Synthesis, antibacterial evaluation and computational studies of new acridone-1,2,3-triazole hybrids

Article abstract of DOI:10.1016/j.molstruc.2021.130636

In continuation of our efforts to develop new drugs with antibacterial properties we have synthesized and evaluated new 1,2,3-triazole derivatives from acridone. The synthetic approach was started by the preparation of acridone skeleton through the Ullman condensation of 2-bromobenzoic acid and aniline derivatives. Subsequently, acridone nucleus was functionalized with propargyl bromide. Then, a click reaction of the latter compound and aromatic azides led to the formation of the title compounds in good yields. The synthesized compounds were screened for their in vitro antibacterial activity against one gram-positive bacteria S. aureus and three gram-negative bacteria P. putida, K. pneumoniae and E. coli. Among the synthesized compounds, 2-methyl-10-((1-(o-tolyl)-1H-1,2,3-triazol-4-yl)methyl)acridone (4e) had the most potent inhibitory activity against S. aureus with MIC = 10.1 μg/mL. Then, in silico docking studies were used in order to understand the binding interactions and mode of action of these compounds.

Full text of DOI:10.1016/j.molstruc.2021.130636

Journal of Molecular Structure 1241 (2021) 130636
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, antibacterial evaluation and computational studies of new
acridone-1,2,3-triazole hybrids
Mohammed Aarjane∗, Siham Slassi, Amina Amine
Laboratory of Chemistry/Biology Applied to the Environment, CMMBA, Faculty of Science, University Moulay Ismail, Zitoune, BP 11201 Meknes, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
In continuation of our efforts to develop new drugs with antibacterial properties we have synthesized
and evaluated new 1,2,3-triazole derivatives from acridone. The synthetic approach was started by the
preparation of acridone skeleton through the Ullman condensation of 2-bromobenzoic acid and aniline
derivatives. Subsequently, acridone nucleus was functionalized with propargyl bromide. Then, a click re-
action of the latter compound and aromatic azides led to the formation of the title compounds in good
yields. The synthesized compounds were screened for their in vitro antibacterial activity against one
gram-positive bacteria S. aureus and three gram-negative bacteria P. putida, K. pneumoniae and E. coli.
Among the synthesized compounds, 2-methyl-10-((1-(o-tolyl)-1H-1,2,3-triazol-4-yl)methyl)acridone (4e)
had the most potent inhibitory activity against S. aureus with MIC = 10.1 μg/mL. Then, in silico docking
studies were used in order to understand the binding interactions and mode of action of these com-
pounds.
Received 5 November 2020
Revised 23 March 2021
Accepted 5 April 2021
Available online 10 May 2021
Keywords:
1,2,3-triazole
Acridone
Antibacterial activity
Molecular docking
ADMET
© 2021 Elsevier B.V. All rights reserved.
Introduction
tance to a wide variety of antibacterial agents [26], there is a
big demand for novel and efficient antimicrobial agents. Herein,
The nitrogen-containing heterocyclic compounds continue to at-
tract considerable attention in different scientific fields because of
their practical usefulness, principally, due to a very wide spectrum
of their pharmacological activities [1–5]. Acridones occupy an in-
teresting position among these compounds and they represent sig-
nificant building blocks in synthetic bioactive compounds, which
display antimalarial [6], anticancer [7,8], antimicrobial [9,10], an-
tiviral [11,12] and antitumor activities [13]. On the other hand,
1,2,3-triazoles derivatives are attractive candidates in medicinal
chemistry as they constitute the building blocks of wide range
of many 1,2,3-triazole compounds possessing an important phar-
macological properties such as antitumoral [14,15], antibacterial
[16–19], antityrosinase [20], anti-inflammatory [21] and anticancer
[22–24]. In addition, many 1,2,3-triazole well-known drugs have
been developed, among them Tazobactam (antifungal), Cefatrizine
(antibacterial) and Rufinamide (anticonvulsants) can be mentioned
(Fig. 1).
in continuation of our studies on the development of new an-
tibacterial agents [27,28], and focusing on the versatile biologi-
cal activity of acridone-1,2,3-triazole system, we synthesized, and
evaluated new 1,2,3-triazole derivatives from acridone against four
pathogenic bacteria. In silico molecular docking and ADMET predi-
cation studies have been performed to rationalize the results of in
vitro studies on antibacterial activity.
Results and discussions
Synthesis
By the strategy briefly depicted in Scheme 1, we have syn-
thesized 1,2,3-triazole derivatives from acridone via cycloaddition
reaction between aromatic azides and N-propargyl acridones. Ini-
tially, acridone (2) was prepared by condensation reaction between
2-bromobenzoic acid with aniline or p-toluidine in the presence
of copper and potassium carbonate in isoamyl alcohol at reflux
to produce 2-arylamino benzoic acids [29,30]. Then compound (1)
was cyclized with sulfuric acid at 80 °C for three hours to give
compounds (2). The N- propargyl acridone was obtained in high
yield by N-alkylation of acridone moiety (2) with the propargyl
bromide in the presence of catalytic amounts of TBAB in DMF at
70 °C. The last step was 1,3-dipolar cycloaddition reaction between
Microbial infections are a growing problem worldwide, pro-
ducing mortality mainly in developing countries [25]. Consider-
ing the many adverse effects and development of bacteria resis-
∗
Corresponding author.
E-mail address: m.aarjane@edu.umi.ac.ma (M. Aarjane).
https://doi.org/10.1016/j.molstruc.2021.130636
0022-2860/© 2021 Elsevier B.V. All rights reserved.

M. Aarjane, S. Slassi and A. Amine
Journal of Molecular Structure 1241 (2021) 130636
Fig. 1. Previously reported antimicrobial compounds.
Scheme 1. Synthesis route of new 1,2,3-triazole derivatives from acridone (4a-h).
aromatic azides and N-propargyl acridones (3) in the presence of
copper sulfate and sodium ascorbate in DMF, the 1,2,3-triazoles (4)
was obtained with good yield.
bons at 125 ppm and 143 ppm corresponding to 1,2,3-triazole
nucleus.
The structures of the synthesized compounds (4a-h) were fully
characterized by IR, 1H & 13C NMR and HRMS analysis. The FTIR
spectra of compounds (4a–h) showed characteristic bands of 1,2,3-
triazole nucleus in the range of 1500–1300 cm−1 corresponding
Antibacterial activity
The antibacterial activity of the synthesized compounds (4a-h)
were investigated against one gram-positive bacteria Staphylocco-
cus aureus and three gram-negative bacteria Pseudomonas putida,
Klebsiella pneumonia,Escherichia coli. The antibacterial activity has
been primarily tested as the observed growth inhibition zones by
disk-diffusion method using Mueller Hinton Broth (MBH) medium.
Then, Minimum inhibitory concentrations (MIC) were determined
for the synthesized compounds. Chloramphenicol and DMSO were
used as positive and negative controls for antibacterial activity, re-
spectively.
=
=
to C C & N N bonds. The characteristic bands of acridone ring
was detected in the range 1640–1635 cm−1 corresponding to C
O
=
bond. The 1H NMR spectra of compounds (4a-h) showed charac-
teristic signals of the protons corresponding to 1,2,3-triazole nu-
cleus between 8.95 ppm and 8.59 ppm, in addition to aromatic
protons in the region of 8.95–7.25 ppm. We also noticed the pres-
ence of signal at 5.89 ppm corresponded to methylene groups at-
tached to acridone and 1,2,3-triazole groups. In 13C NMR spectra
all expected carbon signals corresponding to acridone-1,2,3-triazole
derivatives were observed, principally the signals of methylene car-
bons between 50 ppm and 41 ppm and signals of aromatic car-
The observed minimum inhibitory concentration (MIC) antibac-
terial data of the synthesized compounds 4a-h and the refer-
ence drugs are given in Table 1. The antibacterial activity re-
2

M. Aarjane, S. Slassi and A. Amine
Journal of Molecular Structure 1241 (2021) 130636
Table 1
MIC values (μg/mL) of the synthesized compounds (4a-h) against S. aureus, E. coli, K. pneumonia and P. putida.
Staphylococcus aureus
Escherichia coli
Klebsiella pneumoniae
Pseudomonas putida
2a
122.83
118.43
97.10
83.20
12,31
31,32
19,61
38,46
10,11
31,52
19,61
38,46
11,65
–
133.41
124.22
80.66
70.14
36,61
66,36
56,60
56,64
36,61
60,15
56,60
56,64
22,41
–
137.93
130.43
97.25
102.20
70,45
81,32
90,91
74,07
70,45
80,00
85,90
74,07
15,38
–
156.31
145.52
100.95
115.20
60,13
119,36
122,81
77,16
60,13
119,36
120,81
77,16
37,03
–
2b
3a
3c
4a
4b
4c
4d
4e
4f
4 g
4h
Chloramphenicol
DMSO
sults revealed that the tested compounds exhibited various de-
grees of inhibition against Gram-positive and Gram-negative bac-
teria. Staphyloccocus aureus was observed to be the most sensi-
tive bacteria, Compounds 4e and 4a with o-methylphenyl group on
the acridone-1,2,3-triazole skeleton showed the best antibacterial
activity against Staphyloccocus aureus with MIC values 10.11 and
12.31 μg/mL, respectively, compared to the standard drug Chlo-
ramphenicol (11.65 μg/mL). Beside this, compound 4c and 4 g
with m-methylphenyl group on the 1,2,3 triazole-acridone skele-
ton showed moderate antibacterial activity against Staphylocco-
cus aureus with MIC value 19.61 μg/mL. Also, the compound 4e
and 4a showed moderate antibacterial potential against E. coli
(36.61 μg/mL), compared to the standard drug Chlorampheni-
col (22.41 μg/mL). Moreover, all 1,2,3-triazole derivatives (4a-h)
demonstrated a poor antibacterial activity against the germs Pseu-
domonas putida and Klebsiella pneumonia.
ligand Trimethoprim (TOP) was docked into the active site of Di-
hydrofolate Reductase of S. aureus to determine RMS (Root Mean
˚
˚
Square) distance that was satisfactory (RMSD=1.12 A less than 2 A),
Figure S1 shows that the docked structure (green color) and the
X-ray crystal structure (yellow color) are quite similar. Also, the
synthesized acridones were docked into the binding pocket of Di-
hydrofolate Reductase enzyme successfully. The molecular docking
representation for each synthetic compound and the superposition
of all best docking pose in the enzyme binding pocket are shown
in Figures S2-S10 (supplementary data).
The docking results showed that the synthesized compounds
(4a-h) fit snugly making various close contacts with the residues
lining the active site of Dihydrofolate Reductase enzyme, the in-
teracting amino acids of all compounds with Dihydrofolate Reduc-
tase enzyme are shown at Table 2. The docking pose of the most
active compound (4e) showed high docking score against Dihy-
drofolate Reductase enzyme, as the free energy of binding was
(−7.97 Kcal/mol) (Table 2), the analysis of best scoring pose of
compound (4e) in the Dihydrofolate Reductase pocket of 2W9S re-
vealed important hydrophobic as well as hydrogen bonding inter-
actions between them (Fig. 2). The phenyl group exhibit hydropho-
bic interactions with the residues Ile50, Leu20, Leu28, Leu54 and
Ile31. Moreover phenyl group of acridone nucleus present hy-
drophobic interactions with Ile5, Phe92, Ile14, and Ile31, while car-
bonyl of the acridone ring exhibit hydrogen bonding interaction
with Ala7. Also the active compounds 4a, 4c and 4 g showed one
favorable hydrogen bond between the carbonyl of acridone nucles
and the hydrogen of the side chain of Ala7, and hydrophobic inter-
actions with the residues Ile5, Ile31, Ile50, Leu20 and Ile14. From
the different interactions of the compounds (4a-h) in Table 2, it
can be concluded from the docking results that the most active
compounds 4e, 4a, 4c and 4 g had H-bond interaction with the
hydrogen of the side chain of Ala7 in the active site of Dihydrofo-
late Reductase enzyme.
Structure-activity relationship studies revealed that the pres-
ence of 1,2,3-tiazole ring increased the antibacterial activity against
all bacteria. The results of the antibacterial activity showed that
Staphyloccocus aureus is the most sensitive bacteria to the synthe-
sized compounds (4a–h). Regarding, the effect of the substituent
on the phenyl moiety of the acridone-1,2,3-triazole skeleton, the
results revealed that the best MIC against Staphyloccocus aureus
has been attained by the o-methylphenyl (4e, 4a). However, the
presence of carboxylic acid group on the phenyl moiety of the
acridone-1,2,3-triazole skeleton decreased the antibacterial activity
against Staphyloccocus aureus.
Molecular docking
The molecular-docking study was used to determine the bind-
ing modes of the synthesized compounds against Dihydrofolate Re-
ductase from S. aureus (DHFR). Dihydrofolate reductase is a crit-
ical enzyme that catalyzes the chemical reaction for the reduc-
tion of tetrahydrofolate (THF) from dihydrofolate (DHF) through
NADPH [31]. DHFR is essential in the biosynthesis pathways of the
thymidylate and purines, as well as several other amino acids. Inhi-
bition of DHFR leads to the depletion of tetrahydrofolate and even-
tual cell death [32]. We chose this target because the Dihydrofolate
reductase (DHFR) is the target of many antibiotics and other natu-
ral compounds. Several classes of compounds have been explored
for their potential antifolate activity; among the most outstand-
ing are 1,2,3-triazoles [33,34], diaminotriazines [35], diaminopy-
rimidine [36] and diaminoquinazolines [37].
Furthermore, the synthesized compounds (4a-h) bind to active
site of Dihydrofolate Reductase and share largely homogeneous in
binding mode specially with Ala7, Ile50, Leu20, Leu28, Leu54, Ile31,
Phe92 and Ile14 to several Dihydrofolate Reductase inhibitors re-
ported in the literature [39,40]. Therefore, docking studies revealed
the strong binding affinity of 4e at the active site of Dihydrofolate
Reductase enzyme, which may be responsible for its significant in
vitro antibacterial activity especially against S. aureus.
In silico ADMET prediction
In this study, molecular docking of the most active compounds
have been applied to study the different type of interactions and
elucidate the probable binding modes between acridone deriva-
tives and Dihydrofolate Reductase of S. aureus [38]. In order to val-
idate the applied molecular docking approach, the co-crystallized
In silico metabolic, toxicity and pharmacokinetic parameters of
synthesized compounds (4a-h) were predicted using pkCSM on-
line tool [41] and DruLito software [42]. Hence, Blood-brain bar-
rier penetration (BBB), human intestinal absorption, total clearance,
3

M. Aarjane, S. Slassi and A. Amine
Journal of Molecular Structure 1241 (2021) 130636
Table 2
The interactions and binding affinities of the synthesized compounds.
Compound
Interaction with nucleic acid
Hydrogen bonding
Binding affinity
4a
4b
4c
4d
4e
4f
Ala7, Val6, Ile5, Ile31, Phe92, Ile50, Leu20, Ile14
Ile50, Leu20, Ile14, Lys45, Asn18, Aser49
Ala7
–
−7.62
−7.40
−7.51
−7.74
−7.97
−7.29
−7.66
−7.32
Ala7, Leu28, Ile5, Phe92, Ile50, Leu20, Ile14, Leu54, Val6, Ile31
Tyr98, Gln19, Thr46, Ile50, Leu20, Ala7, Val6, Ile5, Phe92, Ile31, Ile14
Ala7, Val6, Ile5, Phe92, Ile50, Leu20, Ile14, Leu28, Leu54, Ile31
Ile5, Phe92, Ile50, Leu20, Ile31
Ala7-
–
Ala7
–
4 g
4h
Ala7, Val6, Ile5, Phe92, Leu28, Ile31, Ile14, Ile50, Leu20, Leu54
Ser49, Ile50, Leu20, Ile5, Ile31, Phe92, Leu28
Ala7
Ser49
Fig. 2. Binding mode of compound 4e with Dihydrofolate Reductase (DHFR) complex, the hydrogen bonds are presented in green dashed lines.
acute oral toxicity, AMES toxicity, HEGR inhibitor, skin sensitization
and some drug-likeness properties were calculated.
Conclusion
In summary new 1,2,3-triazole derivatives from acridone were
The results of in silico AMDET predication are reported in Ta-
ble S1, showed acceptable range of Blood-brain barrier penetration
(BBB) for an ideal drug candidate, corresponding to its entry to the
central nervous system, is less than 0.3, which indicates that com-
pounds (4a-h) present small chance to cross the blood-brain bar-
rier. Also compounds (4a-h) present good human intestinal absorp-
tion (HIA) with a high percentage (>90%), which indicates that the
synthesized compounds would be easily absorbed from intestine
and circulated through blood. The toxicity profile of the synthe-
sized compounds (4a-h) counting the Hepatoxicity, human ether-
a-go-go related gene (hERG), Max. Tolerated dose (human), Min-
now toxicity and Skin sensitization indicate that the 1,2,3-triazoles
apparently do not have potential toxicity. Moreover, Metabolism
plays an important role in the bioavailability of drugs. Cytochrome
CYP450 enzymes are the most interesting class to study this effect.
Synthesized compounds (4a-h) were studied either to act as in-
hibitors or substrate of Cytochrome CYP450 enzymes. Most of the
compounds were found to be the inhibitors of CYP2C9, CYP2C19
and CYP1A2 and substrate of CYP3A4.
prepared, characterized and biologically evaluated. The synthesized
compounds (4a-h) were screened for their in vitro antibacterial ac-
tivity against four bacteria pathogenic strains, compound 4e was
found to be the most potent against S. aureus compared with
the standard drug Chloramphenicol. Molecular docking studies re-
vealed that, occupation of compounds (4a-h) at the active site of
Dihydrofolate Reductase via hydrogen bonding and hydrophobic in-
teractions may be the reason for its significant in vitro antibacterial
activity against S. aureus. Finally, in silico ADMET predictions sug-
gested that synthesized compounds have good drug-likeness and
ADMET profiles.
Experimental
Materials
All materials were purchased from commercial suppliers. Spec-
trometer.IR spectra were recorded using JASCO FT-IR 4100 spec-
trophotometer. The 1H, 13C NMR spectra was recorded with Bruker
Avance 300. Mass spectrometric measurements were recorded us-
ing ExactiveTM Plus Orbitrap.
The DruliTo software was used to calculate the molecular prop-
erties such as topological polar surface area (TPSA), hydrogen
bond donors and acceptors, partition coefficient (Log P), molecular
weight and rotatable bonds (Table 3). Hence, Lipinski’s rule of five
were calculated to evaluate the drug likeness of the synthesized
compounds. Thus all the synthesized compounds (4a-h) have the
potential to be developed as an orally active drug like candidates
and may be potentially active antibiotic drug candidates against S.
aureus.
Synthesis
2-(Phenylamino)benzoic acid (1)
A
mixture of aniline (0.35 g, 3.6 mmol), o-bromobenzoic
acid (0.5 g, 2.5 mmol), anhydrous potassium carbonate (0.42 g,
4

M. Aarjane, S. Slassi and A. Amine
Journal of Molecular Structure 1241 (2021) 130636
Table 3
Lipinski’s properties of the newly synthesized compounds.
Property
Lipinski
Compound
violation
H-bond
H-bond
donor
Polar surface
area (A2)
Rotatable
Bonds
Molecular
LogP
acceptor
weight
4a
4b
4c
4d
4e
4f
2.62
1.76
2.83
1.97
3.01
2.16
3.23
2.37
5
7
5
7
5
7
5
7
0
1
0
1
0
1
0
1
48.27
85.57
48.27
85.57
48.27
85.57
48.27
85.57
3
4
3
4
3
4
3
4
366.15
396.12
366.15
396.12
380.16
410.14
380.16
410.14
0
0
0
0
0
0
0
0
4 g
4h
3.1 mmol), 0.05 g of metallic copper powder and 0.02 g of cop-
per oxide was refluxed for 4 h in 10 mL of amyl alcohol. The amyl
alcohol was evaporated then poured into (50 mL) hot water, cooled
to room temperature. The medium pH was then adjusted to 4 by
adding HCl (0.5 M). Compound 1 was obtained as a white precipi-
tate which was then recrystallized from ethanol.
10-((1-(o-Tolyl)−1H-1,2,3-triazol-4-yl)methyl)acridin-9(10H)-one (4a)
Yellow solid; yield: 90%, mp = 224–226 °C. IR (KBr): 3112, 3063,
1638, 1600, 1502 cm−1 1H NMR (300 MHz, DMSO–d6, 25 °C, TMS)
.
δ 8.62 (s, 1H, CH-triazole), 8.40 (dd, J = 8.0, 1.7 Hz, 2H, Ar–H), 8.05
(d, J = 8.8 Hz, 2H, Ar–H), 7.86 (ddd, J = 8.7, 6.9, 1.8 Hz, 2H, Ar–H),
7.57 – 7.34 (m, 6H, Ar–H), 5.91 (s, 2H, CH2), 2.11 (s, 3H, CH3). 13C
=
White yellow solid; yield: 70%, mp = 183 °C. IR (KBr): 3330,
NMR (75 MHz, DMSO–d6, 25 °C, TMS) δ 176.6 (C O), 142.5, 141.9
3040, 2984, 1661, 1513, 1415 cm−1
.
1H NMR (300 MHz, DMSO–d6,
(2C), 136.0, 134.1 (2C), 132.9, 131.2, 129.7, 126.9, 126.5 (2C), 125.9,
125.1 (2C), 121.7, 121.4 (2C), 116.3 (2C), 41.5 (CH2), 17.3 (CH3). MS
(ESI) for C23H18 N4O [M + H]+, calcd: 367.1511, found: 367.1511.
25 °C, TMS): 13.06 (s, 1H, OH), 9.68 (s, 1H, NH), 7.93 (m, 1H, Ar-H),
7.39–7.36 (m, 3H, Ar-H), 7.26–7.25 (m, 1H, Ar-H), 7.26 (m, 3H, Ar-
H), 7.08(m, 2H, Ar-H). 13C NMR (75 MHz, DMSO–d6, 25 °C, TMS):
169.0 (C = O), 147.0, 140.8, 134.6, 130.5, 129.3, 123.2, 121.9 (2C),
116.3 (2C), 113.1, 112.2.
4-(4-((9-Oxoacridin-10(9H)-yl)methyl)−1H-1,2,3-triazol-1-yl)benzoic
acid (4b)
Yellow solid; yield: 79%, mp >300 °C. IR (KBr): 3397, 3112,
3063, 1702, 1638, 1600, 1502 cm−1 1H NMR (300 MHz, DMSO–
.
Acridone (2)
The N-phenylantranilic acid (1 g, 4.8 mmol) was taken in
3.5 mL of concentrated sulfuric acid and heated on water bath
for 3 h. Reaction mixture was added to hot water and the result-
ing precipitates were filtered to get acridone (2). The sample of
acridone was recrystallized from acetic acid.
d6, 25 °C, TMS) δ 8.95 (s, 1H, CH-triazole), 8.41 (dd, J = 8.0,
1.7 Hz, 2H, Ar–H), 8.08–7.95 (m, 6H, Ar–H), 7.87–7.81 (m, 2H, Ar–
H), 7.41–7.36 (m, 2H, Ar–H), 5.92 (s, 2H, CH2). 13C NMR (75 MHz,
=
=
DMSO–d6, 25 °C, TMS) δ 176.7 (C O), 164.5 (C O), 144.1, 141.8
(2C), 139.2, 137.2, 134.2 (2C), 132.2, 131.0, 128.0, 126.6 (2C), 121.8,
121.6 (2C), 121.5, 119.8, 117.1, 116.2 (2C), 41.8 (CH2). HRMS (ESI) for
C23H16 N4O3 [M + H]+, calcd: 397.1255, found: 397.1255.
Yellow solide, yield 78%, m.p. > 330 C. IR (KBr) 3275, 3084,
.
1640, 1570 cm−1 1H NMR (300 MHz, DMSO–d6, 25 °C, TMS): 11.74
(s, 1H, NH), 8.23 (dd, J = 8.1, 1.2 Hz, 2H, Ar-H), 7.70 (td, J = 8.4,
1.5 Hz, 2H, Ar-H), 7.53 (d, J = 8.1 Hz, 2H, Ar-H), 7.23 (td, J = 8.4,
1.5 Hz, 2H, Ar-H). 13C NMR (75 MHz, DMSO–d6, 25 °C, TMS): 177.2
(C = O), 141.3, 133.9, 126.4, 121.4, 120.9, 117.8.
10-((1-(m-Tolyl)−1H-1,2,3-triazol-4-yl)methyl)acridin-9(10H)-one (4c)
Yellow solid; yield: 85%, mp >300 °C. IR (KBr): 3120, 3063,
1637, 1606, 1597, 1507 cm−1 1H NMR (300 MHz, DMSO–d6, 25 °C,
.
TMS) δ 8.73 (s, 1H, CH-triazole), 8.40 (dd, J = 8.0, 1.7 Hz, 2H,
Ar–H), 7,99 (d, J = 8,1 Hz, 2H, Ar–H), 7.83 (t, 2H, Ar–H), 7.70 (d,
J = 7.2 Hz, 2H, Ar–H), 7.36 (d, J = 7.2 Hz, 4H, Ar–H), 5.86 (s, 2H,
CH2), 2.36 (s, 3H, CH3). 13C NMR (75 MHz, DMSO–d6, 25 °C, TMS) δ
10-(Prop-2-yn-1-yl)acridone. (3)
To a mixture of acridone (5 g, 25 mmol), potassium carbonate
(5.5 g, 30 mmol) and TBAB (5 g, 25 mmol) in DMF (50 ml), propar-
gyl bromide (4 g, 36 mmol) was added and the mixture was stirred
at room temperature for 6 h. After that, it was poured into water
and the white yellow formed precipitate was recrystallized from
methanol-DMF.
=
177.1 (C O), 144.1, 142.5 (2C), 138.8, 134.6 (2C), 132.7, 131.1, 129.5
(2C), 126.2 (2C), 125.3 (2C), 122.4, 121.9 (2C), 120.5, 116.6 (2C),
42.3 (CH2), 20.9 (CH3). MS (ESI) for C23H16 N4O3 [M + H]+, calcd:
367.1401, found: 367.1404.
White yellow solid; yield: 75%, mp = 206 °C. IR (KBr): 3208,
3010, 2210, 1638, 1598 cm−1. 1H NMR (300 MHz, DMSO–d6, 25 °C,
TMS): δ= 8.34 (d, J = 7.8 Hz,1H, Ar–H), 8.12 (s,1H, Ar–H), 7.87- 7.86
(m, 4H, Ar–H), 7.37–7.38 (m, 2H, Ar–H), 5.32 (s, 2H, CH2), 2.41 (s,
1H, CH), 2,38 (s, 3H, CH3). 13C NMR (75 MHz, DMSO–d6, 25 °C,
TMS) δ 177.1 (C = O), 141.7, 134.7, 134.4, 127.7, 127.0, 123.3 (2C),
122.2, 118.4, 116.3 (2C), 79.1, 76. 1 (CH), 36.1 (CH2).
2-(4-((9-Oxoacridin-10(9H)-yl)methyl)−1H-1,2,3-triazol-1-yl)benzoic
acid (4d)
Yellow solid; yield: 75%, mp >300 °C. IR (KBr): 3405, 3109,
.
3053, 1700, 1639, 1602, 1500 cm−1 1H NMR (300 MHz, DMSO–
d6, 25 °C, TMS) δ 8.93 (s, 1H, CH-triazole), 8.37 (dd, J = 8.0, 1.7 Hz,
2H, Ar–H), 8.04–7.98 (m, 3H, Ar–H), 7.69–7.62 (M, 5H, Ar–H), 7.34–
7.26 (m, 2H, Ar–H), 5.84 (s, 2H, CH2). 13C NMR (75 MHz, DMSO–d6,
25 °C, TMS) δ 177.0 (C = O), 163.9 (C = O), 144.0, 141.9 (C2), 139.3,
137.5, 134.1 (C2), 131.2, 128.1 (C2), 126.5 (C2), 121.8, 121.6, 121.4
(C2), 119.7, 117.3, 116.1 (C2), 41.7(CH2). MS (ESI) for C23H16 N4O3
[M + H]+, calcd: 397.1507, found: 397.1507.
General procedure for the synthesis of acridone-1,2,3-triazole
derivatives (4a-h)
To a solution of 10-(prop-2-yn-1-yl)acridone (0.48 g, 2 mmol)
in DMF (5 mL), aromatic azide (3 mmol), copper sulfate (0.08 g,
0.4 mmol) and sodium ascorbate (0.11 g, 0.6 mmol) were added
and the reaction mixture was stirred at room temperature for 8 h.
After completion of the reaction, water (50 ml) was added, and the
precipitate was filtered off, washed with cold water, and purified
by recrystallization in DMF
2-Methyl-10-((1-(o-tolyl)−1H-1,2,3-triazol-4-yl)methyl)acridin-
9(10H)-one
(4e)
Yellow solid; yield: 89%, mp >300 °C. IR (KBr): 3110, 3065, 1637,
.
1610, 1601, 1502 cm−1 1H NMR (300 MHz, DMSO–d6, 25 °C, TMS)
5

M. Aarjane, S. Slassi and A. Amine
Journal of Molecular Structure 1241 (2021) 130636
δ 8.59 (s, 1H, CH-triazole), 8.38 (d, J = 7.9 Hz, 1H, Ar–H), 8.25 –
8.12 (m, 1H, Ar–H), 8.01 (dd, J = 19.3, 8.7 Hz, 2H, Ar–H), 7.83 (t,
J = 7.9 Hz, 1H, Ar–H), 7.68 (d, J = 8.7 Hz, 1H, Ar–H), 7.58 – 7.25
(m, 5H, Ar–H), 5.89 (s, 2H, CH2), 2.46 (s, 3H, CH3), 2.10 (s, 3H,
CH3). 13C NMR (75 MHz, DMSO–d6, 25 °C, TMS) δ 176.5 (C = O),
144.2, 141.7, 140.0, 136.0, 135.4, 133.9, 132.9, 131.2, 130.6, 129.7,
126.8, 126.6 (C2), 125.9, 125.8, 125.1, 121.6, 121.2, 116.4, 116.2, 41.4
(CH2), 20.1 (CH3), 17.3 (CH3). MS (ESI) for C24H20N4O [M + H]+,
calcd: 381.1669, found: 381.1669.
(0.04 mg/mL) were added to each microplate. The Color changes of
TTC from colorless to red were accepted as microbial growth [44].
Molecular docking studies
Molecular docking of the synthesized compounds (4a-h) with
the Dihydrofolate Reductase complex (PDB ID: 2W9S) of S. aureus
[38] was carried out using the AutoDock software [45]. For prepa-
ration of protein and ligands see supporting information. The Dis-
covery Studio (version 4.5) was used for graphical visualization.
Different types of interactions between protein and the docked
compounds (4a-h) were analyzed using Discovery Studio.
2-Methyl-4-(4-((9-oxoacridin-10(9H)-yl)methyl)−1H-1,2,3-triazol-1-
yl)benzoic acid
(4f)
Yellow solid; yield: 82%, mp >300 °C. IR (KBr): 3398, 3110,
.
3063,1700, 1638, 1609, 1502 cm−1 1H NMR (300 MHz, DMSO–
ADMET and drug-likeness profiles
d6, 25 °C, TMS) δ 8.93 (s, 1H, CH-triazole), 8.40 (s, 1H, Ar–H),
8.14 (s, 1H, Ar–H), 8.04–7.95 (m, 5H, Ar–H), 7.87–7.82 (m, 2H, Ar–
H), 7.37 (t, J = 7.4 Hz, 2H, Ar–H), 5.90 (s, 2H, CH2), 2.29 (s, 3H,
CH3). 13C NMR (75 MHz, DMSO–d6, 25 °C, TMS) δ 176.5 (C = O),
164.9 (C = O), 144.2, 141.7, 139.9, 139.2, 136.4, 135.5, 134.0 (C2),
130.7, 129.3, 126.6 (C2), 125.9, 125.8, 121.6 (C2), 121.2, 116.2, 116.0,
41.6 (CH2), 20.1 (CH3). MS (ESI) for C24H18 N4O3 [M + H]+, calcd:
411.1403, found: 411.1408.
The physicochemical and pharmacokinetic properties of the
1,2,3-triazole derivatives from acridone were predicted using the
pkCSM [41]and DurLiTo [42] online tools.
Declaration of Competing Interest
There are no conflicts to declare.
CRediT authorship contribution statement
2-Methyl-10-((1-(m-tolyl)−1H-1,2,3-triazol-4-yl)methyl)acridin-
9(10H)-one
Mohammed Aarjane: Conceptualization, Methodology, Writing
- original draft. Siham Slassi: Data curation, Software, Investiga-
tion. Amina Amine: Supervision.
(4 g)
Yellow solid; yield: 81%, mp >300 °C. IR (KBr): 3112, 3063,
.
1638, 1600, 1502 cm−1 1H NMR (300 MHz, DMSO–d6, 25 °C, TMS)
δ 8,70(s, 1H, triazole), 8.33 (d, J = 7.2 Hz, 1H, Ar–H), 8.14 (s, 1H,
Ar–H), 7,94–7.53 (m, 6H, Ar–H’), 7.33 (d, J = 7.2 Hz, 3H, Ar–H), 5.78
(s, 2H, CH2), 2,42 (s, 3H, CH3), 2.32 (s, 3H, CH3). 13C NMR (75 MHz,
DMSO–d6, 25 °C, TMS) δ 177.0 (C = O), 144.2, 142.2, 140.4 (C2),
138.8, 135.9, 134.5 (C2), 131.1, 130.6, 127.1, 126.3 (C2), 122.1, 121.8,
121.7, 120.3, 116.8, 116.6 (C2), 42.6 (CH2), 21.0 (CH3), 20.6 (CH3).
MS (ESI) for C24H20N4O [M + H]+, calcd: 381.1669, found: 381.1660.
References
[1] P.V. Babu, S. Mukherjee, D.R. Gorja, S. Yellanki, R. Medisetti, P. Kulkarni,
K. Mukkanti, M. Pal, Zebrafish based strategy for the identification of a po-
tential pharmacophore for apoptosis:
a greener CuAAC approach for novel
1,2,3-triazoles derived from mefenamic acid, RSC Adv. 4 (2014) 4878–4882,
doi:10.1039/c3ra46185h.
[2] S.B. Nallapati, B.Y. Sreenivas, R. Bankala, K.V.L. Parsa, S. Sripelly, K. Mukkanti,
M. Pal, 1,2,3-Triazoles derived from olanzapine: their synthesis via an ultra-
sound assisted CuAAC method and evaluation as inhibitors of PDE4B, RSC Adv.
5 (2015) 94623–94628, doi:10.1039/c5ra20380e.
2-(4-((2-Methyl-9-oxoacridin-10(9H)-yl)methyl)−1H-1,2,3-triazol-1-
yl)benzoic acid
[3] R. Sribalan, G. Banuppriya, M. Kirubavathi, V. Padmini, Synthesis, biological
evaluation and in silico studies of tetrazole-heterocycle hybrids, J. Mol. Struct.
1175 (2019) 577–586, doi:10.1016/j.molstruc.2018.07.114.
(4 h)
Yellow solid; yield: 78%, mp >300 °C. IR (KBr): 3400, 3121,
.
3052, 1704, 1640, 1605, 1501 cm−1 1H NMR (300 MHz, DMSO–d6,
[4] S. Suryapeta, N. Papigani, V. Banothu, P.K. Dubey, K. Mukkanti, S. Pal, Synthe-
sis, biological evaluation, and docking study of a series of 1,4-disubstituted
1,2,3-triazole derivatives with an indole-triazole-peptide conjugate, J. Hetero-
cycl. Chem. 57 (2020) 3126–3141, doi:10.1002/jhet.4020.
25 °C, TMS) δ 8.92 (s, 1H, CH-triazole), 8.39 (d, J = 7.9 Hz, 1H, Ar–
H), 8.15 (s, 1H, Ar–H), 7.96–7.87 (m, 2H, Ar–H), 7.69–7.61 (m, 5H,
Ar–H), 7.31–7.26 (m, 2H, Ar–H), 5.81 (s, 2H, CH2), 2.44 (s, 3H, CH3).
13C NMR (75 MHz, DMSO–d6, 25 °C, TMS) δ 176.0 (C = O), 166.9
(C = O), 142.4, 141.7 (C2), 140.5, 138.3, 136.6, 134.8 (C2), 133.0,
129.8, 126.7 (C2), 125.8, 121.7 (C2), 121.1, 120.8, 116.3 (C2), 115.0,
41.9 (CH2), 20.3 (CH3). MS (ESI) for C24H18 N4O3 [M + H]+, calcd:
411.0883, found: 411.0884.
[5] M. Aarjane, S. Slassi, B. Tazi, A. Amine, Synthesis and biological evaluation of
novel isoxazole derivatives from acridone, Arch. Pharm. (Weinheim). (2020),
doi:10.1002/ardp.202000261.
[6] R. Kumar, S. Sharma, D. Prasad, Acridones, in: Key Heterocycle Cores Des. Mul-
titargeting Mol., Elsevier, 2018, pp. 53–132, doi:10.1016/b978-0-08-102083-8.
00003-0.
[7] M. Kaur, P. Singh, Targeting tyrosine kinase: development of acridone – pyrrole
– oxindole hybrids against human breast cancer, Bioorganic Med. Chem. Lett.
29 (2019) 32–35, doi:10.1016/j.bmcl.2018.11.021.
[8] A. Boumendjel, S. Macalou, A. Ahmed-Belkacem, M. Blanc, A. Di Pietro,
Acridone derivatives: design, synthesis, and inhibition of breast cancer resis-
tance protein ABCG2, Bioorganic Med. Chem. 15 (2007) 2892–2897, doi:10.
1016/j.bmc.2007.02.017.
[9] K.M. Ahua, J.R. Ioset, A. Ransijn, J. Mauël, S. Mavi, K. Hostettmann, Antileish-
manial and antifungal acridone derivatives from the roots of Thamnosma
rhodesica, Phytochemistry 65 (2004) 963–968, doi:10.1016/j.phytochem.2003.
12.020.
Antibacterial activity
The 1,2,3-triazoles (4a-h) were evaluated for their in vitro an-
tibacterial activity by the disk diffusion method, the active com-
pounds were subjected to the determination of the MIC, using the
broth Microdilution method. The microorganisms utilized for the
test were E. coli, Staphylococcus aureus, Pseudomonas putida and
Klebsiella pneumonia. They were collected from clinical isolates.
Bacterial inoculums were prepared by subculturing microorgan-
isms into MHB at 37 °C for 18 h and were diluted to approximately
106 CFU mL−1. Initial solution with concentration 0.5 mg/mL of
the compounds (4a-h) were prepared in DMF, further serial dilu-
tions were made in the microplates and 100 μl of MHB contain-
ing each test microorganism were added to the microplate [43],
then incubated at 36 °C for 24 h. After incubation, 20 μL of TTC
[10] M. Aarjane, A. Aouidate, S. Slassi, A. Amine, Synthesis, antibacterial evalua-
tion, in silico ADMET and molecular docking studies of new N-acylhydrazone
derivatives from acridone, Arab. J. Chem. 13 (2020) 6236–6245, doi:10.1016/j.
arabjc.2020.05.034.
[11] A. Stankiewicz-Drogon, L.G. Palchykovska, V.G. Kostina, I.V. Alexeeva,
A.D. Shved, A.M. Boguszewska-Chachulska, New acridone-4-carboxylic acid
derivatives as potential inhibitors of Hepatitis
C virus infection, Bioorganic
Med. Chem. 16 (2008) 8846–8852, doi:10.1016/j.bmc.2008.08.074.
[12] M. Fujiwara, M. Okamoto, M. Okamoto, M. Watanabe, H. Machida, S. Shigeta,
K. Konno, T. Yokota, M. Baba, Acridone derivatives are selective inhibitors of
HIV-1 replication in chronically infected cells, Antiviral Res 43 (1999) 189–199,
doi:10.1016/S0166-3542(99)00045-5.
6

M. Aarjane, S. Slassi and A. Amine
Journal of Molecular Structure 1241 (2021) 130636
[13] G. Cholewin´ ski, K. Dzierzbicka, A.M. Kołodziejczyk, Natural and synthetic
acridines/acridones as antitumor agents: their biological activities and
methods of synthesis, Pharmacol. Rep. 63 (2011) 305–336, doi:10.1016/
S1734-1140(11)70499-6.
[29] M. Aarjane, S. Slassi, A. Amine, Novel series of N-acylhydrazone based on
acridone: synthesis, conformational and theoretical studies, J. Mol. Struct. 1225
(2021) 129079, doi:10.1016/j.molstruc.2020.129079.
[30] M. Aarjane, S. Slassi, A. Ghaleb, A. Amine, Synthesis, spectroscopic characteri-
zation (FT-IR, NMR) and DFT computational studies of new isoxazoline derived
from acridone, J. Mol. Struct. (2021) 1231, doi:10.1016/j.molstruc.2021.129921.
[31] E. Christaki, Folate Inhibitors, in: Infect. Dis. (Auckl)., Elsevier, 2017, pp. 1280–
1284, doi:10.1016/b978-0-7020-6285-8.00150-7. .e1.
[14] O. Grytsai, O. Valiashko, M. Penco-Campillo, M. Dufies, A. Hagege, S. Martial,
G. Pagès, C. Ronco, R. Benhida, Synthesis and biological evaluation of 3-amino-
1,2,4-triazole derivatives as potential anticancer compounds, Bioorg. Chem. 104
(2020) 104271, doi:10.1016/j.bioorg.2020.104271.
[15] M.A. Almehmadi, A. Aljuhani, S.Y. Alraqa, I. Ali, N. Rezki, M.R. Aouad, M. Hagar,
Design, synthesis, DNA binding, modeling, anticancer studies and DFT calcula-
tions of Schiff bases tethering benzothiazole-1,2,3-triazole conjugates, J. Mol.
Struct. 1225 (2021) 129148, doi:10.1016/j.molstruc.2020.129148.
[16] N. Boechat, M. de L.G. Ferreira, L.C.S. Pinheiro, A.M.L. Jesus, M.M.M. Leite,
C.C.S. Júnior, A.C.C. Aguiar, I.M. Andrade, A.U. Krettli, New Compounds Hybrids
1 H -1,2,3-Triazole-Quinoline Against Plasmodium falciparum, Chem. Biol. Drug
Des. 84 (2014) 325–332, doi:10.1111/cbdd.12321.
[32] B.I. Schweitzer, A.P. Dicker, J.R. Bertino, Dihydrofolate reductase as a therapeu-
tic target, FASEB J 4 (1990) 2441–2452, doi:10.1096/fasebj.4.8.2185970.
[33] Y.I. El-Gazzar, H.H. Georgey, S.M. El-Messery, H.A. Ewida, G.S. Hassan,
M.M. Raafat, M.A. Ewida, H.I. El-Subbagh, Synthesis, biological evaluation
and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-
methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors, Bioorg.
Chem. 72 (2017) 282–292, doi:10.1016/j.bioorg.2017.04.019.
[34] G.S. Hassan, S.M. El-Messery, F.A.M. Al-Omary, S.T. Al-Rashood, M.I. Shabayek,
Y.S. Abulfadl, E.S.E. Habib, S.M. El-Hallouty, W. Fayad, K.M. Mohamed, B.S. El-
Menshawi, H.I. El-Subbagh, Nonclassical antifolates, part 4. 5-(2-Aminothiazol-
4-yl)-4-phenyl-4H-1,2, 4-triazole-3-thiols as a new class of DHFR inhibitors:
synthesis, biological evaluation and molecular modeling study, Eur. J. Med.
Chem. 66 (2013) 135–145, doi:10.1016/j.ejmech.2013.05.039.
[35] P. Huovinen, L. Sundstrom, G. Swedberg, O. Skold, Trimethoprim and sulfon-
amide resistance, Antimicrob. Agents Chemother. 39 (1995) 279–289, doi:10.
1128/aac.39.2.279.
[17] M. Aarjane, S. Slassi, B. Tazi, M. Maouloua, A. Amine, Novel series of
acridone-1,2,3-triazole derivatives: microwave-assisted synthesis, DFT study
and antibacterial activities, J. Chem. Sci. 131 (2019) 1–11, doi:10.1007/
s12039-019-1653-2.
[18] K. Sri, S. Praveena, N. Yadagiri, S. Murthy, S. Pal, Syntheses and biological ac-
tivities of 1,4-disubstituted-1,2,3-triazoles, Available Online Www.jocpr.com, J.
Chem. Pharm. Res. 7 (2015) 506–522 www.jocpr.com. (accessed February 1,
2021).
[19] N. Kuntala, J.R. Telu, V. Banothu, S.B. Nallapati, J.S. Anireddy, S. Pal, Novel
benzoxepine-1,2,3-triazole hybrids: synthesis and pharmacological evaluation
[36] H.C. Jackson, K. Biggadike, E. McKilligin, O.S. Kinsman, S.F. Queener, A. Lane,
J.E. Smith, 6,7-disubstituted 2,4-diaminopteridines: novel inhibitors of Pneu-
mocystis carinii and Toxoplasma gondii dihydrofolate reductase, Antimicrob.
Agents Chemother. 40 (1996) 1371–1375, doi:10.1128/aac.40.6.1371.
[37] X. Li, M. Hilgers, M. Cunningham, Z. Chen, M. Trzoss, J. Zhang, L. Kohnen,
T. Lam, C. Creighton, K. Gc, K. Nelson, B. Kwan, M. Stidham, V. Brown-Driver,
K.J. Shaw, J. Finn, Structure-based design of new DHFR-based antibacterial
agents: 7-aryl-2,4-diaminoquinazolines, Bioorganic Med. Chem. Lett. 21 (2011)
5171–5176, doi:10.1016/j.bmcl.2011.07.059.
[38] H. Heaslet, M. Harris, K. Fahnoe, R. Sarver, H. Putz, J. Chang, C. Subramanyam,
G. Barreiro, J.R. Miller, Structural comparison of chromosomal and exogenous
dihydrofolate reductase from Staphylococcus aureus in complex with the po-
tent inhibitor trimethoprim, Proteins Struct. Funct. Bioinforma. 76 (2009) 706–
717, doi:10.1002/prot.22383.
as potential antibacterial and anticancer agents, Medchemcomm
1612–1619, doi:10.1039/c5md00224a.
6 (2015)
[20] Z. Peng, G. Wang, Q.-.H. Zeng, Y. Li, Y. Wu, H. Liu, J. Jing Wang, Y. Zhao, Syn-
thesis, antioxidant and anti-tyrosinase activity of 1,2,4-triazole hydrazones as
antibrowning agents, Food Chem (2020) 128265, doi:10.1016/j.foodchem.2020.
128265.
[21] M.J. Assarzadeh, A. Almasirad, A. Shafiee, M.N. Koopaei, M. Abdollahi, Synthe-
sis of new thiazolo[3,2-b][1,2,4]triazole-6(5H)-one derivatives as potent anal-
gesic and anti-inflammatory agents, Med. Chem. Res. 23 (2014) 948–957,
doi:10.1007/s00044-013-0697-y.
[22] C.P. Kaushik, J. Sangwan, R. Luxmi, D. Kumar, D. Kumar, A. Das, A. Kumar,
D. Singh, Design, synthesis, anticancer and antioxidant activities of amide
linked 1,4-disubstituted 1,2,3-triazoles, J. Mol. Struct. (2020) 129255, doi:10.
1016/j.molstruc.2020.129255.
[23] K.S.S. Praveena, E.V.V. Shivaji Ramarao, N.Y.S. Murthy, S. Akkenapally, C. Ganesh
Kumar, R. Kapavarapu, S. Pal, Design of new hybrid template by linking
[39] U. Rashid, W. Ahmad, S.F. Hassan, N.A. Qureshi, B. Niaz, B. Muhammad, S. Im-
dad, M. Sajid, Design, synthesis, antibacterial activity and docking study of
some new trimethoprim derivatives, Bioorganic Med. Chem. Lett. 26 (2016)
5749–5753, doi:10.1016/j.bmcl.2016.10.051.
quinoline, triazole and dihydroquinoline pharmacophoric groups:
a
greener
[40] M. Dinari, F. Gharahi, P. Asadi, Synthesis, spectroscopic characterization,
antimicrobial evaluation and molecular docking study of novel triazine-
quinazolinone based hybrids, J. Mol. Struct. 1156 (2018) 43–50, doi:10.1016/j.
molstruc.2017.11.087.
approach to novel polyazaheterocycles as cytotoxic agents, Bioorganic Med.
Chem. Lett. 25 (2015) 1057–1063, doi:10.1016/j.bmcl.2015.01.012.
[24] J. Mareddy, S.B. Nallapati, J. Anireddy, Y.P. Devi, L.N. Mangamoori, R. Ka-
pavarapu, S. Pal, Synthesis and biological evaluation of nimesulide based new
class of triazole derivatives as potential PDE4B inhibitors against cancer cells,
Bioorganic Med. Chem. Lett. 23 (2013) 6721–6727, doi:10.1016/j.bmcl.2013.10.
035.
[41] D.E.V. Pires, T.L. Blundell, D.B. Ascher, pkCSM: predicting small-molecule phar-
macokinetic and toxicity properties using graph-based signatures, J. Med.
Chem. 58 (2015) 4066–4072, doi:10.1021/acs.jmedchem.5b00104.
[42] Drug Likeness Tool (DruLiTo 1), (n.d.). http://www.niper.gov.in/pi_dev_tools/
DruLiToWeb/DruLiTo_index.html (accessed July 20, 2020).
[43] P. Smith, W. Finnegan, T. Ngo, G. Kronvall, Influence of incubation temperature
and time on the precision of MIC and disc diffusion antimicrobial susceptibility
test data, Aquaculture 490 (2018) 19–24, doi:10.1016/j.aquaculture.2018.02.020.
[44] A. Veiga, M. da G.T. Toledo, L.S. Rossa, M. Mengarda, N.C.F. Stofella, L.J. Oliveira,
A.G. Gonçalves, F.S. Murakami, Colorimetric microdilution assay: validation of a
standard method for determination of MIC, IC50%, and IC90% of antimicrobial
compounds, J. Microbiol. Methods. 162 (2019) 50–61, doi:10.1016/j.mimet.2019.
05.003.
[25] E.A. Scott, E. Bruning, R.W. Nims, J.R. Rubino, M.K. Ijaz, A 21st century view
of infection control in everyday settings: moving from the Germ Theory of
Disease to the Microbial Theory of Health, Am. J. Infect. Control. (2020), doi:10.
1016/j.ajic.2020.05.012.
[26] S.E. Walsh, J.Y. Maillard, A.D. Russell, C.E. Catrenich, D.L. Charbonneau, R.G. Bar-
tolo, Development of bacterial resistance to several biocides and effects
on antibiotic susceptibility, J. Hosp. Infect. 55 (2003) 98–107, doi:10.1016/
S0195-6701(03)00240-8.
[27] M. Aarjane, S. Slassi, A. Ghaleb, B. Tazi, A. Amine, Synthesis, biological evalu-
ation, molecular docking and in silico ADMET screening studies of novel isox-
azoline derivatives from acridone, Arab. J. Chem. (2021) 103057, doi:10.1016/j.
arabjc.2021.103057.
[45] G.M. Morris, D.S. Goodsell, R.S. Halliday, R. Huey, W.E. Hart, R.K. Belew, A.J. Ol-
son, Automated docking using a Lamarckian genetic algorithm and an em-
pirical binding free energy function, J. Comput. Chem. 19 (1998) 1639–1662,
doi:10.1002/(SICI)1096-987X(19981115)19:14ꢀ1639::AID-JCC10ꢁ3.0.CO;2-B.
[28] M. Aarjane, S. Slassi, B. Tazi, M. Maouloua, A. Amine, Synthesis, antibacte-
rial evaluation and molecular docking studies of novel series of acridone-
1,2,3-triazole derivatives, Struct. Chem. 31 (2020) 1523–1531, doi:10.1007/
s11224-020-01512-0.
7