Novel series of acridone-1,2,3-triazole derivatives: microwave-assisted synthesis, DFT study and antibacterial activities

Article abstract of DOI:10.1007/s12039-019-1653-2

Abstract: A series of novel acridones bearing a 1,2,3-triazole unit have been synthesized and characterized. The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was performed using both a conventional method and a microwave-assisted synthetic metho

Full text of DOI:10.1007/s12039-019-1653-2

J. Chem. Sci.
(2019) 131:85
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1653-2
REGULAR ARTICLE
Novel series of acridone-1,2,3-triazole derivatives:
microwave-assisted synthesis, DFT study and antibacterial
activities
MOHAMMED AARJANEa, SIHAM SLASSIa, BOUCHRA TAZIb, MOHAMED MAOULOUAc
and AMINA AMINEa,∗
aLCBAE, CMMBA, Faculty of Science, University Moulay Ismail, BP 11201, Zitoune, Meknes, Morocco
bDépartement des Sciences de Base, Ecole Nationale d’Agriculture, Meknes, Morocco
cMedical Microbiology Laboratory, Mohamed V. Hospital, Meknes, Morocco
E-mail: amine_7a@yahoo.fr
MS received 4 April 2019; revised 27 May 2019; accepted 28 May 2019
Abstract. A series of novel acridones bearing a 1,2,3-triazole unit have been synthesized and characterized.
The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was performed using both a conventional method
and a microwave-assisted synthetic method. The in vitro antibacterial potencies of all the synthesized compounds
were determined against five clinically isolated strains: Escherichia coli, Klebsiella pneumonia, Pseudomonas
putida, Serratia marcescens and Staphyloccocus aureus. Furthermore, DFT quantum chemical calculations
were carried out to investigate geometry structures, frontier molecular orbital and gap energies, and molecular
electrostatic potential maps (MEP). Lipophilicities of the studied compounds were also determined.
Keywords. Acridone; 1, 2, 3-triazole; microwave; DFT study; antibacterial activitiy.
1. Introduction
applications in biochemical and medicinal chemistry
such as anti-HIV,19 antimicrobial,20 antioxidant,21 anti-
Acridones are heterocyclic compounds with impor- cancer,22 and acetylcholinesterase and butyrylcholine-
tant biological activities.1 Acronycine was the first sterase inhibitory23 activities. Click reaction is the most
acridone alkaloid that has been isolated from an Acrony- popular method for the construction of 1,2,3-triazoles.
chia baueri Schott plant,2 and which displayed a This synthetic method, introduced by Sharpless,24 is an
broad-spectrum activity against a variety of experimen- important topic in organic synthesis since it constitutes
tal tumor models.3,4 Due to their planar ring, these a powerful bond forming reaction with many applica-
molecules could intercalate between nucleotide base tions including different fields from materials science to
pairs in the helix of the cancer cell DNA.5–7 Many drug discovery.25 The copper(I)-catalyzed azide-alkyne
Acridone derivatives such as nitracrine, amsacrine, cycloaddition (CuAAC) makes the reaction quantitative
DACA and asulacrine8–10 are used clinically or are under and selective for the synthesis of 1,4-disubstituted 1,2,3-
clinical observations. Moreover, exhaustive research triazole and decreases the completion reaction time.26,27
has been conducted on acridine and acridone deriva-
Considering the many adverse effects and devel-
tives showing anti-cancer,11 antitumor,12 antiviral,13 opment of antimicrobial resistance,28 there is a big
antimalarial,14 antimicrobial15 and anti-inflammatory16 demand for novel and efficient antimicrobial agents.29
bioactivities.
Inspired with the biological profile of acridone and
On the other hand, 1,2,3-triazole and its derivatives 1,2,3-triazoles and their increasing importance in phar-
are an important class of heterocycles, that attract the maceutical fields, we have synthesized novel acridon-
attention of organic chemists17 due to their significant 1,2,3-triazole compounds using the copper(I)-catalyzed
pharmacological potential18 and a broad spectrum of azide-alkyne cycloaddition (CuAAC) to obtain novel
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1653-2) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

85 Page 2 of 11
J. Chem. Sci.
(2019) 131:85
drugs with antibacterial potential. The new molecules
were prepared under microwave irradiations condi-
tions then tested against five clinically isolated bacterial
strains.
Additionally, a theoretical study using DFT quantum
chemical calculations was carried out in order to explore
the electronic properties of the synthesized compounds.
Hence, optimized geometry structures, frontier molec-
ular orbital and gap energies, molecular electrostatic
potential maps (MEP) were investigated. Lipophilici-
ties were determined to help understand the relationship
between structure and biological activities of our com-
pounds.
Yellow solid; yield: 81%, M.p.> 300 ◦C. IR (KBr): 3266,
3088, 2985, 1703, 1630, 1614, 1598, 1563, 1499 cm−1
.
1HNMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ 10.40
(s, 1H, NH), 8.36 (dd, J = 8.0, 1.7 Hz, 2H, H1-H8),
8.16 (s, 1H, triazole), 7.98 (d, J = 8.8 Hz, 2H, H4,
H5), 7.82 (td, J = 8.8, 6.9, 1.8 Hz, 2H, H3, H6), 7.51
(d, J = 7.8 Hz, 2H, H1ꢀ, H5ꢀ), 7.32 (m, 4H), 7.04 (t, 1H,
H3ꢀ), 5.84 (s, 2H, CH2), 5.27 (s, 2H, CH2); 13C NMR (75
MHz, [D6]DMSO, 25 ◦C, TMS): 177.06, 164.52, 142.72,
142.25, 138.81, 134.66, 129.34, 127.12, 125.49, 124.21,
122.18, 121.99, 119.65, 116.82, 52.69, 41.97. MS (ESI) for
C24H19N5O2 [M + 1]+, calcd: 410.45, found: 410.44.
2-(4-((9-oxoacridin-10(9H)-yl)methyl)-1H-1,2,3-triazol-1-
yl)-N-(p-tolyl)acetamide (4b).
Yellow solid; yield: 84%, M.p. > 300 ◦C. IR (KBr): 3267,
3078, 2935, 1704, 1629, 1616, 1594, 1555 Cm−1. HNMR
1
2. Experimental
(300 MHz, [D6]DMSO, 25 ◦C, TMS): δ 10.31 (s, 1H, NH),
8.35 (dd, J = 8.0, 1.7 Hz, 2H), 8.15 (s, 1H), 7.98 (d,
J = 8.8 Hz, 2H), 7.82 (td, J = 8.8, 6.9, 1.8 Hz, 2H), 7.45–
7.28 (m, 4H), 7.1 (d, J = 8.0 Hz, 2H), 5.83 (s, 2H, CH2),
5.24 (s, 2H, CH2), 2.22 (s, 3H, CH3); 13C NMR (75 MHz,
[D6]DMSO, 25 ◦C, TMS) δ 177.06, 164.25, 142.69, 142.25,
136.30, 134.66, 133.19, 129.70, 127.12, 125.47, 122.18,
121.99, 119.64, 116.82, 52.66, 41.96, 20.89. MS (ESI) for
C25H21N5O2 [M + 1]+, calcd: 424.47, found: 424.29.
2.1 Materials
All materials were purchased from commercial suppliers.
Infrared spectra were recorded using a JASCO FT-IR 4100
spectrophotometer. The 1H and 13C NMR spectra were
recorded with a Bruker Avance 300 at 25 ◦C. Mass spectro-
metric measurements were recorded using SHIMADZU 8040
LC/MS/MS. MicrowaveirradiationwascarriedoutwithCEM
DiscoverTM
.
2-(4-((9-oxoacridin-10(9H)-yl)methyl)-1H-1,2,3-triazol-1-
yl)-N-(o-tolyl)acetamide (4c).
2.2 Synthesis
Yellow solid; yield: 88%, M.p. > 300 ◦C. IR (KBr): 3260,
3121, 3064, 2936, 1670, 1630, 1600, 1542, 1495 cm−1
.
General procedure for the synthesis of acridon-1,2,3-
triazole derivatives (4a-h) Conventional procedure: A
mixture of 10-(prop-2-yn-1-yl)acridone (0.1g, 0.42 mmol),
2-azido-N-phenylacetamide (0.11g, 0.63 mmol), copper sul-
fate (20 mg, 0.08 mmol) and sodium ascorbate (33 mg, 0.16
mmol) in DMF (5 mL) was stirred at room temperature for 10
h. After completion of the reaction (monitored by TLC), the
mixture was diluted with water, poured onto ice, and the pre-
cipitate was filtered off, washed with cold water, and purified
by flash chromatography on silica gel using hexane/diethyl
ether to afford desire product.
1HNMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ 9.76 (s, 1H,
NH), 8.36 (d, J = 7.8 Hz, 2H, H1-H8), 8.19 (s, 1H, tria-
zole), 7.99 (d, J = 8.7 Hz, 2H, H4, H5), 7.83 (t, J = 7.8 Hz,
2H, H3, H6), 7.36 (m, 3H), 7.15 (m, 3H), 5.85 (s, 2H, CH2),
5.34 (s, 2H, CH2), 2.16 (s, 3H, CH3); 13C NMR (75 MHz,
[D6]DMSO, 25 ◦C, TMS) δ 177.08, 164.76, 142.77, 142.24,
135.91, 134.68, 133.94, 132.00, 130.88, 127.13, 126.15,
126.01, 125.5, 122.17, 121.48, 117.81, 52.44, 41.95, 18.22.
MS (ESI) for C25H21N5O2 [M + 1]+, calcd: 424.47, found:
424.32.
Microwave-assisted procedure: A mixture of 10-(prop-2-
yn-1-yl)acridone (0.1g, 0.42 mmol), copper sulfate (20 mg,
0.08 mmol) and sodium ascorbate (33 mg, 0.16 mmol) were
suspended in 5 mL of solvent in a glass vial equipped
with a small magnetic stirring bar. To this, 2-azido-N-
phenylacetamide (0.11g, 0.63 mmol) was added and the vial
was tightly sealed. The mixture was then irradiated for 10
min at a fixed temperature (40−100 ◦C). Microwave irradi-
ation power was set at 200 W maximum. After completion
of the reaction, the vial was cooled and the reaction mixture
poured into ice cold water, and purified by flash chromatog-
raphy on silica gel using hexane/diethyl ether to afford desire
product.
2-(2-(4-((9-oxoacridin-10(9H)-yl)methyl)-1H-1,2,3-
triazol-1-yl)acetamido)benzoic acid (4d).
Yellow solid; yield: 73%, M.p. > 300 ◦C. IR (KBr): 3401,
3240, 2933, 2842, 1700, 1630, 1612, 1597, 1475 cm−1
.
1HNMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ 11.57 (br
s,1H, OH), 10.19 (s, 1H, NH), 8.60 (d, J = 8.5 Hz, 1H, H2’),
8.36 (dd, J = 8.0, 1.7 Hz, 2H, H1-H8), 8.15 (s, 1H, tri-
azole), 8.01 (d, J = 8.8 Hz, 2H, H4, H5), 7.69–7.61 (m,
5H, Ar-H), 7.34–7.26 (m, 2H, Ar-H), 5.83 (s, 2H, CH2),
5.28 (s, 2H, CH2); 13C NMR (75 MHz, [D6]DMSO, 25 ◦C,
TMS): 177.82,171.59,164.31,140.88,140.62,139.29, 133.29,
129.98, 129.71, 128.88, 125.97, 125.17, 123.11, 122.85,
121.61, 120.86, 120.49, 117.27, 115.77, 115.43, 115.39,
2-(4-((9-oxoacridin-10(9H)-yl)methyl)-1H-1,2,3-triazol-1- 52.68, 41.96. MS (ESI) for C25H19N5O4 [M + 1]+, calcd:
yl)-N-phenylacetamide (4a).
454.45, found: 454.40.

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85
2-(4-((2-methyl-9-oxoacridin-10(9H)-yl)methyl)-1H-1,2,
3-triazol-1-yl)-N-phenylacetamide (4e).
OH), 10.58 (s, 1H, NH), 8.60 (d, J = 8.5 Hz, 1H, H2’), 8.39
(d, J = 8.1 Hz, 1H, H1), 8.27 (d, J = 8.5 Hz, 1H, H5’), 8.18
Yellow solid; yield: 80%, M.p. > 300 ◦C. IR (KBr): 3263, (s, 1H, H8), 8.15 (s, 1H, triazole), 7.96 (d, J = 8.7 Hz, 1H, H4),
3137, 3085, 2926, 1703, 1632, 1618, 1592, 1498 cm−1
.
7.90 (d, J = 9 Hz, 1H, H5), 7.69–7.61 (m, 3H, Ar-H), 7.31–
1HNMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ 10.59 (s, 7.26 (m, 2H, Ar-H), 5.80 (s, 2H, CH2), 5.27 (s, 2H, CH2),
1H, NH), 8.38 (d, J = 8.1 Hz, 1H, H1), 8.16 (s, 1H, H8), 2.44 (s, 3H, CH3); 13C NMR (75 MHz, [D6]DMSO, 25 ◦C,
8.15 (s, 1H, triazole), 7.96 (d, J = 8.7 Hz, 1H, H4), 7.90 (d, TMS):176.80,171.60,164.38,140.98,140.32,139.00, 133.66,
J = 9 Hz, 1H, H5), 7.81 (td, J = 8.8, 6.9, 1.8 Hz, 1H, H3), 129.33, 129.11, 128.69, 125.12, 124.97, 122.99, 121.85,
7.68 (dd, J = 9, 2 Hz, 1H, H6) 7.56 (d, J = 7.5 Hz, 2H, 121.69, 120.77, 120.19, 117.55, 115.37, 115.39, 52.65, 41.86,
H1’, H5’), 7.34 (m, 3H), 7.07 (t, 1H, H3’), 5.83 (s, 2H, CH2), 20.60. MS (ESI) for C26H21N5O4 [M + 1]+, calcd: 468.48,
5.28 (s, 2H, CH2), 2.43 (s, 3H, CH3); 13C NMR (75 MHz, found: 468.26.
[D6]DMSO, 25 ◦C, TMS) δ 176.90, 164.56, 142.08, 140.35,
138.83, 135.98, 134.49, 131.22, 129.36, 127.15, 126.34,
124.22, 122.09, 121.72, 119.63, 119.53, 116.85, 116.67,
3. Results and Discussion
52.66, 41.83, 20.67. MS (ESI) for C25H21N5O2 [M + 1]+,
calcd: 424.16, found: 424.04.
3.1 Chemistry
2-(4-((2-methyl-9-oxoacridin-10(9H)-yl)methyl)-1H-1,2,
In this work, the synthesis of acridone 1,2,3-triazole
hybrid derivatives entails a three steps pathway
(Scheme 1). The synthetic strategy started from the
3-triazol-1-yl)-N-(p-tolyl)acetamide (4f).
Yellow solid; yield: 75%, M.p. > 300 ◦C. IR (KBr): 3277,
3124, 3079, 2910, 1705, 1632, 1616, 1594, 1499 cm−1
.
preparation of 10-(prop-2-yn-1-yl)acridone (1) as the
terminal alkyne component by the substitution reac-
tion of acridone with propargyl bromide, using NaH
in dimethylformamide (DMF) at 80 ◦C. In the second
setup, 2-azido-N-phenylacetamide derivatives are pre-
pared by reacting aniline derivatives (1.0 equiv.) and
chloroacetyl chloride (1.5 equiv.) in K2CO3/CH2Cl2
at 0 ◦C to give 2-chloroN-phenylacetamide (2). The
crude amide (2) was then reacted with sodium azide
in DMF as solvent under moderate heat to give 2-
azido-N-phenylacetamide (3). The last step was the
click reaction, where the 10-(prop-2-yn-1-yl)acridone
undergoes a 1,3-dipolar cycloaddition with 2-azido-N-
phenylacetamide (3) in the presence of copper sulfate
and sodium ascorbate leading to the 1,4-disubstituted
regioisomer (4).
1HNMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ 10.30 (s,
1H, NH), 8.34 (dd, J = 8.0, 1.7 Hz, 1H, H1), 8.14 (s, 1H,
H8), 8.10 (s,1H, triazole), 7.92 (dd, J = 19.2, 8.8 Hz, 2H,
H4-H5), 7.79 (td, J = 8.7, 6.9, 1.8 Hz, 1H, H3), 7.64 (dd,
J = 8.9, 2.3 Hz, 1H, H6), 7.48–7.35 (m, 2H), 7.31 (td,
J = 7.8, 6.9, 0.8 Hz, 1H, H2), 7.09 (d, J = 8.2 Hz, 2H,
H2’-H4’), 5.81 (s, 2H,CH2), 5.23 (s, 2H,CH2), 2.42 (s, 3H,
CH3), 2.22 (s, 3H, CH3); 13C NMR (75 MHz, [D6]DMSO,
25 ◦C, TMS):176.88, 164.25, 142.78, 142.08, 140.36, 136.30,
135.96, 134.46, 133.19, 131.20, 129.70, 127.13, 126.33,
125.41, 122.07, 121.70, 119.64, 116.84, 116.65, 52.64, 41.84,
20.88, 20.66. MS (ESI) for C26H23N5O2 [M + 1]+, calcd:
438.50, found: 438;36.
2-(4-((2-methyl-9-oxoacridin-10(9H)-yl)methyl)-1H-1,2,
3-triazol-1-yl)-N-(o-tolyl)acetamide (4g).
Yellow solid; yield: 88%, M.p. > 300 ◦C. IR (KBr): 3275,
Along with the conventional method, the assisted
microwave irradiation was also employed for the 1,3-
dipolar cycloaddition reaction. A number of variables
including solvent, copper catalyst, reducing agent and
time were examined in the reaction of 10-(prop-2-
yn-1-yl)acridone (1a) and 2-azido-N-phenylacetamide
(3a) for the optimization of the click reaction. The
obtained results are summarized in (Table 1). Based
on previous studies, the model click reaction was
performed in water:tBuOH (1:1) as a solvent and
CuSO4.5H2O/NaAsc as a catalytic system at room tem-
perature,30 the expected product (4a) was obtained in
55% yield with conventional method and 60% yield
with microwave irradiation. In an attempt to increase
the yield of the cycloaddition reaction, we have tested
other solvents (DMF, DMF/H2O, and CH2Cl2). An
interesting increase in the yield of (4a) was observed
3127, 3072, 2917, 1701, 1630, 1615, 1590, 1509 cm−1
.
1HNMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ 0.36 (s, 1H,
NH), 8.38 (dd, J = 8.0, 1.7 Hz, 1H,1H), 8.18 (s, 1H, H8),
8.10 (s,1H, triazole), 7.96 (dd, J = 19.1, 8.9 Hz, 2H, H4-H5),
7.83 (td, J = 8.7, 6.9, 1.8 Hz, 1H,H3), 7.68 (dd, J = 8.9, 2.3
Hz, 1H, H6), 7.56–7.29 (m, 3H), 7.12 (d, J = 8.2 Hz, 2H,H2-
H4’), 5.85 (s, 2H, CH2), 5.26 (s, 2H, CH2), 2.45 (s, 3H, CH3),
2.25 (s, 3H, CH3); 13C NMR (75 MHz, [D6]DMSO, 25 ◦C,
TMS) δ 176.41, 163.75, 141.59, 139.87, 135.78, 135.50,
133.99, 132.72, 130.73, 129.21, 126.64, 125.83, 121.57,
121.23, 119.17, 116.34, 116.16, 52.15, 41.36, 20.39, 20.18.
MS (ESI) for C26H23N5O2 [M + 1]+, calcd: 438.50, found:
438.41.
2-(2-(4-((2-methyl-9-oxoacridin-10(9H)-yl)methyl)-1H-1,
2,3-triazol-1-yl)acetamido)benzoic acid (4h).
Yellow solid; yield: 76%, M.p. > 300 ◦C. IR (KBr): 3401,
1
3240, 2933, 2842, 1700, 1630, 1612, 1597, 1475 cm−1. H
NMR (300 MHz, [D6]DMSO, 25 ◦C, TMS): δ 11.57 (br s,1H, in DMF, affording 73% yield after 10 h stirring at

85 Page 4 of 11
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Scheme 1. The synthetic route of title compounds (4a–h).
room temperature whereas a decrease in the yield was
Structures of novel acridon-1,2,3-triazole derivatives
observed when water was added as a co-solvent. This is were characterized by IR, H NMR, 13C NMR. The
probably due to the low solubility of 10-(prop-2-yn-1- IR spectra of the novel acridon-1,2,3-triazole com-
yl)acridone (1a) in aqueous media. Any change in the pounds (4a–h) showed characteristic absorption band at
amount of copper catalyst and sodium ascorbate, even at 1630 cm−1 corresponding to a conjugated ketone (C=O)
reflux, was not efficient compared to optimized condi- ofthe acridone ring and absorption bands in the region of
tions. In order to increase the efficiency of the reaction, 1704−1670 cm−1 corresponding to (C=O) of the amide
we used copper iodide as a source of copper and tri- group.
1
ethylamine as a protective agent. As shown in Table 1,
the use of CuI in DMF as solvent gives moderate yield glet for NH proton at around 10.59–9.76 ppm and
(60%). another singlet for triazole proton in the range of 8.19–
1H NMR spectra of compounds 4a–h showed a sin-
By the protocol of entry 3 in Table 1, novel acridone 8.10 ppm. Aromatic protons of acridone ring and N-
1,2,3-triazole derivatives were synthesized with both phenylacetamide group are visible between 8.38–7.10
microwave-assistedprocedureandconventionalmethod. ppm, while the methyl proton of substituted acridone
By using MWI, the target compounds were synthe- appear at 2.45 ppm. The N–CH2 attached to the acridone
sized in 10 min with excellent overall yields of 86–69% ring and N–CH2 attached to the amide group protons
(Table 2). Whereas with the conventional procedure, the resonate at around 5.84–5.27 ppm. The substituted N-
overall yields were in the range of 60–75% and it took phenylacetamide group yielded an intense singlet at
more than 10 h to complete the reaction.
around 2.25–2.16 ppm corresponding to the methyl

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Page 5 of 11
85
Table 1. Optimization of reaction condition 4a.a
Time
Yield (%)d
NO-MW
NO-MW
MWf
MWf
Entry
Copper salt
Reducing agent
Solvent (1:1)
1
2
3
4
CuSO4.5H2O
CuSO4.5H2O
CuSO4.5H2O
CuSO4.5H2O
CuSO4.5H2O
CuSO4.5H2O
CuI
NaAsc
NaAsc
NaAsc
NaAsc
NaAsc
NaAsc
–
t-BuOH/H2O
t-BuOH
DMF
DMF/H2O
CH2Cl2
DMF
24h
24h
10h
24h
24h
4h
15min
15min
10min
15min
15min
–
55
55
73
61
68
69
60
60
60
81
72
71
–
5
6c
7b
DMF
24h
10min
63
aReaction conditions: 3a (1.2 mmol), 1a (1 mmol), Copper salt (20 mol%), sodium ascorbate (50 mol%.), solvent (5mL) at
room temperature. b0.5 eq Et3N. cReflux. dIsolated yield. fMicrowave conditions, 200 W maximum.
group, while the acid proton appear at 11.57 ppm. In between the nitrogen of the triazole ring and the amide
the 13C NMR spectrum, the chemical shifts of the car- hydrogen.
bonyls of the acridone ring and CONH groups of the
N-phenylacetamide resonate at around 177.8–176.4 and
3.2a Frontier molecular orbitals (FMOs): The most
164.7–163.7 ppm, respectively and another signal cor-
important orbitals in molecules are the frontier molecu-
responding to the carbon of acid group are resonate at
lar orbitals, which refer to HOMO and LUMO orbitals
171.5. Tow signals at a range of 63.0–54.0 ppm corre-
are the most important factors that affect the bioac-
sponding to N–CH2 attached to the acridone ring and
tivity.31 The energy gap (ꢀEgab = ELUMO − EHOMO
)
N–CH2 attached to the amide group protons confirmed
by DEPT 135. The signal at around 125.4–142.7 ppm
corresponding to the aromatic carbons of triazole ring.
between HOMO and LUMO reflect the chemical activ-
ity and kinetic stability.32–36 The gap energies, HOMO
and LUMO for the novel acridone 1,2,3-triazole deriva-
tives were calculated and their FMOs are displayed in
(Table 3) sketched in (Figure 2). The calculated energy
gap is almost constant for all the synthesized com-
3.2 Computational studies
Molecular geometries obtained through theoretical pounds and the results showed that the substitution has
methods are useful to explain the structures of com- an insignificant effect on the energy gap except for
pounds. Optimization of all compounds was carried molecules 4d and 4h that are substituted by an acid
out at the B3LYP/6-31G (d) level of DFT. Optimized group. For these compounds, small decreases in the
geometries of compounds (Figure 1) showed that the LUMOlevelsareobservedandleadtostabilizationof4d
acridone ring is not completely planar; it is a little and 4h. The distributions charges in HOMO orbitals are
bend of approximately 2.6◦ relative to the axis that mainly situated over the acridone ring. In effect, they
passes through the nitrogen of the amino group and the are not influenced by the nature of the substituent on
keto, and the interplanar angle between the acridone the triazole rings. Concerning the LUMO orbitals, they
ring and the triazole ring is 47◦. On the other hand are also located over the acridone ring for all studied
in both compounds 4d and 4h bearing an acid group, compounds except 4d and 4h that are substituted by a
intramolecular hydrogen bonds are formed between carboxylic acid group. LUMO orbitals for compounds
amide hydrogen and the acidic oxygen. For the other 4d and 4h are located on the benzoic acid unit due to the
compounds, intramolecular hydrogen bonds are formed attractive effect of the acid group.

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Table 2. Scope of target compounds through the reaction of terminal alkynes (1a–b) and 2-azido-N-phenylacetamide (3a–d).
Yield(%) Yield(%)
NO-MW NO-MW
Compounds
Compounds
MW
MW
73
81
70
84
69
80
75
79
77
86
70
81
64
69
60
72
Furthermore, the HOMO and LUMO energy values propensity or capacity of a species to accept elec-
are used to compute global chemical reactivity descrip- trons.38 It is a measure of the stabilization in energy
η
ω
tors such as chemical hardness ( ), electrophilicity ( ) after a system accepts an additional amount of elec-
χ
and electronegativity ( ) are reported in Table 3. Chem- tronic charge from the environment. Electronegativity
2
η
ω
ical hardness is related to the stability and reactivity is given by expression = μ /2 and (μ =chemical
η
χ
of a chemical system represented by = (ELUMO
−
potential). Electronegativity is given by expression
=
E
HOMO)/2. This parameter is used as a measure of resis- −(EHOMO + ELUMO)/2, which is defined as the power
tance to change in the electron distribution or charge of an atom in a molecule to attract electrons towards
in a molecule.37 Electrophilicity index measures the it.39

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85
Figure 1. The optimized geometries of 4a, 4d, 4e and 4h at the B3LYP/6-31G (d) level of DFT.
Table 3. Quantum chemical parameters of acridone 1,2,3-triazole compounds calculated by B3LYP/6-31G(d) level of theory.
Chemical
hardness
(η)
Chemical
softness
(S)
Electro-
negativity
(χ)
Electro-
philicity
(ω)
Lipo-
phylicity
Log(P)
Compounds
E
HOMO (eV)
ELUMO (eV) Egap (eV)
4a
4b
4c
4d
4e
4f
− 0.214
− 0.213
− 0.214
− 0.214
− 0.209
− 0.209
− 0.209
− 0.209
− 0.065
0.149
0.148
0.149
0.140
0.146
0.146
0.146
0.136
0.074
0.074
0.074
0.070
0.073
0.073
0.073
0.068
13.42
13.51
13.42
14.28
13.69
13.69
13.69
14.70
0.139
0.139
0.139
0.144
0.136
0.136
0.136
0.141
0.129
0.130
0.129
0.148
0.126
0.126
0.126
0.146
3.89
4.40
4.40
4.20
4.40
4.92
4.92
4.71
− 0.065
− 0.065
− 0.074
− 0.063
− 0.063
− 0.063
− 0.073
4g
4h
Lipophilicity is defined by the partitioning of a com- of the molecule in electrophilic and nucleophilic.42–44
pound between an aqueous and a nonaqueous phase. Thus, it allows envisaging centers and their relative reac-
Log P is an important physicochemical parameter in tivity towards electrophilic and nucleophilic attacks.45
the development of lipophilicity index.40,41 It is gener- The molecular electrostatic potential surface was cal-
ally accepted that more lipophilic molecule will interact culated at the B3LYP/6-31G(d) optimized geometry for
more easily with the fatty acid tails of the lipid bilayer, structures 4a–4h. As showing in (Figure 3), electrophilic
thus allowing the molecule to cross cell membranes.41 sites are red in color which designates the negative
As shown in Table 3 the lipophilicity of the synthesized regions of the molecule, while the nucleophilic sites are
compounds increases with substitution of acridone ring colored in blue and designate the positive regions of the
and N-phenylacetamid unit by a methyl group.
molecule. The molecular electrostatic potential (MEPs)
of compounds 4a–4h shows that the region with the most
electronegative potential was located on nitrogen atoms
in heteroaromatic 1,2,3 triazole ring and the two oxygen
atoms of the carbonyl group of amide and acridone ring.
3.2b Molecular electrostatic potential surface: The
molecularelectrostaticpotentialisrelatedtotheelectron
density and is important to identify the reactive sites

85 Page 8 of 11
J. Chem. Sci.
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Figure 2. HOMO and LUMO plots of compounds 4a-h.
Figure 3. The molecular electrostatic potential surface of molecules 4b, 4d and 4e.
3.3 Antibacterial activity
conditions using Mueller-Hinton agar medium, accord-
ing to the Clinical and Laboratory Standards Institute
The synthesized compounds were screened in vitro guidelines.46 Then the minimum inhibitory concentra-
for their antibacterial activities against four gram- tion (MIC) measurement were conducted to examine
negative bacteria Escherichia coli, Klebsiella pneu- the antibacterial activities ofthe synthesized compounds
monia, pseudomonas putida, Serratia marcescens and (4a–h). MIC data showed in Table 4 indicate that com-
one gram-positive bacteria Staphyloccocus aureus. Ini- pounds 4c, 4e, 4f and 4g exhibited good inhibitory activ-
tially, antibacterial activities of synthesized compounds ities against S. aureus (MIC = 12.3−19.6 μg/mL) and
were tested on the basis of the growth inhibition S. marcescens (MIC = 43.6−75.2 μg/mL). Moreover,
zone utilizing the disc diffusion method under standard the compounds 4e and 4f showed modest inhibitory

J. Chem. Sci.
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Page 9 of 11
85
Table 4. Antibacterial data for the synthesized compounds.
Compounds
Antibacterial activity data in MIC (μg/ml)
S. aureus
E. coli
K. pneumonie
P. putida
S. marcescens
1a
1b
4a
4b
4c
4d
4e
4f
122.8
118.4
38.5
28.5
19.6
72.9
19.6
12.3
19.6
38.5
11.6
–
133.4
124.2
107.1
74.1
90.6
90.9
65.4
38.5
36.6
56.6
22.4
–
137.9
130.4
137.9
86.9
70.4
122.8
74.1
56.6
56.6
107.1
15.3
–
156.3
145.5
109.9
90.1
88.8
120.3
77.1
74.9
115.0
121.8
37.1
–
129.3
127.3
89.1
66.1
43.6
109.0
75.2
48.3
46.2
51.3
20.3
–
4g
4h
Chloramphenicol
DMF (control)
activity against P. putida (MIC = 74.9 μg/mL) and activities against Escherichia coli, Klebsiella pneu-
the compounds 4f and 4g present MIC = 56.6 μg/mL monia, Pseudomonas putida, Serratia marcescens and
againstK. pneumonia. Noticeably, compound4gwasthe Staphyloccocus aureus, indicating that the substitu-
most potent inhibitor against E. coli with a MIC value tion of the acridone ring by a 1,2,3-triazole nucleus
at 36.6 μg/mL. It was found that 4f was the most potent increases the antibacterial potential of our compounds.
compound against Gram-positive and Gram-negative The best antibacterial effect was exhibited by com-
organisms, the activity of 4f was slightly weaker than pound 4f against S. aureus. Theoretical calculations
that of Chloramphenicol against S. aureus (MIC = based on DFT were performed to determine the HOMO,
12.3 μg/ml).
LUMO, gap energies and MEPs. Results showed that
The MIC values listed in Table 4 showed an improve- gap energies are almost similar for all the synthesized
ment in antibacterial activity after the substitution of the compounds and that the substitution has a negligible
acridone ring by a triazole ring for all the germs, against effect on the gap energies. The molecular electrostatic
the Staphyloccocus aureus the MIC was decreased from potential (MEPs) maps show that the negative potential
122.8 to 19.6 μg/mL. Thus the substitution of acridone sites are on nitrogen atoms in heteroaromatic 1,2,3 tri-
at position 2 by a methyl increases the antibacterial effi- azole ring and the two oxygen atoms of the carbonyl
ciency against all the germs. It can be observed that group of amide and acridone ring.
methyl substitution on the benzene ring was favorable
Supplementary Information (SI)
to increase the antibacterial activity of the compounds.
We can see that the antibacterial activity of the synthe-
sized compounds may be due to the evolvement of the
lipophilic character of the molecules, which help the
crossing through the biological membrane of the bacte-
ria and thereby inhibit their growth.
The method of determination of minimum inhibitory con-
centration, quantum chemical calculation, synthesis method,
1HNMR, 13CNMR spectra are available at www.ias.ac.in/
chemsci.
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