Evaluation of Novel N -(Dibenzylcarbamothioyl)benzamide Derivatives as Antibacterial Agents by Using DFT and Drug-Likeness Assessment

Article abstract of DOI:10.1155/2018/9176280

Isomers of monothioureas, 2a-2d, derived from the reaction of disubstituted benzoyl isothiocyanate and dibenzylamine were synthesised and characterised by using elementary analysis CHNS and IR, ¹H NMR, and ¹³C NMR spectroscopies. The compounds were screened for their in vitro antibacterial activity by using selected Gram-positive bacteria, and moderate inhibition activity was displayed for compound 2b with the value of inhibition zone 11 ± 0.8 mm at a concentration of 50 mg/ml. The outcomes of Lipinski's rule of five assessment appeared to be in agreement with all compounds as they adhered to most of the rules, in which they can be preliminarily classified as active drug-like. The frontier molecular orbitals (HOMO and LUMO) for halogen-substituted 3,4-dichloro (2a) and 3,4-difluoro (2b) were also determined by applying the computational method of density functional theory (DFT) to determine their relationship as a molecular descriptor in antibacterial activities. The value of LUMO energy for compound 2b (1.8229 eV) is lower than that of compound 2a (1.8492 eV) which indicates higher antibacterial activities.

Full text of DOI:10.1155/2018/9176280

Hindawi
Journal of Chemistry
Volume 2018, Article ID 9176280, 5 pages
https://doi.org/10.1155/2018/9176280
Research Article
Evaluation of Novel N-(Dibenzylcarbamothioyl)benzamide
Derivatives as Antibacterial Agents by Using DFT and
Drug-Likeness Assessment
,
2
HudaMisral,1 SuhailaSapari,1 TajudinRahman,1 NazlinaIbrahim ,1 BohariM. Yamin,1
and Siti Aishah Hasbullah
1
1School of Chemical Sciences and Food Technology, Faculty of Science and Technology, National University of Malaysia,
43600 Bangi, Selangor, Malaysia
2Faculty of Science & Technology, University Sains Islam Malaysia (USIM), Bandar Baru Nilai, 71800 Nilai, Negeri Sembilan,
Malaysia
Correspondence should be addressed to Siti Aishah Hasbullah; aishah80@ukm.edu.my
Received 12 July 2018; Revised 25 September 2018; Accepted 25 October 2018; Published 22 November 2018
Academic Editor: Henryk Kozlowski
Copyright © 2018 Huda Misral et al. +is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Isomers of monothioureas, 2a–2d, derived from the reaction of disubstituted benzoyl isothiocyanate and dibenzylamine were
synthesised and characterised by using elementary analysis CHNS and IR, 1H NMR, and 13C NMR spectroscopies. +e
compounds were screened for their in vitro antibacterial activity by using selected Gram-positive bacteria, and moderate
inhibition activity was displayed for compound 2b with the value of inhibition zone 11 0.8 mm at a concentration of
50 mg/ml. +e outcomes of Lipinski’s rule of five assessment appeared to be in agreement with all compounds as they adhered
to most of the rules, in which they can be preliminarily classified as active drug-like. +e frontier molecular orbitals (HOMO
and LUMO) for halogen-substituted 3,4-dichloro (2a) and 3,4-difluoro (2b) were also determined by applying the com-
putational method of density functional theory (DFT) to determine their relationship as a molecular descriptor in antibacterial
activities. +e value of LUMO energy for compound 2b (1.8229 eV) is lower than that of compound 2a (1.8492 eV) which
indicates higher antibacterial activities.
many derivatives in new compounds [5]. Oxygen, nitro-
gen, and sulphur atoms of thiourea derivatives provide
a multitude of bonding possibilities that may contribute
to a broad spectrum of thiourea applications in the
pharmaceutical field, such as antiparasitic, anticancer,
antioxidant, antibacterial, antifungal, antimalarial, and
anti-HIV [6–8]. Furthermore, Mandava et al. explained in
his research that the amide and indole groups at the moiety
of thiourea showed considerable interaction with active
site amino acid of ribosyltranferase [9]. In the literature
survey and to the best of our knowledge, the disubstituted
carbonyl thiourea derived from the secondary amines is
still in scarcity [10].
1. Introduction
In recent times, the occurrence of microbial infections has
tremendously raised in many countries around the world
due to antimicrobial resistance [1]. +is phenomenon has
led to the design of novel antimicrobial as well as antibiotic
divergent from the current classes of compounds [2].
Specifically, the growth of the new classes of antibacterial
agents and modification to the known drugs must be
conducted in such a way that would induce them to
preserve their physiological action, but a reduction in their
resistance towards the agents [3]. +iourea is known as
a versatile compound that has been intensely synthesised
due to its ability to undergo structural modification [4].
Having two units of reactive primary amine group has led
thiourea to be a suitable precursor for the synthesis of
In this study, the synthesis and characterisation of novel
disubstituted carbonyl monothioureas (Figure 1) are re-
ported after conducting related antibacterial screening. +e

2
Journal of Chemistry
1186. 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 4.68, 5.24 (s,
4H, 2 × C-H2); 7.19–7.90 (m, 8H, Ar-H); 11.08 (s, 1H, NH).
13C NMR (DMSO-d6, 150 MHz) δ (ppm): 56.2, 55.2 (2 ×
CH2), 118.2–153.5 (Ar-C), 162.8 (CꢀO), 183.4 (CꢀS).
DMSO (100%) as the
negative control
3.13 mg/ml
2.2.2. 3,4-Dichloro-N-(dibenzylcarbamothioyl)benzamide
(2b). Percentage of yield, 65%; Mp: 365.4–366.5°C, (found:
C, 62.80; H, 4.77; N, 7.91%; C22H18Cl2N2OS requires C,
50.0 mg/ml
−1
61.54; H, 4.22; N, 6.53%); IR (KBr pellets) ] (cm ): 3171,
1697, 1185. 1H NMR (DMSO-d6, 600 MHz): δ 4.71, 5.24 (2 ×
s, 4H, CH2); δ 7.05–7.87 (8 × m, 8H, Ar); δ 8.54 (s, 1H, NH).
13C NMR (DMSO-d6, 150 MHz): δ 56.9, 55.9 (2 × CH2), δ
126.9–135.6 (Ar), δ 162.4 (CꢀO), δ 180.6 (CꢀS) [12].
6.25 mg/ml
25.0 mg/ml
12.5 mg/ml
2.2.3. 2-Chloro-4-ꢁuoro-N-(dibenzylcarbamothioyl)benza-
mide (2c). Percentage of yield, 70%; Mp: 366.4–367.3°C,
(found: C, 64.03; H, 3.71; N, 7.94%; C22H18Cl2N2OS requires
Figure 1: Antibacterial activity of compound 2b towards bacte-
rium Bacillus subtilis.
−1
C, 64.00; H, 4.40; N, 6.79%); IR (KBr pellets) ] (cm ): 3271,
1702, 1189. 1H NMR (DMSO-d6, 600 MHz): δ 4.83, 5.20 (2 ×
s, 4H, CH2); δ 7.22–7.94 (8 × m, 8H, Ar); δ 11.29 (s, 1H, NH).
13C NMR (DMSO-d6, 150 MHz): δ 55.9, 55.2 (2 × CH2), δ
114.9–162.2 (Ar), δ 163.8 (CꢀO), δ 182.4 (CꢀS).
frontier molecular orbitals (HOMO and LUMO) were also
determined via the computational method of DFT to de-
termine their relationship as a molecular descriptor in an-
tibacterial activities.
2.2.4. 2-Chloro-5-ꢁuoro-N-(dibenzylcarbamothioyl)benza-
mide (2d). Percentage of yield, 63%; Mp: 366.3–367.5°C,
(found: C, 64.75; H, 4.84; N, 6.91%; C22H18Cl2N2OS requires
2. Experimental
2.1. Physical Measurement. All synthesis processes were
carried out by using the conventional method of reux, and
no preventative measure was taken to exclude air or moisture.
Chemical and solvents were purchased from Sigma-Aldrich
or Merck and directly used without further puri‚cation.
Infrared spectra were recorded by using FTIR Perkin Elmer
−1
C, 64.00; H, 4.40; N, 6.79%); IR (KBr pellets) ] (cm ): 3179,
1708, 1190. 1H NMR (DMSO-d6, 600 MHz): δ 4.81, 5.20 (2 ×
s, 4H, CH2); δ 7.14–7.42 (8 × m, 8H, Ar); δ 8.70 (s, 1H, NH).
13C NMR (DMSO-d6, 150 MHz): δ 56.3, 55.9 (2 × CH2), δ
117.7–134.6 (Ar), δ 161.9 (CꢀO), δ 180.4 (CꢀS) [13].
−1
Model Spectrum GX in the range of 400–4000 cm . Že
1H NMR and 13C NMR spectra of the samples were veri‚ed
by using a spectrometer NMR model Joel EX 400 MHz in
d6-DMSO4.
2.3. Computational Method. Computational-assisted ge-
ometry optimisation, conformational analysis, and total
energy calculation were carried out in the gas phase with
Gaussian 09 suite of program using Beck’s three-parameter
hybrid method, B3LYP, with 6-31G (d, p) basis set to gain
better comprehension regarding the molecular structure of
the thiourea derivatives [14, 15].
2.2. General Synthesis of ꢀiourea Derivatives. A mixture of
disubstituted 3,4-diuorobenzoyl chloride (1a) (0.317 g,
0.0018 mol) and NH4SCN (0.1370 g, 0.0018 mol) in 10 ml
acetone was stirred at room temperature for 15 minutes.
Že mixture was ‚ltered and directly uses “in situ” into
a round bottom ask containing dibenzylamine (0.355 g,
0.0018 mol). Že solution was reuxed for 3 hours [11]. Že
solution was ‚ltered and poured into a beaker containing
ice cubes to form a precipitate, which was then ‚ltered, and
the precipitate was proceeded for characterisation. Že
procedure was repeated for the synthesis of 2b–2d using
3,4-dichlorobenzoyl chloride (1b) (0.377 g, 0.0018 mol), 2-
chloro-4-uorobenzoyl chloride (1c) (0.0.612 g, 0.0018 mol),
and 2-chloro-5-uorobenzoyl chloride (1d) (0.3430 g,
0.0018 mol).
2.4. Antibacterial Screening. Antibacterial screening was
carried out using the disc diªusion technique with strains
of bacteria from Gram-positive bacteria (Staphylococcus
aureus, Enterococcus faecalis, and Bacillus subtilis). Že
control positive was chloramphenicol (50 mg/ml), while
DMSO (100% of concentration) was the control negative.
Že bacteria were cultured in nutrient broth and left
for 18–24 hours to grow. Že nutrient agar and nutrient
broth were in aseptic condition to prevent the bacteria from
air, which may aªect the results. Že thioureas were dis-
solved in DMSO with 5 diªerent concentrations: 50 mg/ml,
25 mg/ml, 12.5 mg/ml, 6.25 mg/ml, and 3.125 mg/ml.
Žen, the single colony of bacteria was picked from the
nutrient agar and placed into the nutrient broth. By using
a micropipette, 5 μl of each compound with diªerent
concentrations was dropped onto the ‚lter paper (6 mm
2.2.1. 3,4-Diꢁuoro-N-(dibenzylcarbamothioyl)benzamide
(2a). Percentage yield, 74%; Mp: 365.7–366.3°C, (found: C,
63.08; H, 4.42; N, 6.54%; C22H18F2N2OS requires C, 66.65;
−1
H, 4.58; N, 6.54%); IR (KBr pellets) ] (cm ): 3170, 1690,

Journal of Chemistry
3
Table 1: Antibacterial screening of compounds 2a, 2b, 2c, and 2d.
increases, the lipophilicity interaction increases and as
a result, penetration of the compounds into the bacterial
membrane is eased [19]. Furthermore, the position of the
chlorine atom at the meta-para (2b) position generally
correlates well but not for ortho-substituted ones (2c and 2d)
due to the ortho steric effect and ortho polar effects which
resulted to no antibacterial activity for compounds 2c and 2d
that in contrast to 2b [20].
Besides, in reference to Lipinski’s rule of five regarding
drug-likeness, all of the compounds appeared to adhere to
most of the rules with only one violation, where lip-
ophilicity (log P) value exceeded 5 (Table 2). +is, however,
concludes that compounds 2a–2d can be classified as drug-
like [21]. +e evaluation of Lipinski’s rule on the desig-
nated compound is crucial as the preliminary study on the
ability of the compound to act as a drug, which then can be
further carried out and tested in various related analyses.
In detail, thiourea 2b displayed the highest lipophilicity
value (6.6), when compared to 2a, 2c, and 2d which is 5.8
that corresponded to the result of antibacterial analysis.
+e higher the lipophilicity, the higher is the inhibition of
the compound towards the bacteria. Further structural
modification, including changing of substituents group,
might be necessary for the other compounds 2a, 2c, and 2d
to refine their ability as antibacterial agents for them to
display exceptional criteria as a drug from Lipinski’s rule
evaluation.
In addition, this antibacterial study is also supported by
the computational calculation of density functional theory
(DFT) at level theory of hybrid functional B3LYP/6-31G (d,
p) basis set method to determine the band gap energy of
HOMO-LUMO and the value of LUMO energy. +e
comparative study was conducted between (3,4-dichloro) 2a
and (3,4-di-fluoro) 2b which have similar position for
halogen substituted. +e results reported in Table 3 show
that the value of the LUMO energy for compound 2b
(1.8229 eV) is lower than that of 2a (1.8492 eV), which is in
agreement to the antibacterial result. Compound 2b
exhibited higher antibacterial activity, when compared to
compound 2a, as tabulated in Table 1. +is is related to the
lowest energy value of LUMO for compound 2b, which
contributed to its higher antibacterial activity as well as the
size of the halogen (Cl) substituent [17, 22]. +e collected
data from the frontier molecular orbitals (HOMO-LUMO)
analysis of thioureas 2a and 2b are recorded in Table 3 and
illustrated in Figure 2.
Gram-positive bacteria
(mm)/concentration of sample (mg/mL)
Compound
Staphylococcus Enterococcus
Bacillus
subtilis
aureus
faecalis
2a
2b
—
—
—
11 0.8
(50 mg/ml)
—
8
0.4
—
(50 mg/ml)
—
2c
2d
—
—
—
—
Positive control
(chloramphenicol)
30.1 0.0
(50 mg/ml)
20.0 0.0
(50 mg/ml) (50 mg/ml)
32.8 0.0
“—” denotes no activity.
diameter). +e inhibition result of the bacteria was noted
after 18–24 hours of incubation at 37°C–48°C. +e bacteria
tests were performed in triplicate, and the results are shown
in Table 1 [16].
3. Results and Discussion
+e compounds 2a–2d were synthesised in good yield
(63–74%) by the reaction between disubstituted benzoyl
chlorides (1a–1d) and ammonium thiocyanate to give the
disubstituted benzoyl isothiocyanate as the intermediate
which is later to be reacted with dibenzylamine (Scheme 1).
+e formations of products were confirmed by NMR, IR,
and elemental analysis.
3.1. Antibacterial Analysis. +e activity of compounds
2a–2d against bacteria was observed after 24 hours of
inhibition at 37°C–42°C. At concentration of 25.0, 12.5,
6.25, and 3.13 mg/ml, the compound showed no inhibition
activity except for concentration of 50 mg/ml. Gram-
positive bacteria of Staphylococcus aureus and Bacillus
subtilis except Enterococcus faecalis exhibited positive re-
sults towards compound 2b, which contradicted to com-
pounds 2a, 2c, and 2d, as no inhibition was recorded,
as shown in Table 1. Figure 1 illustrates the antibacterial
activity of compound 2b towards bacteria Bacillus subtilis.
100% concentration of DMSO was used as a negative
control and shows no clear expansion which indicates no
inhibition of bacterial activity.
Overall, the synthesised compound 2b displayed a sig-
nificant inhibition activity compared to compounds 2a, 2c,
and 2d. It was clear from the study that the disubstituted
halogen compound (3,4-chloro, 2b) on the phenyl group
showed comparatively potent activity than the 3,4-fluoro
(2a), 2-chloro-4-fluoro (2c), and 2-chloro-5-fluoro (2d)
substituted. +is is due to the size of chlorine atom that is
bigger than that of fluorine, thus exerting a significant
impact on the London dispersion force and also the lip-
ophilicity [17, 18]. In general, the addition of halogen
substituents (in particular, Cl, Br, and I) increases the lip-
ophilicity of a molecule. Larger and heavier atoms or
molecules demonstrate stronger dispersion forces than
smaller and lighter ones. As the London dispersion force
4. Conclusion
+e compounds 2a–2d were successfully synthesised and
fully characterised via spectroscopic analyses. From the
antibacterial study, only thiourea 2b exhibited moderate
inhibition activity against selected Gram-positive bacteria,
which are 11
0.8 mm (50 mg/ml) towards bacteria
Staphylococcus aureus and 8 0.4 mm (50 mg/ml) towards
bacteria Bacillus subtilis, in comparison to chloramphen-
icol as the control positive. +eoretical calculation unveiled
that the antibacterial activity has some relationship with the
LUMO energy value. +e lower the LUMO value, the

4
Journal of Chemistry
O
O
R4
R3
R4
R3
O
S
NH4SCN
C S
N
Cl
NH
R4
R3
N
rt, acetone
15 min
N
H
R1
R1
Refux, 3 hr
R2
R2
R1
R2
1a, 1b, 1c, 1c
2a, 2b, 2c, 2d
1a = R1:H, R2:F, R3:F, R4:H
1b = R1:H, R2:Cl, R3:Cl, R4:H
1c = R1:Cl, R2:H, R3:F, R4:H
1d = R1:Cl, R2:H, R3:H, R4:F
Scheme 1: Reaction scheme to synthesis thiourea derivatives 2a, 2b, 2c, and 2d.
Table 2: Evaluation of Lipinski’s rule of ‚ve for compounds 2a, 2b, 2c, and 2d.
Lipinski rule/compounds
2a
5.8
2b
6.6
2c
5.8
2d
5.8
1
2
1. Log P (lipophilicity) < 5
2. Hydrogen bond donor < 5
1
1
1
3. Hydrogen bond acceptor < 10
4. Molecular weight < 500 g/mol
2
2
2
396.46
429.36
412.91
412.91
Table 3: List of HOMO-LUMO energy of compounds 2a and 2b.
Compounds
HOMO (eV)
LUMO (eV)
HOMO-LUMO (eV)
2a
2b
5.8295
5.9541
1.8492
1.8229
3.980
4.131
LUMO 2b
= 1.8229 eV
LUMO 2a
= 1.8492 eV
HOMO-LUMO
= 4.131 eV
HOMO-LUMO
= 3.980 eV
HOMO 2a
= 5.8295 eV
HOMO 2b
= 5.9541 eV
(a)
(b)
Figure 2: Frontier molecular orbitals (HOMO and LUMO) of thioureas 2a and 2b.
higher the antibacterial activity. Assessment from Lip-
inski’s rule of ‚ve depicted that all of the valuable com-
pounds can be classi‚ed as drug-like, thus suggesting an
exceptional starting point for the compounds to be ex-
plored in future development. Žis study oªers good in-
sight towards selective applications in the antibacterial ‚eld

Journal of Chemistry
5
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Data Availability
+e data used to support the findings of this study are
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Conflicts of Interest
+e authors declare that they have no conflicts of interest.
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Acknowledgments
+e authors would like to thank the School of Chemical
Sciences and Food Technology (PPSKTM), Universiti
Kebangsaan Malaysia, Centre of Research and Instrumen-
tation (CRIM), Ministry of Higher Education Malaysia for the
Ph.D SLAB Scholarship, and also to those who were involved
in the success of this research. +is study was conducted
under research grants GUP-2017-086 and DIP-2015-015.
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Volume 2018
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Journal of
Bioinorganic Chemistry
and Applications
Materials
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Volume 2018
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Volume 2018
International Journal of
Advances in
Journal of
International Journal of
BioMed
Tribology
Chemistry
Research International
Spectroscopy
Electrochemistry
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Volume 2018
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Volume 2018
Volume 2018
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Volume 2018
Volume 2018
Enzyme
Research
Journal of
Journal of
Biochemistry
Spectroscopy
Nanotechnology
Research International
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Volume 2018
Volume 2018
Volume 2018
Volume 2018