Synthesis, characterization, antimicrobial activity and computational exploration of ortho toludinium carboxylate ionic liquids

Article abstract of DOI:10.1016/j.molstruc.2021.131087

As Ionic Liquids (IL) was considered as designer molecules for use in chemical and biological sectors, its demands and researches have been increasing day by day. To design new ILs and evaluate its antimicrobial activities, the ortho-toludinium carboxylat

Full text of DOI:10.1016/j.molstruc.2021.131087

Journal of Molecular Structure 1245 (2021) 131087
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, characterization, antimicrobial activity and computational
exploration of ortho toludinium carboxylate ionic liquids
Ajoy Kumer, Md Wahab Khan∗
Organic Research Laboratory, Department of Chemistry, Bangladesh University of Engineering and Technology (BUET), Dhaka 1000, Bangladesh
a r t i c l e i n f o
a b s t r a c t
Article history:
As Ionic Liquids (IL) was considered as designer molecules for use in chemical and biological sectors, its
demands and researches have been increasing day by day. To design new ILs and evaluate its antimi-
crobial activities, the ortho-toludinium carboxylate ionic liquids (OTILs) were synthesized through the
Brønsted acid-base neutralization reaction between ortho toluidine and carboxylic acids with yields (74
to 88)%. The synthesized OTILs were characterized by FT-IR, UV and 1H-NMR, which had confirmed their
conversion of the reaction and their structure. The eight human pathogenic bacteria were used for an-
tibacterial screening, as well as three antifungal activities had estimated against three fungi. However,
the synthesized ILs showed the good result to antimicrobial activity against both bacteria and fungi. Due
to show high antimicrobial activity, MIC was performed against two bacteria whereas the MIC had found
the range 250 to 500 mM. Furthermore, density functional theory (DFT) had used for determining the
HOMO, LUMO and chemical reactivity descriptors for the computational investigation of OTILs, as well
as molecular docking screening had performed against three pathogens. By the molecular docking score
as binding affinity and chemical descriptors, the effect of alkyl chain and electronegative atom in anion
had direct contribution on antimicrobial activity which was the similar result from the experimental data
of antimicrobial activity. Finally, attaching Fluorine atom in anion could show the highest antimicrobial
activity and docking score among chlorine, bromine, iodine even alkyl chain.
Received 22 April 2021
Revised 6 July 2021
Accepted 9 July 2021
Available online 17 July 2021
Keywords:
FTIR
Antimicrobial activity
Well-diffusion method
DFT
HOMO
LUMO and Docking
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
placing as green solvent [19, 20]. Besides, it was opened a new
window for drug discovery in pharmaceutics and medicine [21] as
ILs, a fascinating class of materials for concurrent era, com-
poses of discrete cation and anion. Initially, it was synthesized
in 1914 as ethanolammonium nitrate for commercial use in elec-
trochemical applications, especially in non-volatile electrolytes for
batteries [1]. Afterwards, it was attracted to research for its tun-
able chemical and thermophysical and chemical properties, such
as high ionic conductivity and a wide electrochemical window [2],
good thermal stability [3], low flammability [4], tunable polarity,
solvation power for organic [5] and inorganic compounds [6], sur-
face activity [7], low melting point and negligible vapor pressure
[8]. Due to its desirable properties, ILs was used in membrane
development [9], reaction catalyst [10], biochemistry [11], bioor-
ganic process or engineering [12], chemical process [13], organic
synthesis [14], electrochemistry [15], analytical chemistry [16], ex-
traction of nano particles [17, 18], absorber of CO2 and SO2 [10].
With beginning of 21st century, ILs has considered as the alter-
native organic solvent or traditional reaction solvent in synthesis
bioactive molecules of anticancer [22], antimicrobial agents [23-
27], antiviral [28, 29], antifungal and antiparasitic drugs [30, 31],
anti-infective defense, as well as in the pharmaceutical and food
industries, agrochemistry, artificial enzymes biocides and biotech-
nology [32, 33]. Regarding the biological activity, the phospho-
nium and ammonium-based ionic liquids have been used as poten-
tial molecules for treatment of cancer [34], insect detergents [35],
blood and tissue preservatives [36], phenol degradation [37] wood
preservatives [38], antibacterial agents, antiviral agents, antifungal
agents, antiparasitic drugs and herbisides [39, 40] due to its low
toxicity [41, 42]. Mainly, the chains, that can be connected to the
central N+ atom forming quaternary ammonium ILs, could be pre-
pared to tune the physical properties, such as melting point, water
miscibility, conductivity and viscosity by selection and modifica-
tion of the anion and cation of the ILs [43, 44]. Moreover, it was
illustrated that alkyl chain was shown a vast antimicrobial potency
in various infection diseases as that larger alkyl chain was illus-
trated the higher activity [45], and come to think of bifuctional
group [46] or multi functional group [47]. It must be added that di-
cationic part of ILs can show a variable effect on microbial potency
∗
Corresponding author.
E-mail address: mwkhan@chem.buet.ac.bd (M.W. Khan).
https://doi.org/10.1016/j.molstruc.2021.131087
0022-2860/© 2021 Elsevier B.V. All rights reserved.

A. Kumer and M.W. Khan
Journal of Molecular Structure 1245 (2021) 131087
[48]. In addition, according to Holbrey and Rogers et al., reported
the various factors with main importance on biological activity of
ILs are the charge, size, alkyl chain, electronegative group and dis-
tribution of charge on the ions and small changes in the shape of
covalent bonds with protein or micromolecules interaction, as well
as its thermal properties [49-51]. One of the most recent fields by
ILs to be explored is that of biologically active compounds [30, 52].
Thus, Smiglak et al. highlighted the potential use of ILs drug de-
liverers through the improvement of solubility of active pharma-
ceutical ingredients (APIs) proteins and amino acids in ILs with
strong hydrogen bond acceptors [53] which had considered the 3rd
generation ILs. Among of 3rd generation ILs, hydrophobic quater-
nary ammonium-based salts can show dual biological tasks, such
as sweet and anti-microbial activity [54] that led to select the ani-
line base for acting the cation making ammonium ion in IL, called
as the protic ILs (PILs), to estimate the antimicrobial agents of hu-
man pathogenic micro-organism. To kick off about the PILs, it is
a sub-division of ILs which are easily synthesized by preparation
formula of a Brønsted acid and a Brønsted base [55], and used as
potential selective drug design and delivery system [56]. As a re-
sult, the quaternary ammonium-based ILs was chosen for investi-
gation of study with organic alkyl chain and electronegative atom
effect examination combining organic base as cations to produce
ammonium salt with different types of organic acids as an anion.
The ammonium-based ILs is introduced as new fields of bioactive
against different bacteria, fungi, and plant and virus pathogen [57-
59]. With experimental work, to evaluate the hydrogen bonding
and hydrophobic bonding, the molecular docking was performed
against the pathogens which were compared with the experimen-
tal data of antimicrobial activity. Before docking, chemical reactiv-
ity descriptors was estimated by DFT functional to say about its
ligand acceptability in part of HOMO or LUMO and chemical sta-
bility.
toluidinium carboxylate [60]. The ILs purification process consisted
of a strong agitation and slight heating, at 100 C under pressure,
º
under a vacuum of 20 KPa and found a limpid and viscous appear-
ance liquid. The ortho toluidinium salt formation and their struc-
ture were confirmed by FT-IR spectra, UV spectra and 1H NMR. The
structure of synthesized IL is shown in the figure 3 and synthe-
sized reaction scheme was presented in figure 1.
2.3. Characterization
For the characterization by 1H NMR spectrum of ortho tolui-
diniumtrifluroaccetate (IL05) was accounted for the chemical shift
at 8.15 (s, 3H, PhNH3), 7.31 (s, 1H, Ph), 7.30 (s, 1H, Ph), 7.26 (s, 1H,
Ph), 7.21 (s, 1H, Ph), 2.27 (s, 3H, PhCH3). There was not presence
any chemical shift at 3.55 ppm which was confirmed the absence
of peak for -NH2 group, and in case of the –COOH group, the orig-
inal peak of that functional group was not shown at 11.42 ppm
considering its conversion. However, the absence chemical shift at
original peak region of –COOH and -NH2 group pointed out the
conversion into carboxylate groups and ammonium group in am-
monium carboxylate ILs. For the fact of FTIR, the strongest peaks at
about 3440 cm−1 (N-H) asymmetry and 3007 cm−1 (N-H) symme-
try make available the existence of ammonium ion [61], on top of
the another two peaks at 1760 cm−1 (C-O) asymmetry, 1655 cm−1
(-CO) symmetry prove the existence of carboxylate ion [62]. Finally,
the FTIR spectrum of IL01, IL02, IL03 and IL04 were similar to ILs
and confirmed their functional groups as ILs. Withal, the UV spec-
tra for IL05 shows the similar absorption at about 240 nm wave-
length which is almost same for IL01, IL02, IL03 and IL04.
ortho toluidiniummethanoate (IL01), [CH3PhNH3] [HCOO],
M.W.: 153.0,Yield (%): 81.0%., Physical state: liquids, FT-IR (KBr) in
cm−1: 3457 (N-H) asymmetry, 3024 (C=C) in benzene ring, 3366
(N-H) symmetry, 2903 (C-H) asymmetry, 2859 (C-H) symmetry,
2596 (PhNH3+), 1622 (C-O) asymmetry, 1667 (-CO) symmetry.
ortho toluidiniumacetate (IL02), [CH3PhNH3] [C2OOH3],
M.W.:167.0, Yield (%): 78.0%., Physical state: liquids, FT-IR (KBr) in
cm−1: 3416 (N-H) asymmetry, 3021 (C=C) in benzene ring, 3361
(N-H) symmetry, 2930 (C-H) asymmetry, 2859 (C-H) symmetry,
2360 (PhNH3+), 1617 (C-O) asymmetry, 1587 (-CO) symmetry.
ortho toluidiniumpropanoate (IL03), [CH3PhNH3] [C3OOH5],
M.W.: 179.0,Yield (%): 77.0%., Physical state: semi-melted, FT-IR
(KBr) in cm−1: 3433 (N-H) asymmetry, 3020 (C=C) in benzene
ring, 3330 (N-H) symmetry, 2990 (C-H) asymmetry, 2874 (C-H)
symmetry, 2370 (PhNH3+), 1621 (C-O) asymmetry and 1612 (-CO)
symmetry.
2. Methodology and Experiment
2.1. Materials and reagents
The Formic acid, acetic acid, propanoic acid, butanoic acid, tri-
fluroacetic acid, ortho toluidine, thin layer chromatography powder
and agar media were analytical grade purchased and used with-
out purification, but solvents were distilled before use. The bac-
terial and fungal strains were collected from the Department of
Pharmacy in the University of Dhaka and conducted as sub cul-
ture before use each time. The FT-IR spectrophotometer, (Model:
IRAffinity-1S and type Double beam) SHIMADZU, Japan, range 600-
4500 cm−1 was used with KBr disc technique for taking the FTIR
spectra. The work of synthesis, purification and analysis were done
at the department of chemistry in Bangladesh University of Engi-
neering and Technology (BUET), Dhaka-1000, Bangladesh. The an-
timicrobial activity was done at Pharmacy at University of Dhaka,
Bangladesh. The 1H NMR Spectroscopy (Bruker, 400 MHz, Switzer-
land, Model: Avance-III HD) was recorded in Jahangirnagar Univer-
sity, Bangladesh.
ortho toluidiniumbutanoate (IL04), [CH3PhNH3] [C4OOH7],
M.W.: 195.0, Yield (%): 78.0%., Physical state: melted solid, FT-IR
(KBr) in cm−1: 3457 (N-H) asymmetry, 3024 (C=C) in benzene
ring, 3366 (N-H) symmetry, 2903 (C-H) asymmetry, 2859 (C-H)
symmetry, 2360 and 2596 (PhNH3+), 1622 (C-O) asymmetry, 1667
(-CO) symmetry.
ortho
toluidiniumtrifluroaccetate
(IL05),
[CH3PhNH3]
[C2F3OOH3], M.W.: 221.0, Yield (%): 88%., Physical state: white
solid crystal, FT-IR (KBr) in cm−1: 3440 (N-H) asymmetry, 3007
(N-H) symmetry, 2830 (C-H) symmetry, 2602 (PhNH3+), 1760
(C-O) asymmetry, 1655 (-CO) symmetry. 1H NMR chemical shifts:
8.15 (s, 3H, PhNH3), 7.31 (s, 1H, Ph), 7.30 (s, 1H, Ph), 7.26 (s, 1H,
Ph), 7.21 (s, 1H, Ph), 2.27 (s, 3H, PhCH3).
2.2. Synthesis and Purification of Ionic Liquids
The ortho toluidinium carboxylate ILs was synthesized by an
acid-base neutralization reaction [60]. The base, ortho toluidine,
was added with carboxylic acids under stirring maintaining low
temperature by ice-bath around the round bottle flux. At first, the
equimolar carboxylic acid was added in a slow by dropwise about
15- 20 minutes, maintaining the temperature. Then the mixture
was stirred for 18-24 hours at room temperature until obtaining
a clear, viscous liquid which was monitored by thin-layer chro-
matography (TLC). The reaction product was a viscous salt of ortho
2.4. Antimicrobial test against bacteria and fungi
2.4.1. Preparation of IL solutions in different concentrations
For preparation of sample, the ILs sample was measured for
preparation of mili-Molar (mM) solution with high level of accu-
rately so that no impurities were obtained. Moreover, the five var-
ious solutions, such as 1000 mM, 750 mM, 500 mM, 250 mM, and
2

A. Kumer and M.W. Khan
Journal of Molecular Structure 1245 (2021) 131087
NH2
NH3
Stirring for about
24-30 hours
CH3
CH3
H/R-COOH
H/R-COO
Room temparature
toluidinium
carboxylate
Here, R= CH3, CH3CH2, CH3CH2CH2,
and CF3
Fig. 1. Reaction scheme for synthesis
Table 1
Data of Zone of Inhibition for antibacterial activity
IL-1
IL-2
IL-3
IL-4
IL-5
Control
Starting
Bacillus cereus(+)
Staphylococcus aureus(+)
Bacillus subtilis(+)
Sarcina lutea(+)
7
8
14
13
11
12
20
18
19
18
22
20
22
22
0
0
0
0
0
0
0
0
12
12
10
9
9
11
Escherichia coli(-)
13
15
13
12
13
11
12
11
14
13
14
14
18
18
16
18
20
21
22
22
0
0
0
0
0
0
0
0
Salmonella typhi(-)
Pseudomonaaeroginosa(-)
Shigella dysenteriae(-)
125 mM, were prepared for determination of minimum inhibitor
concentration (MIC).
determination the MIC against two antibacterial stain and analyzed
the recorded mean result using origin graph to calculate the MIC
by graphical method.
2.4.2. Antibacterial test
A beginning examination for the antibacterial activities of pure
ILs, well diffusion method taking 20 μL ILs solution in each well
with concentration 1000 mM was executed for primary screen-
ing both gram-positive, Bacillus cereus, Staphylococcus aureus,
Sarcina lutea and Bacillus subtilis, and gram-negative bacteria,
Escherichia coli, Salmonella typhi, Pseudomonas aeroginosa and
Shigella dysenteria [63, 64]. For this procedure the auto-clave (Sys-
tec V-40 and Systec V-55: 220-240 V, 50/60 Hz, 16A) was used
for sterilized and this full work was done in Laminar flow [Model:
HHS-1000/1300/1600/1800 (-U)] for removal of contamination. The
zone of inhibition (including the well diameter 8.0 mili meter as
mm) was measured in mm scale with consideration 1.0 with all
taking values. All the measurements were done in triplicate, and
the average value was listed in table 1. The initial concentration
was maintained for all ILs in 1000 mM distilled water. A control
plate was always observed during working procedure by the sol-
vent.
2.5. Computational Methods
For molecular modelling and theoretical investigation, Material
studio 8.0 (Accelrys, now BIOVIA 2019) [65] were used for molec-
ular optimization and determination the chemical descriptor us-
ing DFT functional [66-69] of DMol code [70, 71]. Afterwards, the
optimized structure was taken in to protein data bank (pdb) file
for molecular docking as ligand. The molecular docking was per-
formed by PyRx software using autodocking option by obtaining
required condition to calculate the binding affinity while ILs was
the ligand, and protein of pathogens as micromolecules. Then, the
docking complex of ligand-protein was analysis by discovery stu-
dio [72]. Lastly, the ADMET was obtained the online data base
admetSAR (http://lmmd.ecust.edu.cn/admetsar2/) [73] for calculat-
ing absorption, distribution, metabolism, excretion and toxicity pa-
rameters, and other online portal named SwissADME (http://www.
swissadme.ch/) [74] was used to calculate the Lipinski rule.
To explain the chemical descriptors calculating from the com-
putational tools using DFT functionals, the HOMO and LUMO are
the crucial parameters which are used to calculate the ionization
potential (I), electron affinity (A), energy gap, chemical potential,
electronegativity, electrophilic index, hardness and softness by the
following equations 1-8.
2.4.3. Antifungal test
In analogous ways, antifungal investigation against three phy-
topathogenic fungi, such as Aspergillus niger, Saccharomyces cere-
visiae and Candida albicans, was finished from end to end well dif-
fusion method. With beginning, the amount of 100 μL of ILs solu-
tion for 1000 mM was kept in petri plate before adding the freshly
prepared media with well shaking for right proportion of mixing.
After waiting about 30 minutes for solidification, the fungal strain
was transferred in incubator for growing the fungal strain during
72 hours. Finally, the result was traced in mm scale, and this pro-
cedure was performed triplet time for avoiding errors.
Egap = (ELUMO − EHOMO
I = −EHOMO
)
(1)
(2)
(3)
A = −ELUMO
I + A
2.4.4. Determination of MIC
The five subsequence concentrations, such as 1000 milimolar
(mM), 750 mM, 500 mM, 250 mM, and 125 mM were taken for
μ = −
( )
(4)
2
3

A. Kumer and M.W. Khan
Journal of Molecular Structure 1245 (2021) 131087
25
20
15
10
5
0
Bacillus
cereus(+)
Staphylococcus
aureus(+)
Bacillus
subtilis(+)
Sarcina lutea(+) Escherichia
Salmonella
typhi(-)
coli(-)
Formate
Acetate
Propanoate
Butanoate
Trifluroaccetate
Control
Fig. 2. Comparative study for anion on antibacterial activity
The antifungal analysis was as well measured by the term
of the growth percentage compared with the control while the
growth of control is 100% percent using the following formula
which shows a ILs how can be able to show it potency agonist any
fungal stain.
I − A
η =
(5)
(6)
(7)
(8)
( )
2
1
S
( )
=
η
Percentage of Inhibition = Growth percentage of control
(
)
I + A
χ
( )
=
− Growth percentage of ILs sample
(
)
2
From table 3, the percentage of inhibition was shown that the
IL05 was found the highest percentage in almost three fungi. The
main fact of this reason is to be noted that the halogen atom in
the anion molecule is the main fact. To test the anion effect on an-
tifungal activity of ILs, the formate, acetate, propanoate, butanoate,
and trifluoroacetate anion were used whereas the butanoate an-
ion can also show the antifungal activity more than formate, ac-
etate but less than propanoate. It was evaluated that anion has
slightly antifungal activity even the antibacterial activity was af-
fected the negative charge distribution of anion although the same
cation was attached for all ILs. It was summarized that increasing
the length of anion, the antifungal activity was increased while at-
taching electronegative atom (F) could show similar effect.
μ2
2η
ω =
( )
3. Results and Discussions
The protic Ionic Liquids (PILs) consists of Brønsted acid and
Brønsted base. In this study, the use acids, aliphatic carboxylic
acids, as anion in ILs have considered the Brønsted acid and or-
tho toluidine acting as cation in IL has recognized as Brønsted
based. According to that literature, the IL01-IL09 is called PILs, and
reported their computational and biological study with in-silico
study.
3.1. Antibacterial studies
3.3. Minimum inhibition concentration(MIC)
To evaluate the antibacterial activity of synthesized five ILs, well
diffusion method was performed for taking zone of inhibition in
mm scale without 8 mm hole of well for 1000mM for ortho tolu-
idinium based Ionic Liquids, and it was listed in table 1 while
the four Gram positive bacteria and Gram negative bacteria was
taken. It must be noted that there were no effect of the control
and starting material (ortho toluidine), and when it was converted
into ionic liquids by adding carboxylic acids, the antibacterial ac-
tivity was increased.
To explain the MIC, the zone of inhibition was accounted for
different concentrations, such as 1000 mM, 750 mM, 500 mM, 250
mM and 125 mM. These calculated results were plotted in view of
zone of inhibition touching at zero point called the MIC value. The
MIC was presented in table 4 against the Bacillus cereus(+) and
Escherichia coli(-) pathogens. It was found for the MIC for tested
ILs about ranging 500 mM to 125 mM, and it was the lowest mag-
nitude for IL05 and IL04 for bacteria.
4. Computational Approaches
From the table 1 and figure 2, it was shown that the zone of
inhibition of IL05 is maximum both of gram-positive and gram-
negative bacteria, showing about more than 20 mm while the IL04
was placed below the IL05 having about 17 mm. It could be con-
cluded that the alkyl chain has an effect on antibacterial activity
even the substituent group attaching with anion where electroneg-
ative atom (Fluorine) can show the height activity among others.
4.1. Optimized structure of ILs
The molecular structural geometry or stable configuration af-
ter optimization through computational functional of DFT, which
contains the values of the reactivity indices and biological activity,
is presented in the in figure 3 for nine ILs. The molecules belong
to the class asymmetry, and non-planar, and they have more than
one element of symmetry and the plane of the molecule with their
charge.
3.2. Antifungal activity
Regarding the antifungal analysis, the growth percentage com-
pared with the control was illustrated by following formula where
the growth percentage of control was 100%.
4.2. Chemical reactivity using HOMO and LUMO
The energy levels of the molecular orbitals using the terms,
HOMO and LUMO, provides in rank on the possible electronic tran-
Growth of fungi with ILs solution
%Growth percentage =
× 100
Growth of fungi without ILs solution as control
4

A. Kumer and M.W. Khan
Journal of Molecular Structure 1245 (2021) 131087
Table 2
Data of %, growth percentage against fungal
Zone of growth (in mm)
%, growth percentage
Aspergillus niger
Chemicals
Control
Aspergillus niger
24
Saccharomyces cerevisiae
Candida albicans
38
Saccharomyces cerevisiae
100%
Candida albicans
100 %
37
100 %
S. material
IL01
22
16
15
14
13
12
35
23
21
19
18
15
35
21
19
18
17
17
91.67%
66.67 %
62.50 %
58.33%
54.16%
50.00%
94.60 %
62.26%
56.75%
51.35%
48.65%
40.54%
92.10 %
55.26%
50.00%
47.36%
44.75%
44.75%
IL02
IL03
IL04
IL05
Table 3
Percentage of inhibition
Tested chemicals
Aspergillus niger
Saccharomyces cerevisiae
Candida albicans
Control
Staring material
IL01
0%
0%
0 %
8.33%
33.33%
37.50%
41.67%
45.84%
50.00%
5.40%
7.90%
37.25%
53.25%
48.65%
51.35%
59.46 %
44.74%
50.00%
52.25%
55.25%
55.25%
IL02
IL03
IL04
IL05
Fig. 3. Optimized structure of ILs
sition, electron upcast and downcast part in molecule which are
highlighted in figure 4. The larger value of the LUMO indicates the
easily attached to the protein of pathogens which has shown in
figure 5, and the colors: deep yellow is a positive value, and light
blue is a negative value. In addition, the HOMO is the region of
the molecule whereas the electrophilic group can be attached. En-
ergy difference between HOMO and LUMO orbital, known as en-
ergy gap, indicates the chemical stability for structure or molecules
which is listed in table 5, and greater value of energy gap indicates
lower chemical stability [75-83]. From the table 5, it has found that
the energy gap is about 6.579 kcal/mol to 5.329 kcal/mol, but IL04
showed the highest energy gap 8.144 kcal/mol.
To make a comparative study and alkyl chain effect on biologi-
cal study, the optimized alkyl chain and halogen atoms containing
ILs was designed. The hardness and softness are directly related
with Lewis acid and base and chemical stability. A small HOMO-
LUMO gap automatically means small excitation energies to the
manifold of excited states. The softness and hardness are listed in
table 5 where the softness are in 0.304, 0.375, 0.323, 0.245, 0.303,
0.297, 0.323, 0.304 and 0.335 and hardness are in 3.289, 2.664,
3.092, 4.072, 3.292, 3.358, 3.095, 3.286 and 2.981, respectively of
IL01 to IL09.
Electrophilicity index of a molecule reports to about the binding
ability of a compound with biomolecules, and the greater value of
5

A. Kumer and M.W. Khan
Journal of Molecular Structure 1245 (2021) 131087
Fig. 4. Orbital picture of HOMO and LUMO
Fig. 5. Docking interaction diagram of 2D and 3D
electrophilicity index of molecule demonstrated the higher bind-
ing capacity with proteins acting as an electrophilic species. The
obtained value of electrophilicity index is about 3.243 to 3.937 eV
while the larger value is for IL02 and second larger value is IL09.
Table 4
Specific value of MIC
Bacillus cereus(+)
1000 mM
750 mM
500 mM
250 mM
125mM
MIC mM
IL01
IL02
IL03
IL04
IL05
7
3
0
0
6
8
9
0
0
0
3
5
0
0
0
0
0
500
500
250
125
125
4.3. Molecular Docking
8
3
14
20
22
9
The foremost undertaking of docking study has employed to in-
vestigate the possible interaction between ligands (ILs) and macro-
molecules, such as Bacillus cereus (+), Escherichia coli (-), and As-
pergillus niger (fungi).The protein pocket, hydrogen bonding and
2D diagram have showed in figure 5, S2 and S3, and their binding
affinity with these pathogens in table 6. It already was established
that the binding affinity of standard drug is almost 6.0 kcal/mol
or above [84, 85]. From the table 6, it is shown that the starting
11
14
Escherichia coli(-)
IL01
IL02
IL03
IL04
IL05
13
13
14
18
20
8
4
0
3
7
8
0
0
0
3
3
0
0
0
0
0
250
500
250
125
125
6
8
12
12
6

A. Kumer and M.W. Khan
Journal of Molecular Structure 1245 (2021) 131087
Table 5
Data for HOMO LUMO and chemical reactivity parameters
Chemical descriptors
IL01
IL02
IL03
IL04
IL05
IL06
IL07
IL08
IL09
HOMO, eV
-7.909
-1.330
6.579
7.909
1.330
3.289
0.304
4.619
-4.619
3.243
-7.245
-1.916
5.329
7.245
1.916
2.664
0.375
4.580
-4.580
3.937
-7.598
-1.414
6.184
7.598
1.414
3.092
0.323
4.506
-4.506
3.283
-8.704
-0.560
8.144
8.704
0.560
4.072
0.245
4.632
-4.632
2.634
-8.243
-1.659
6.584
8.243
1.659
3.292
0.303
4.951
-4.951
3.723
-7.748
-1.031
6.717
7.748
1.031
3.358
0.297
4.389
-4.389
3.242
-7.827
-1.637
6.190
7.827
1.637
3.095
0.323
4.732
-4.732
3.617
-8.241
-1.668
6.573
8.241
1.668
3.286
0.304
4.954
-4.954
3.737
-7.747
-1.785
5.962
7.747
1.785
2.981
0.335
4.766
-4.766
3.809
LUMO, eV
LUMO–HOMO gap, eV
Ionization potential (I), eV
Electron affinity (A), eV
Chemical Hardness, (η), eV
Chemical Softness, (S), eV
Electronegativity, (χ), eV
Chemical Potential, (μ), eV
Electrophilicity Index, (ω),eV
Table 6
Docking score by interaction between ligand and macromolecule
Bacillus cereus(+)
Escherichia coli(-)
Binding affinity
Aspergillus niger (1ks5)
Binding affinity
Binding affinity
(kcal/mol)
No of H bond Total bonds
(kcal/mol)
No of H bond Total bonds
(kcal/mol)
No of H bond Total bonds
IL01
IL02
IL03
IL04
IL05
IL06
IL07
IL08
IL09
starting
-5.3
-5.7
-6.2
-5.9
-6.4
-5.8
-5.8
-5.3
-5.9
-2.8
0
07
03
06
04
06
08
07
07
06
03
-4.9
-5.1
-5.5
-5.2
-5.7
-5.6
-5.8
-5.8
-5.8
-2.9
00
02
05
01
02
06
03
03
02
00
07
05
10
05
06
09
07
07
06
03
-5.0
-5.2
-5.6
-5.5
-6.0
-5.5
-5.6
-5.6
-5.6
-2.7
03
03
03
02
04
03
03
03
02
00
04
05
05
04
09
05
07
07
06
04
01
00
00
03
05
03
03
02
00
material named aniline can show very poor binding affinity which
is about -2.8, -2.9, -2.7 kcal/mol. But it was increased almost two
times after converting into ortho toluidinium carboxylate ILs show-
ing in table 6. From the table 6, it is noted that IL05 illustrates the
highest binding affinity, which is more than 6.0 kcal/mol against
three pathogens although all are about slightly below 6.0 kcal/mol.
From the full analysis of table 6, containing docking score, it can be
summarized that alkyl chain of anion has a regular effect on bio-
logical activity with protein while fluorine atoms on anion (IL05)
can show the highest binding score.
illustrate the positive response for Human Intestinal Absorption,
Caco-2 Permeability and Blood Brain Barrier. In addition, the sub-
cellular localization is found at Lissome.
In case of toxicity shown in table S5, all ILs are non carcino-
genic molecules although they have medium water solubil-
ity, LogS, which have been changed with increasing alkyl
chain and found the maximum value for IL09. For case of
AMES toxicity, all can not show this toxicity except IL01, IL02
and IL03. They show the medium affinity to Acute Oral Tox-
icity, Oral Rat Acute Toxicity (LD50), Fish Toxicity pLC50 and
T.Pyriformis toxicity.
On the other hand, the orbital picture of H bonding, hydropho-
bicity, 2D diagram and molecular interaction shown in table S1,
and S2, it is clear that the hydrogen bonding, hydrophobic bond-
ing and van dar Waal force with protein are occurred for binding
as drug presented in figure 5. In case of IL05, showing higher bind-
ing affinity causes the extra halogen bond forming which are not
formed for other ILs. Moreover, IL04 can show the second high-
est binding affinity although there are not formed halogen bonds.
Though the halogen atoms are attached in the IL07, IL08 and IL09,
they can not form the halogen bond with proteins which lead a
vast contribution for making larger binding affinity.
5. Conclusion
The synthesis of ortho toluidinium carboxylate ILs is synthe-
sized with high yield without solvent just 24-30 hours stirring
by the acid-base neutralization. Afterward, the purification, ana-
lytical data of IR, UV and NMR give the supports for the confir-
mation of reaction and structure of the molecule. To estimate the
bioactivity of OTILs, the well diffusion methods was use while the
starting material was near to zero or very poor zone of inhibi-
tion as antimicrobial agent against all taken pathogens. But, there
were a huge change of antimicrobial activity of ILs from start-
ing, and the zone of inhibition was found almost 07 nm to 22
nm whereas the IL05 showed the highest antibacterial activity. In
case of antifungal activity, it was found that the antifungal activ-
ity was increased about 60% in term of zone of inhibition com-
pared with control, and IL05 illustrated the same result like an-
tibacterial. It could be said that the effect on alkyl chain of anion
on the antibacterial and antifungal activity of ILs had to be change
with increasing the length of anion although adding fluorine atom
with ethanoate anion can show the best result among tested ILs.
On the other hand, the theoretical investigation through compu-
tational approaches, the chemical reactivity and molecular dock-
ing score have been changed in a regular fashion on base their
chain length of anions. The chemical reactivity regarding the term
4.4. ADMET Study
The ADMET stands for absorption, distribution, metabolism, ex-
cretion and toxicity, which have been considered as
The crucial parts of any drug development program and essen-
tial for compliance with regulatory guidelines. It conveys a theoret-
ical model involved whole-animal to save time-consumption and
cost.
First of all, table-S3 conveys that all ILs are satisfied by Lipinski
rule, means that they have good binding affinity. The hydrophilic-
ity, logp, has been increased with increasing the alkyl chain and
attaching halogens atoms in anion.
All of ILs are negative response in P- I glycoprotein inhibitor, P-
II glycoprotein substrate, Renal Organic Cation Transporter, CYP450
2C9 Substrate and CYP450 1A2 Inhibitor listed table S4. But they
7

A. Kumer and M.W. Khan
Journal of Molecular Structure 1245 (2021) 131087
of LUMO-HOMO gap gradually increases with increasing the alkyl
chain, and found the highest in IL04, as well as the inverse ef-
fect was found for softness. According to molecular docking, with
increasing alkyl chain, the binding affinity was increased though
electronegative atoms fluorine could make the best docking score
rather than other halogen atoms, and the IL05 could show the su-
perior binding affinity against antimicrobial pathogens. Moreover,
it was estimated that halogen bond was created for IL05 not other
halogen containing ILs. However, halogen atom has a capacity to
form the interaction with protein of pathogens in anion of ILs.
From the AMDET study, it could be said that all of tested ILs are
non carcinogenic, low toxic with low water solubility.
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Declaration of Competing Interest
[21] Celso M.M.A. Santos, Joana Silva, Catarina Florindo, Alexandra Costa,
Željko Petrovski, Isabel
M Marrucho, Rui Pedrosa, Luís C Branco, An-
The authors declare that they have no conflict of interest. All
authors gave final approval for publication.
timicrobial activities of highly bioavailable organic salts and ionic liq-
uids from fluoroquinolones, Pharmaceutics 12 (2020) 694, doi:10.3390/
pharmaceutics12080694.
[22] João A.R.C.R. Dias, Maria Helena Fernandes, Ricardo Ferraz, Cristina Prudên-
cio, The anticancer potential of ionic liquids, ChemMedChem 12 (2017) 11–18,
doi:10.1002/cmdc.201600480.
Acknowledgement
I
am grateful to the Department of Chemistry, Bangladesh
[23] Ismail M. Hossain, Ajoy Kumer, Synthesis and characterization of ammonium
benzilate bioactive ionic liquids and their antimicrobial activity, Asian Journal
of Physical and Chemical Sciences 4 (2017) 1–13, doi:10.9734/AJOPACS/2017/
38386.
University of Engineering and Technology (BUET), Dhaka-1000,
Bangladesh, for all kind of supports. I am also grateful to Prof. Dr.
M. Abdur Rashid, Professor, Department of Pharmacy, University of
Dhaka, Dhaka, Bangladesh, for all kind of support for the working
of antimicrobial studies.
[24] Ismail M. Hossain, Ajoy Kumer, Synthesis and Characterization of Ammonium
Ionic Liquids and Their Antimicrobial and Computational Overview, Asian jour-
nal of chemical science 3 (2017) 1–10, doi:10.9734/AJOCS/2017/38877.
[25] M.I.K. Hossain, Synthesis and Characterization of Ammonium Benzilate Bioac-
tive Ionic Liquids and Their Antimicrobial Activity, Asian Journal of Physical
and Chemical Sciences 4 (2018) 1–13, doi:10.9734/AJOPACS/2017/38386.
[26] M.I. Hossain, Ajoy Kumer, Sayeda Halima; Begum, Synthesis and Characteriza-
tion of Ammonium Benzoate and Its Derivative Based Ionic Liquids and Their
Antimicrobial Studies, Asian journal of physical and chemical science 3 (2018)
1–9, doi:10.9734/AJOCS/2017/38877.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131087.
[27] M.I.K. Hossain, Synthesis and Characterization of Ammonium Ionic Liquids and
Their Antimicrobial and Computational Overview, Asian journal of chemical
science 3 (2018) 1–10.
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