl}acetic acid (4f)
1
3
(
75 MHz, [D ]DMSO, 25 °C, TMS): 177.08, 168.91, 142.79,
6
1
5
3
42.23, 134.66, 127.12, 125.21, 122.16, 122.00, 116.78,
Yellow solid; yield: 81%, R 0.65 (hexane:diethyl ether = 1:4),
f
+
1.08, 41.93. MS (ESI) for C H N O [M + 1] , calcd
mp > 300 °C. IR (KBr): 3400, 3118, 2976, 1700, 1635, 1601,
1
8
14
4
3
−1 1
35.10, found 335.12.
1490, 1237 cm . H NMR (300 MHz, [D ]DMSO, 25 °C,
6
TMS): 10.85 (s,1H, OH), 8.34 (d, J = 7.8 Hz,1H, H1), 8.12
(s,1H, H8), 8.06 (s,1H, triazole), 7,94–7.75 (m, 3H, H3,H4,
H5), 7.64 (d, J = 8.1 Hz, 1H, H6), 7.30 (t, J = 7.5 Hz, 1H, H2),
1
0-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)acridin-9(10H)-one
(
4c)
1
3
5.78 (s, 2H, CH2), 5.13(s, 2H, CH2), 2.40(s,3H, CH3).
C
White solid; yield: 82%, R 0.69 (hexane:diethyl ether = 1:4),
NMR (75 MHz, [D ]DMSO, 25 °C, TMS): 176.89, 167.55,
f
6
mp > 300 °C. IR (KBr): 3111, 1638, 1614, 1593, 1502,
142.07, 140.34, 135.96, 134.46, 131.20, 127.13, 126.32,
125.19, 122.06, 121.70, 116.80, 116.62, 50.87, 41.84, 20.66.
−1 1
1
255 cm . H NMR (300 MHz, [D ]DMSO, 25 °C, TMS):
6
+
8
,71(s, 1H, triazole), 8.42 (d, J = 7.2 Hz,2H, H1-H8), 7,98 (d,
MS (ESI) for C H N O [M + 1] , calcd 349.13, found
1
9 16 4 3
J = 8,1 Hz, 2H, H4, H5), 7.81–7.62 (m, 4H, H3, H6, H1’,H4’),
349.13.
7
.35 (t, J = 7.2 Hz, 5H, H2,H7,H2’,H3’,H4’), 5.87 (s, 2H,
1
3
CH2).
C NMR (75 MHz, [D ]DMSO, 25 °C,
2-methyl-10-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)
acridin-9(10H)-one (4 g)
6
TMS):177.12, 144.07, 142.57, 138.75, 134.61, 130.85,
27.24, 122.32, 121.91, 120.42, 116.44, 42.49. MS (ESI) for
1
+
C H N O [M + 1] , calcd 353.13, found 353.12.
White solid; yield: 80%, R 0.69 (hexane:diethyl ether = 1:4),
2
2
16
4
f
mp > 300 °C. IR (KBr): 3110, 3054, 1636, 1614, 1601, 1500
−1 1
10-{[1-(4-methylphenyl)-1,2,3-triazol-4-yl]
1266 cm . H NMR (300 MHz, [D ]DMSO, 25 °C, TMS):
6
methyl}acridin-9-one (4d)
8,71(s, 1H, triazole), 8.32 (d, J = 7.2 Hz,2H, H1), 8.14 (s, 1H,
H8), 7,94–7.78 (m, 2H, H4, H5), 7.71–7.62 (m, 4H, H3, H6,
H1’,H5’), 7.37 (d, J = 7.2 Hz, 5H, H2,H2’,H3’, H4’), 5.82 (s,
Yellow solid; yield 90%, R 0.70 (hexane:diethyl ether = 1:4),
f
1
3
mp > 300 °C. IR (KBr): 3110, 3060, 1637, 1617, 1598, 1504,
2H, CH2), 2,38 (s, 3H, CH3). C NMR (75 MHz,
−1 1
1
265 cm . H NMR (300 MHz, [D ]DMSO, 25 °C, TMS):
[D ]DMSO, 25 °C, TMS): 177.01, 144.29, 142.13, 140.10,
6
6
8
,72(s, 1H, triazole), 8.40 (d, J = 7.2 Hz,2H, H1-H8), 7,98 (d,
138.74, 136.12, 134.57,134.12, 131.18, 130.21, 127.22,
126.35, 122.30, 121.13, 120.71, 120.37, 116.92, 116.84,
J = 8,1 Hz, 2H, H4, H5), 7.82 (t, 2H, H3, H6), 7.73 (d, J =

Struct Chem
Scheme 1 Synthesis of acridone linked to 1,2,3-triazole derivatives 4
+
4
3
2.36, 20.86. MS (ESI) for C H N O [M + 1] , calcd
67.14, found 367.15.
(75 MHz, [D ]DMSO, 25 °C, TMS): 177.02, 144.23,
142.23, 140.50, 138.81, 136.00, 134.67,134.52, 131.18,
2
3
18
4
6
1
1
30.61, 127.12, 126.33, 122.15, 121.83, 121.71, 120.37,
16.82, 116.64, 42.16, 20.99, 20.68. MS (ESI) for
2
-methyl-10-{[1-(4-methylphenyl)-1,2,3-triazol-4-yl]
+
C H N O [M + 1] , calcd 381.17, found 381.16.
2
4 20 4
methyl}acridin-9-one (4 h)
Yellow solid; yield: 87%, R 0.70 (hexane:diethyl ether = 1:4),
f
Results and discussion
mp > 300 °C. IR (KBr): 3112, 3063, 1638, 1616, 1600, 1502
−1 1
1
267 cm . H NMR (300 MHz, [D ]DMSO, 25 °C, TMS):
6
Synthesis
8
,72(s, 1H, triazole), 8.35 (d, J = 7.2 Hz,2H, H1), 8.14 (s, 1H,
H8), 7,94–7.78 (m, 2H, H4, H5), 7.71–7.62 (m, 4H, H3, H6,
H1’,H4’), 7.36 (d, J = 7.2 Hz, 3H, H2,H2’,H3’), 5.83 (s, 2H,
CH2), 2,41 (s, 3H, CH3), 2.32(s, 3H, CH3). C NMR
The synthesis of novel acridone bearing 1,2,3-triazole com-
pounds was performed as described in (Scheme 1). Initially
acridone 2 was synthesized by Ullmann condensation reaction
of o-bromobenzoic acid with various aniline derivatives in the
presence of potassium carbonate and copper in isoamyl alco-
hol at reflux to produce 2-arylamino benzoic acids 1 [25],
which was cyclized with sulfuric acid in water bath at 85 °C
for 4 h to give compounds 2. The propargylation of acridone
was attempted by refluxing excess of propargyl bromide with
acridone derivatives in DMF using sodium hydride.
1
3
Table 1 Synthesized compounds (4a-h) from alkynes and azides
Entry Compounds
R
1
R
2
Yield (%)
Conventional MW
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
H
–
CH
2
COOEt
74
70
70
80
82
82
90
84
81
80
87
CH
Ph
2
COOH
We synthesized various azides by utilizing literature proto-
cols [9, 26]. Alkyl azides were prepared by refluxing alkyl
–
–
p-CH3-C6H4 75
halides with NaN in DMF at 80–90 °C; 4-Azidotoluene and
CH
3
CH
CH
Ph
2
COOEt
COOH
76
69
75
3
azidobenzene were prepared from p-toluidine and aniline
using diazotization followed by adding NaN3.
–
2
4g
4h
–
1,3-diploar cycloaddition was performed with 10-(prop-2-
–
p-CH3-C6H4 73
yn-1-yl)acridone derivatives (1 equiv) (3) and aromatic,

Struct Chem
Fig. 1 The NMR 2D HMBC of compound 4a
aliphatic azides (1.5 equiv) in the presence of copper sulfate
(4a-h) were obtained with good yields (Scheme 1). In the goal
to obtain these 1,2,3-triazoles with excellent yields and shorter
reaction times under mild reaction conditions, we focused our
attention to microwave-assisted synthesis. The model reaction
was examined in various solvents with controlled MW powers
(100–300 W). The best result was obtained in DMF as solvent
at 200 W. The desired products of 4a–h were obtained in
yields ranging from 85 to 98%. The reaction times under
(
0.1 equiv), and sodium ascorbate (0.2 equiv). The reaction
was conducted at room temperature in DMF for 12 h. Then the
mixture was poured into ice water; the precipitate was filtered
off and purified by flash chromatography using hexane/
diethyl ether (1:4); the novel 1,4-disubstituted 1,2,3-triazoles
Table 2 Antibacterial data for the synthesized compounds (4a-h)
compounds
S. aureus E.coli
K. pneumoniae P. putida
2
2
4
4
4
4
4
4
4
4
a
b
a
b
c
d
e
f
122.8
118.4
90.91
56.60
46.60
38.46
56.60
56.60
41.32
19.61
133.4
124.2
137.9
130.4
156.3
145.5
122.81
122.81
126.12
107.14
115.04
107.14
119.36
122.81
37.03
–
122.81 122.81
122.81 137.93
112.36 138.32
90.91
74.07
74.07
66.36
56.60
22.41
–
107.14
74.07
56.60
81.32
90.91
15.38
–
g
h
Chloramphenicol 11.65
DMF
–
Fig. 2 Redocking pose and RMSD value of 0.9 Å (blue = docked, gray =
original)

Struct Chem
Table 3 Docking score,
intramolecular hydrogen bonds
Compounds
Docking score
C=O—ALA7 (d in Å)
Hydrophobic interactions
(
C=O⋯Ala7), and hydrophobic
4
a
6.74
6.42
6.80
6.98
6.75
6.58
6.98
7.04
–
Ile 50, Ile 31, Ile 14, Leu 20, Leu 54, and Leu 28
Ile 31, Ile 14, and Leu 20
interactions of the synthesized
compounds
4b
–
4
4
4
4
4
4
c
d
e
f
C=O---ALA7 (2.49 Å)
C=O---ALA7 (2.50 Å)
–
Ile 50, Ile 31, Ile 14, and Leu 20
Ile 50, Ile 31, Ile 14, and Leu 20
Ile 50, Ile 31, Ile 5, and Phe 92
Ile 50, Ile 31, Ile 5, Leu 20, and Phe 92
Ile 50, Ile 14, and Leu 20
–
g
C=O---ALA7 (2.55 Å)
C=O---ALA7 (2.55 Å)
h
Ile 5 and Phe 29
1
3
microwave irradiation are more acceptable than those of con-
ventional methods (Table 1).
The structure of the 1,2,3-triazoles were demonstrated by
their spectral data. The IR spectra of compounds (4a-h)
supported by C and DEPT NMR spectra, which showed all
the expected carbon signals corresponding to acridone–
triazole derivatives, essentially the aromatic carbons resonat-
ing at δ 125.2–143.0 ppm corresponding to triazole ring and
C
showed characteristic absorption bands in the region of
1
signals of CH2 carbons resonated at δ 50.8–41-9 ppm.
C
746–1700 cm− (C=O) due to the presence of ester and car-
1
The regioselectivity of the cycloaddition reaction under
microwave irradiation was confirmed by using 1 H and 13C
long-range NMR experiments (HMBC). The selective forma-
tion of 1,4-disubstituted 1,2,3-triazoles was confirmed by the
3-bond HMBC correlations of the methylene protons H1a (δ
5.83 ppm) and H4a (δ 5.31 ppm) with the carbon of triazole
C (δ 125 ppm). Also, we observe that the signal of the H (δ
boxylic acid groups, and characteristic bands of 1,2,3-triazole
−1
ring was detected in the range 1500–1300 cm which corre-
sponds to N=N & C=C bonds. However, the desperation of
−
1
the vibration bonds of alkyne group in the region of 2110 cm
−1
and 3210 cm confirmed the formation of compounds.
1
The H NMR spectra of compounds 4a–h showed a singlet
at δ 8.10–8.72 ppm attributable to the proton H of the
3
a
Tz
8.10 ppm) correlate with the C3a (δ 125 ppm) (Fig. 1).
H
3’
triazole moiety and signals in the aromatic region δ 8.40–
H
7
.31 ppm relative to the aromatic protons. In addition, the
Antibacterial activity
compounds 4a-d showed signals at δH 5.83–5.13 ppm
corresponded to –CH2– groups attached to triazole ring, and
the compounds 4e-f present singlet peak that appeared at δH
The antibacterial activity of the compounds (4a-h) was tested
in vitro against one gram-positive bacteria Staphyloccocus
aureus and three gram-negative bacteria Pseudomonas putida,
2
.3 ppm corresponded to CH . These structures were further
3
Fig. 3 The binding conformations and ligand interactions of the compound 4h at the active site of S. aureus DHFR

Struct Chem
Fig. 4 The binding conformations and ligand interactions of the compound 4b at the active site of S. aureus DHFR
Klebsiella pneumonia, and Escherichia coli. Primary screen-
ing test of the antibacterial effect of the compounds elicited as
inhibition zones of the growth of the tested bacteria.
Therefore, the MIC was determined for synthesized
compounds.
compounds 4e-h show moderate activity against
Escherichia coli and Klebsiella pneumonia with the
MIC values between 56.6–74.0 μg/mL. The low anti-
bacterial activity was observed against Pseudomonas
putida with MIC value 107.1 μg/mL. The results indi-
cate that the substitution of the acridone ring at position
2 with methyl increase the antibacterial activity. In the
methyl-substituted series, the antibacterial activity of the
compound 4e showed higher activity against gram-
negative bacteria. Moreover, there is a development in
According to the antibacterial activity results
(
Table 2), all compounds (4a-h) were found to have
good antibacterial activity against Staphylococcus
aureus, the compound 4h was found to be the best
active derivatives with MIC = 19.6 μg/mL. The tested
Fig. 5 Structure-activity
relationship (SAR) of the
acridone-1,2,3-triazole skeleton

Struct Chem
antibacterial activity after the substitution of acridone
ring with triazole ring for all bacteria. The results of
the antibacterial activity revealed that the compounds
These docking results indicate that the compound 4h played
a significant role in binding with the active site of S. aureus
DHFR receptor, and this may explain its high antibacterial
activity. Furthermore, the study shows that all compounds
with high potency for antibacterial activity present a hydrogen
bond interaction with Ala7 and hydrophobic interactions into
S. aureus DHFR active site.
(
4a-h) have good antibacterial activity against gram-
positive bacteria compared with gram-negative bacteria.
Molecular docking studies
The results of the antibacterial activity and docking studies
revealed that the substitution of the acridone ring with methyl
group and the acridone-1,2,3-triazole skeleton by aromatic
moiety increases the antibacterial activity against S. aureus;
this could be explained by the hydrophobic interactions in
S. aureus DHFR active site (Fig. 5).
The antibacterial potency of the compounds (4a-h) was sub-
jected for docking study to understand the interaction of our
compounds and methicillin-resistant Staphylcoccus aureus
(
MRSA). The dihydrofolate reductase (DHFR) is an impor-
tant enzyme whose role is to regenerate folic acid into reduced
form of tetrahydrofolate [27]. The dihydrofolate reductase
(
DHFR) is an interesting target for antibacterial agents in sev-
eral studies [2, 28, 29]. Crystal structure of S. aureus DHFR
PDB ID: 2W9S) with trimethoprim as co-crystallized ligands
Conclusion
(
and NADPH with 1.80 Å resolution was retrieved from
Protein Data Bank. In order to evaluate and validate the bind-
ing prediction of docking protocol, the co-crystallized ligand
TOP was redocked into the active site of S. aureus DHFR
protein (2W9S). The evaluation of the precision of the
docking protocol was based on the RMSD parameter. The
RMSD was calculated on the basis of the difference between
redocking and original poses using the MOE software. The
results show the redocked ligand superimposed on the co-
crystallized one (Fig. 2) with a low RMSD value of 0.9 Å.
The analysis of the binding site revealed that the synthe-
sized ligands is stabilized by several favorable interactions
including polar, hydrogen bond, hydrophobic, and Van der
Waals interactions (Table 3); the binding site pocket contains
the following amino acids: Ala 7, Ile 31, Ile 14, Leu 20, Ile 50,
Ile 5, Phe 92, Ser 49, Leu 28, Tyr 98, Thr 111, Gly 93, Thr 46,
Gly 94, Gly 15, Trp 22, Val 6, His 30, and Asp 27.
The present work reports synthesis of novel heterocyclic com-
pounds combining the 1,2,3-triazole and acridone rings.
Efficient microwave-assisted synthesis of novel acridone
bearing 1,2,3-triazole compounds has been carried out effec-
tively with short time reaction and in good yields. The com-
pounds (4a-h) were investigated for their in vitro antibacterial
activity against Escherichia coli, Klebsiella pneumoniae,
Pseudomonas putida, and Staphyloccocus aureus, indicating
that the introduction of 1,2,3-triazole ring on the acridone ring
increases the antibacterial activity. The docking results
showed that compounds with high antibacterial potency
showed hydrogen bond and hydrophobic interactions with
S. aureus DHFR active site.
According to molecular docking analysis, 4h showed a
docking score value of 7.04, reflecting that 4h could bind with
the S. aureus DHFR receptor well. Table 3 indicates that the key
residues Ala 7, Ile 31, Ile 14, Leu 20, Ile 50, Ile 5, and Phe 92 are
involved in the recognition of compound 4h in the active site of
S. aureus DHFR. 2D interactions of compounds 4c, 4d, 4g, and
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