Synthesis, characterization and antibacterial effect of diarylmethylamine-based imines

Article abstract of DOI:10.1016/j.molstruc.2020.128150

Firstly, starting from benzoic acid the diarylmethanone compound was synthesized. The diarylmethanone was converted to the corresponding oxime and then reduced to the diarylmethylamine compound. Four different imine compounds were obtained from the condensation of the diarylmethylamine compound with four different salicylaldehyde derivatives. Antimicrobial activities against Gram (+) and Gram (?) microorganisms (Staphylococcus aureus, Bacillus cereus as the Gram (+); Escherichia coli and Salmonella typhimurium as the Gram (?); and Candida albicans as the fungi) were investigated.

Full text of DOI:10.1016/j.molstruc.2020.128150

Journal of Molecular Structure 1214 (2020) 128150
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis, characterization and antibacterial effect of
diarylmethylamine-based imines
a
a
b
a, *
€
Sultan Onur , Muhammet Kose , Ferudun Koçer , Ferhan Tümer
a Chemistry Department, K. Maras Sutcu Imam Univ, TR-46100, K Maras, Turkey
b Bioengineering Sciences, K. Maras Sutcu Imam Univ, TR-46100, K Maras, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Firstly, starting from benzoic acid the diarylmethanone compound was synthesized. The diary-
lmethanone was converted to the corresponding oxime and then reduced to the diarylmethylamine
compound. Four different imine compounds were obtained from the condensation of the diary-
lmethylamine compound with four different salicylaldehyde derivatives. Antimicrobial activities against
Gram (þ) and Gram (ꢀ) microorganisms (Staphylococcus aureus, Bacillus cereus as the Gram (þ);
Escherichia coli and Salmonella typhimurium as the Gram (ꢀ); and Candida albicans as the fungi) were
investigated.
Received 27 January 2020
Received in revised form
26 March 2020
Accepted 28 March 2020
Available online 4 April 2020
Keywords:
© 2020 Elsevier B.V. All rights reserved.
Diarylmethylamine
Imine compounds
X-ray structure
Antibacterial activity
1. Introduction
high activity against tuberculosis, various viruses and HIV [17e19].
Also, many of the molecules containing the diarylmethylamine
In our days, the source of many active pharmaceutical agents are
laboratories. It has even become possible to synthesize many drugs
that can be obtained naturally. Pharmaceutical companies prefer
this way when it is cost effective. While the first drugs used
medically are simple molecules [1], it is now seen that more
complex active substances are used today [2,3]. Misuse of the active
substances has led to the increasing resistance of some microbes to
drugs [4e6]. In addition to combating harmful microbes, such
active substances should not cause any side effects in the body. In
order to overcome this situation, synthesis of new drug candidate
molecules has gained importance [7e10]. Human beings are
exposed to very different chemicals in daily life. These chemical
compounds can themselves be toxic or become toxic compounds as
a result of biotransformation within the organism [11]. It is thought
to cause mutation by making covalent bonds with proteins con-
taining eSH, eNH2 or eOH groups and macromolecules such as
RNA and DNA [12e15].
skeleton are currently used as pharmaceutical drugs. Examples
include Levocetirizine, Zyrtec, Solifenacin, Meclozin, etc. Found.
Moreover, the diarylmethylamine based compounds have been
shown to possess antimicrobial properties [20a]. Schiff base ligands
and metal complexes are used successfully in many fields such as
agricultural chemistry, medicine, optical and electrochemical sen-
sors [20b]. Imine derivatives and metal complexes are extremely
important compounds because of these effective properties. All of
these advantages emphasize that Schiff bases are pioneering
compounds in the pharmaceutical industry [21e25]. Nowadays, the
first step of pharmaceutical studies is the synthesis of target mol-
ecule(s). 2-Hydroxybenzaldehyde and its derivatives are widely
used for the synthesis of novel imine derivatives [26e28].
The aim of this study was to investigate the synthesis, structural
characterization and antimicrobial effects of new imine compounds
which could be drug candidate molecules. In order to investigate
the antimicrobial properties, diarylmethylamine-based imine
compounds (Scheme) have been synthesized. The hydroxy and
methoxy substitute groups on the phenyl ring have been found to
affect the biological properties of the Schiff base compounds. The
effect of the substitute groups on the antimicrobial activity was also
examined. The single crystals of the ligands 7a and 7d were ob-
tained from ethanol (7a) and ethylacetate/hexane (7d) solution by
the slow evaporation at room temperature and their molecular
Diarylmethylamines are important compounds because of their
pharmacological properties and easy availability [16]. In recent
years, diarylmethylamines have attracted attention due to their
* Corresponding author.
E-mail address: ftumer@ksu.edu.tr (F. Tümer).
https://doi.org/10.1016/j.molstruc.2020.128150
0022-2860/© 2020 Elsevier B.V. All rights reserved.

2
S. Onur et al. / Journal of Molecular Structure 1214 (2020) 128150
structures were examined by the X-ray diffraction studies. The
antimicrobial and antifungal properties of all compounds were
investigated.
FTIR: (nmax, cmꢀ1): 3435, 3021, 2917, 1632, 1583, 1503, 1469, 1368,
1281, 1229, 1172, 1122, 621.1H NMR (400 MHz, CDCl3,
ppm): 8.02
d
d
(s, 1H), 7.26e7.37 (m, 5H, ArH), 7.22 (d, J ¼ 8.1 Hz, 2H, ArH), 7.16 (d,
J ¼ 8.0 Hz, 2H, ArH), 6.92 (d, J ¼ 8.6 Hz, 1H, ArH), 6.44 (d, J ¼ 2.2 Hz,
1H, ArH), 6.30 (dd, J ¼ 8.6, 2.3 Hz, 1H, ArH), 5.63 (s, 1H, HC]N), 2.34
2. Experimental
(s, 3H, CH3). 13C NMR (100 MHz, CDCl3,
d ppm): 168.73, 163.28,
2.1. Materials and measurements
163.05, 163.04, 141.75, 138.59, 137.43, 134.16, 129.53, 128.81, 127.60,
127.41, 111.57, 107.87, 104.19, 72.93, 21.07. Anal. Calcd for
All reagents and solvents were of reagent-grade quality and
obtained from commercial suppliers (Aldrich or Merck) and used as
received, unless otherwise noted. Elemental analyses (C, H, N) were
performed using a Costech ECS 4010 (CHN). Infrared spectra were
obtained using KBr disc (4000-400 cmꢀ1) on a PerkinElmer Spec-
trum 100 FT-IR. 1H and 13C NMR spectra were recorded on a Bruker
400 MHz instrument and TMS was used as an internal standard.
C21H19NO2:C, 79.47; H, 6.03; N, 4.41. Found C, 79.35; H, 5.93; N, 4.37.
2.3. X-ray crystallography
X-ray crystallographic data for the compounds 7a and 7d were
collected at 293 (2) K on a Bruker D8 QUEST diffractometer using
Mo-K
a
radiation (
l
¼ 0.71073 Å). Data reduction was completed
using Bruker SAINT [32]. SHELXT 2018/2 was used to solve and
SHELXL-2018/3 to refine the structures [33]. The structures were
solved by direct methods and refined on F2 using all the reflections.
All the non-hydrogen atoms were refined using anisotropic atomic
displacement parameters and hydrogen atoms bonded to carbon,
nitrogen and oxygen atoms were inserted at calculated positions
using a riding model and refined with temperature factors. The
crystal data and refinement details are given in Table 1 and the rest
of the crystallographic data are given in the supplementary docu-
ments (Tables S1eS12).
2.2. General method for the synthesis of imine compounds (7a-d)
The synthesis of diarylmethanon 3, oxime 4 and diarylmethyl-
amine 5 were carried out using a method available in the literature
[29e31]. Phenyl (p-tolyl) methanamine (4 g; 20.27 mmol) was
dissolved in CH2Cl2 (30 mL). To this solution, potassium carbonate
(4 g; 29 mmol), 2-hydroxy-3-methoxy benzaldehyde (3.08 g;
20.27 mmol) and sodium sulfate (4 g; 28 mmol) were added
respectively, and stirred under nitrogen gas at room temperature
for 24 h. The progress of the reaction was controlled by TLC. The
solids in the reaction media were removed by filtration. After
removal of the solvent, the oily residue was filtered over silica gel
(10 g) with ethylacetate/hexane (1:9). The solvents were removed
and the product was crystallized from ethanol.
2.4. Preparation and cultivation of bacterial strains
The imine compounds were evaluated in vitro antibacterial and
antifungal activity against the Staphylococcus aureus, Bacillus cereus
as the gram (þ); Escherichia coli and Salmonella typhimurium as the
gram (ꢀ); and Candida albicans as the fungi. Antibiotics (Genta-
micin and amikacin) were used as positive control groups. The
susceptibility of a microorganism to antimicrobial agents and an-
tibiotics was determined by assay plates incubated at 37 ꢁC for
18e24 h for bacteria and 25 ꢁC for three days for yeasts. In the
antimicrobial activity studies, Malt Extract Agar (MEA) for the yeast
strain and Müeller Hinton Agar (MHA) for bacteria was used as a
stock medium. Bacteria standardized with 0.5 McFarland standard
was inoculated to sterile prepared petri dishes and incubated for
1 h at 37 1 ꢁC [30,31]. DMSO was used as control. Amikacin (AK:
7a: Yield 4.60 g (69%), color: Yellow. melting point:91e93 ꢁC.
FTIR: (nmax, cmꢀ1): 3423, 3025, 2956, 1624, 1460, 1381, 1334, 1253,
1081, 1048, 969, 838, 800, 775, 733, 694, 545.1H NMR (400 MHz,
CDCl3,
d ppm): 14.20 (s, 1H, phenolic OH), 8.65 (s, N]CH, 1H),
7.33e7.40 (m, 4H, ArH), 7.26e7.28 (m, 3H, ArH), 7.17 (d, J ¼ 8.0 Hz,
2H, ArH), 6.97 (dd, J ¼ 7.8, 1.5 Hz, 1H, ArH), 6.92 (dd, J ¼ 7.8, 1.5 Hz,
1H, ArH), 6.85 (t, J ¼ 7.8 Hz, 1H, ArH), 5.63 (s, 1H, HC]N), 3.95 (s,
3H, OCH3), 2.35 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3,
d
ppm):164.84, 151.60, 148.47, 142.75, 139.64, 137.12, 129.40, 128.69,
127.34, 123.19, 118.76, 118.18, 114.23, 76.25, 56.13, 21.07. Anal. Calcd
for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found C, 79.68; H, 6.41; N,
4.26.
30 mg) and Gentamicin (CN: 10 mg) were used as standards. The
7b: Yield 4.8 g (72%), color: Light yellow. melting point:
122e124 ꢁC. FTIR: (nmax, cmꢀ1): 3435, 2963, 2928, 2847, 1625, 1574,
1512, 1443, 1399, 1376, 1288, 1204, 1168, 1114, 1043, 1025, 963, 840,
antimicrobial activity of the imine compounds was determined
using Kirby-Bauer Disk Diffusion Method [34,35]. The imine com-
pounds (12.50 mg/mL) were dissolved in 10% DMSO and impreg-
813, 735, 700, 650, 524.1H NMR (400 MHz, CDCl3,
d
ppm) 14.10 (s,
nated with disks at a concentration of 25 mL to discs made of blank
1H, phenolic OH), 8.37 (s, N]CH, 1H), 7.38 (d, J ¼ 4.4 Hz, 4H, ArH),
7.26e7.32 (m, 3H, ArH), 7.16e7.20 (m, 3H, ArH), 6.53 (d, J ¼ 2.3 Hz,
1H, ArH), 6.47 (dd, J ¼ 8.5, 2.4 Hz, 1H, ArH), 5.60 (s, 1H, HC]N), 3.85
(s, 3H, OCH3), 2.37 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3,
sterile whatman papers of 6 mm diameter. Prepared discs were
placed on the cultivation of bacteria in the MHA. Discs were placed
on planted cultures of bacteria in MHA and yeast strains in MEA.
Discs were incubated at 37
1
ꢁC for 18e24 2 h to determine
d
ppm):164.22,163.94,163.58,142.93,139.81,137.05,132.90,129.38,
inhibition zones [34e39]. The study was performed in three rep-
licates and the mean values were given.
The samples (7a-d) were 12.5 mg/mL,1.25 mg/mL and 0.125 mg/
mL dissolved in 10% DMSO to determine the minimum inhibitory
concentration (MIC) against Gram positive (þ), Gram negative (ꢀ)
bacteria and yeast strains and the value was determined.
128.66, 127.45, 127.29, 112.71, 106.52, 101.17, 75.78, 55.40, 21.09.
Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23. Found C, 79.71;
H, 6.32; N, 4.18.
7c: Yield 5.35 g (84%), color: Orange, melting point: 113e115 ꢁC.
FTIR: (nmax, cmꢀ1):3429, 3020, 2919, 2857, 1630, 1463,1380, 1273,
1205, 1084, 1045, 843, 800, 777, 724, 700, 537.1H NMR (400 MHz,
CDCl3,
d
ppm): 8.40 (s, N]CH, 1H), 7.16e7.42 (m, 11H, ArH and
3. Results and discussion
ArOH), 7.04 (dd, J ¼ 7.7, 1.6 Hz, 1H, ArH), 6.84 (dd, J ¼ 7.9, 1.5 Hz, 1H,
ArH), 6.77 (t, J ¼ 7.8 Hz, 1H, ArH), 5.71 (s, 1H, HC]N), 2.39 (s, 3H,
In the current work, four different imine compounds were
synthesized in order to investigate biological activities. The syn-
thesis of diaryl methylamine, which is the key molecule for the
synthesis of four new imine compounds, was carried out from
benzoic acid (Scheme). For this purpose, benzoic acid was first
converted to benzoyl chloride and then the corresponding ketone
CH3). 13C NMR (100 MHz, CDCl3,
d ppm): 164.71, 151.64, 145.62,
142.05, 138.91, 137.44, 129.54, 128.82, 127.60, 127.46, 126.90, 122.37,
118.13, 117.53, 116.96, 74.93, 21.11. Anal. Calcd for C21H19NO2:C,
79.47; H, 6.03; N, 4.41. Found C, 79.31; H, 6.24; N, 4.46.
7d: Yield 4.30 g (66%), color: orange, melting point: 167e169 ꢁC.

S. Onur et al. / Journal of Molecular Structure 1214 (2020) 128150
3
Table 1
X-ray crystallographic data for compounds 7a and 7d.
Compound
7a
7 d
Formulae
C22H21NO2
331.40
293 (2) K
0.71073 Å
Orthorhombic
Yellow
C21H19NO2
317.37
293 (2)
0.71073 Å
Triclinic
Orange
Molecular weight
Temperature
Wavelenght
Crystal system
Crystal color
Space group
Unit cell parameters
P212121
P-1
a ¼ 6.2645 (5) Å
a
¼ 90ꢁ
a ¼ 9.7556 (7) Å
a
¼ 88.664 (7)ꢁ
b ¼ 16.1190 (15) Å
b
¼ 90ꢁ
b ¼ 11.8979 (10) Å
c ¼ 15.3674 (14) Å
1746.2 (3)
4
b
g
¼ 78.304 (7)ꢁ
¼ 89.548 (6)ꢁ
c ¼ 18.0294 (16)Å
g
¼ 90ꢁ
Volume (Å3)
1820.6 (3)
Z
4
Density (calc.) (Mg/m3)
1.209
0.077
1.207
0.077
Absorption coefficient (mmꢀ1
Crystal size (mm3)
)
0.16 ꢂ 0.11 x 0.09
0.18 ꢂ 0.12 x 0.10
Ref. collected
7271
11,280
Indepent ref.
Final R values [I > 2 sigma(I)]
R indices (all data)
Completeness to
CCDC Number
4101 [Rint ¼ 0.0837]
7511 [Rint ¼ 0.0261]
R1 ¼ 0.0796, wR2 ¼ 0.1073
R1 ¼ 0.3036, wR2 ¼ 0.1702
99.7%
R1 ¼ 0.0955, wR2 ¼ 0.2177
R1 ¼ 0.1610, wR2 ¼ 0.2574
99.0%
q
¼ 25.242ꢁ
1,973,960
1,973,961
compound was synthesized with the aid of AlCl3/toluene. The tar-
geted phenyl (p-tolyl) methanamine molecule was synthesized by
converting the diarylmethanone compound to oxime and followed
by reduction to corresponding amine. The condensation of 5 with
salicylaldehyde derivatives, (2-hydroxy-3-methoxybenzaldehyde,
2-hydroxy-4-methoxybenzaldehyde 2,3-dihydroxybenzaldehyde,
and 2,4-dihydroxybenzaldehyde), gave four new imine compounds
(7a-d). After required purification, the structure of each molecule
was characterized using analytical and spectroscopic methods. The
elemental analysis data of the synthesized compounds are
consistent with the calculated values of the proposed structures.
(Scheme 1).
3.1. Spectroscopic characterization of the imine compounds
FT-IR spectra of the imine compounds were carried out and the
data are given in the experimental section. FT-IR spectra of the
compounds were given in the supplementary documents
(Figs. S1eS4). The broad peaks around 3400-300 cmꢀ1 are due to
the n(OH) stretchings. The bands observed at 1623, 1619, 1628 and
Scheme 1. Synthesis route of Schiff base ligands.

4
S. Onur et al. / Journal of Molecular Structure 1214 (2020) 128150
Table 2
of the new imine compounds were examined; Singlets for 7a,7b, 7c
Selected bond lengths (Å) and angles (ꢁ) for 7a and 7d.
and 7d observed at 8.49, 8.37, 8.40 and 8.02 ppm respectively are
the proton signals of the characteristic azomethine group (CH]N).
Singlets observed at 5.63, 5.60, 5.71 and 5.63 ppm in the spectra of
all ligands are dibenzylic proton signals adjacent to the imine
group, respectively. The methyl group in the structure of imine
compounds resonated as singlet at 2.35, 2.37, 2.39 and 2.34 ppm,
respectively. Singlets, which are seen at 3.95 and 3.80 ppm in 7a
and 7b spectra respectively, belong to OMe protons.
7a
7 d
N1eC14
O1eC20
C14eC15
O3eC41
N2eC35
C8eC7eC6
N1eC14eC15
C14eN1eC7
1.279 (9)
1.352 (9)
1.417 (10)
e
1.304 (5)
1.305 (4)
1.404 (5)
1.295 (4)
1.309 (4)
114.9 (4)
123.5 (4)
127.1 (4)
e
110.4 (8)
122.4 (9)
117.6 (7)
The 13C NMR spectra of the ligands appear to be in complete
agreement with the proposed structures. The characteristic imine
carbons resonated at 164.84, 163.94, 164.85 and 163.28 ppm,
respectively. The other carbon atoms of 7a-d compounds resonated
between 168.07 and 21.07 ppm.
1627 cmꢀ1 are characteristic signals of the imine groups. The
absence of the carbonyl group stretchings of the starting salicy-
laldehyde derivatives also confirmed the formation of the imine
compounds.
3.2. X-ray structure solution and refinement of 7a and 7 d
In the 1H NMR spectra of synthesized compounds (Figs. S5eS8),
especially the expected ortho and meta interactions in the salicy-
laldehyde ring can be seen very clearly. When the 1H NMR spectra
The single crystals of the compounds suitable for X-ray
diffraction experiments were obtained from slow evaporation of
Fig. 1. Molecular structures of 7d and 7a with atom numbering. Hydrogen bonds are shown as dashed lines. The hydrogen atoms bonded to carbon atoms are not shown for clarity
in 7d.

S. Onur et al. / Journal of Molecular Structure 1214 (2020) 128150
5
Table 3
Hydrogen bond parameters for 7a Ligand.
Compound
D-H … ∙A
d (D-H)
d (H … ∙A)
d (D … ∙A)
<(DHA)
7a
7d
O (1)eH (1) … ∙N (1)
O (2)eH (2) … ∙O (3)i
N (1)eH (1) … ∙O (1)
O (4)-H (4A) … ∙O (1)
N (2)-H (2B) … ∙O (3)
0.82
0.82
0.86
0.82
0.86
1.86
1.76
1.90
1.74
1.93
2.564 (9)
2.579 (4)
2.591 (4)
2.552 (4)
2.604 (4)
143.7
173.8
135.8
172.8
134.0
Symmetry transformations used to generate equivalent atoms: i: x-1,y,z.
Fig. 2. Packing diagram of 7d showing 1D OH … ∙O hydrogen bond chain.
ethanol for 7a and ethyl acetate-hexane mixture for 7d. Crystallo-
graphic data of are given in Table 1 and the selected bond lengths
and angles are given in Table 2. The X-ray data showed that com-
pound 7a crystalizes in the orthorhombic crystal system and P212121
space group, while compound 7 d is in the triclinic crystal system
and P-1 space group. Perspective view of the compounds are given
in Fig. 1. The asymmetric unit of 7d contains two crystallographi-
cally independent molecules. The two independent molecules
show similar bond lengths and angles with different dihedral an-
gles between the phenyl rings. In the structure of 7a, the imine
(N1eC14) bond distance of 1.279 (9) Å is within the range of
characteristic carbon nitrogen double bond (C]N). The compound
7a favors the phenol-imine tautomeric form in the solid state.
However, in the structure of 7d the imine bond [N1eC14 and
Fig. 3. CH … ∙∙
p
interactions in 7d.
Fig. 4. Packing diagram of 7a showing CH … ∙∙p and CH … ∙∙O interactions.

6
S. Onur et al. / Journal of Molecular Structure 1214 (2020) 128150
Table 4
Antimicrobial activity values of the bacteria and fungi (mm).
N2eC35] distances are longer than those characteristic C]N dis-
tances and phenolic [C20eO1 and C41eO3] bond distances are
shorter than phenolic CeO bond distances (Table 2). This suggests
that the compound 7d favors the keto-enol tautomeric form in the
solid state.
The compounds showed an expected phenol-imine and keto-
amine intramolecular hydrogen bonding. The compound 7d con-
tains second hydroxyl group which is involved in intermolecular
hydrogen bonding with the phenolic oxygen of an adjacent mole-
cule. The hydrogen bond parameters for 7a and 7d are listed in
Table 3. The intermolecular hydrogen bond contacts form a 1D
hydrogen bond chains as shown in Fig. 2. In the structure of 7d, no
phenyl-phenyl stacking interactions were observed and instead CH
strains, the change of the position of the hydroxy group in com-
pound 7d results in a sharp decline in the activity towards the same
microorganisms. However, compound 7d has considerable anti-
microbial activity against Salmonella typhimurium when compared
to the standard antibiotics (amikacin and gentamicin). All com-
pounds are almost no-toxic towards Staphylococcus aureus at the
concentration studied (12.50 mg/mL).
4. Conclusion
Four imine compounds (7a-d) were prepared by the Schiff base
condensation reaction of phenyl (p-tolyl) methanamine and 2-
hydroxy-3-methoxybenzaldehyde
(for
7a),
2-hydroxy-4-
… ∙∙p
interactions stabilize the structure of the compound (Fig. 3).
methoxybenzaldehyde (for 7b), 2,3-dihydroxybenzaldehyde (for
7c) and 2,4-dihydroxybenzaldehyde (for 7d) in dichloromethane.
Molecular structure of compounds7a and 7d were determined by
single crystal X-ray diffraction study. In the solid state, compound
7d exists in keto-amine tautomeric form. Antimicrobial activity
studies of the imine compounds were studied using the E. coli, S.
typhimurium, S. aureus, B. cereus, as bacteria and C. albicans as fungi.
Imine 7a showed the high activity against to the E. coli, 7c B. cereus
and 7d S. aureus while the ligand 7b do not showed the activity
towards the bacteria and fungi. Compound 7a and 7c showed the
good activity against to the C. albicans.
The molecules of 7a are linked by CH … ∙∙
p
and CH … ∙∙O in-
teractions. Packing diagram of 7a is shown in Fig. 4.
3.3. Biological activity findings
In the in vitro antimicrobial activity studies, we used the
Staphylococcus aureus and Bacillus cereus as the Gram (þ); Escher-
ichia coli and Salmonella typhimurium as the Gram (ꢀ); and Candida
albicans as the fungi. The antimicrobial activities of the ligands (7a-
d) used in the study were investigated by disc diffusion method
against Gram (þ), Gram (ꢀ) bacterial strains and Candida albicans
fungi. The results were compared with the standard antibiotics
amikacin and gentamicin. The observed antimicrobial activities of
the ligands are shown in Table 4. According to the findings, 7a
ligand showed significant activity against Escherichia coli and
Candida albicans strains, 7c ligand against Bacillus cereus and
Candida albicans strains and 7d ligand against Salmonella typhi-
murium strain. It was determined that ligand 7b showed no zone of
inhibition against the microorganisms used in the study. According
to the findings, an important point is that antifungal effect of 7a and
7c ligands against Candida albicans fungus (see Table 4). Com-
pounds 7a and 7b are isomers differing only in the position of the
methoxy groups on the phenol ring. The change of position of the
methoxy groups cause significant change in the activity of the
compounds. While compound 7a exhibits significant activity
against Escherichia coli, compound 7b has very low activity against
the all microorganisms studied. This may be due to the cell
permeation properties of these compounds that may be changed
with the position of the methoxy group. Similar results were
observed for compounds 7c and 7d. Although compound 7c in-
hibits the bacterial growth of Bacillus cereus and Candida albicans
CRediT authorship contribution statement
€
Sultan Onur: Investigation. Muhammet Kose: Data curation,
Software, Writing - review & editing. Ferudun Koçer: Investigation.
Ferhan Tümer: Supervision, Project administration, Writing -
original draft.
Acknowledgment
The authors are thankful to Scientific Research Projects Unit of K.
Maras Sütcü Imam University (Project code: BAP- 2017/6e34 M),
(Turkey). We would like to thank the Research council of Turkish
Council of Higher Education (YOK 100/2000) for the award of a
postgraduate scholarship (to SO).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2020.128150.

S. Onur et al. / Journal of Molecular Structure 1214 (2020) 128150
7
in vitro evaluation for antioxidant and antibacterial properties of diary-
lmethylamines: a novel class of structurally simple and highly potent phar-
macophore, Eur. J. Pharmaceut. Sci. 88 (2016) 202e209;
b) E. Yildiz, M. Kose, M. Tumer, S. Purtas, F. Tumer, Thiophene based imine
compounds: structural characterization, electrochemical, photophysical and
thermal properties, J. Mol. Struct. 1150 (2017) 55e60.
Authors declare no conflict of interests for this article.
References
[1] M. Betti, On the addition of amine benzal to the naphtole, Gazz. Chim. Ital. 30
(1900) 301e309.
[2] W. Erb, J. Zhu, From natural product to marketed drug: the tiacumicin odys-
sey, Nat. Prod. Rep. 30 (2013) 161e174.
[21] G.Y. Yeap, S.T. Ha, N. Ishizawa, K. Suda, P.L. Boey, W.A.K. Mahmood, Synthesis,
crystal structure and spectroscopic study of para substituted 2-hydroxy-3-
methoxybenzalideneanilines, J. Mol. Struct. 658 (1) (2003) 87e99.
[22] F. Cesare, G. Düsing, W. Lürken, Reaktionen der organischenSynthese: 2700
[3] A. Bedeschi, P. Fonte, G. Fronza, C. Fuganti, S. Serra, The co-identity of lip-
iarmycin A3 and tiacumicin B, Nat. Prod. Commun. 9 (2014) 237e240.
[4] A.J. Alanis, Resistance to antibiotics: are we in the post-antibiotic era? Arch.
Med. Res. 36 (2005) 697e705.
[5] S.B. Levy, B. Marshall, Antibacterial resistance worldwide: causes, challenges
and responses, Nat. Med. 10 (2004) 122e129.
€
technische und praparativeHerstellungs-und Umwandlungsreaktionen, Georg
ThiemeVerlag, 1978.
[23] K. Othmer, Encyclopedia of Chemical Technology, vol. 16, Wiley, 1938,
pp. 795e804.
[24] S. Helmut, Metal Ions in Biological Systems, vol. 5, Marcel Dekker Inc, 1976,
pp. 2e50.
[25] C.M. Metzler, A. Cahill, D.E. Metzler, Equilibriums and absorption spectra of
Schiff bases, J. Am. Chem. Soc. 102 (19) (1980) 6075e6082.
[26] A. Akbari, H. Ghateazadeh, R. Takjoo, B. Sadeghi-Nejad, M. Mehrvar,
J.T. Mague, Synthesis & crystal structures of four new biochemical active Ni(II)
complexes of thiosemicarbazone and isothiosemicarbazone-based ligands:
in vitro antimicrobial study, J. Mol. Struct. 1181 (2019) 287e294.
[27] M. Azarkish, A. Akbari, T. Sedaghat, J. Simpson, Heteroleptic complexes of
[6] P.M. Wright, I.B. Seiple, A.G. Myers, The evolving role of chemical synthesis in
antibacterial drug discovery, Angew. Chem. Int. Ed. 53 (2014) 8840e8869.
[7] B.P. Mathew, A. Kumar, S. Sharma, P.K. Shukla, M. Nath, An eco-friendly
synthesis and antimicrobial activities of dihydro-2H-benzo- and naphtho-
1,3-oxazine derivatives, Eur. J. Med. Chem. 45 (2010) 1502e1507.
[8] P.S. Jogi, J.S. Meshram, J. Sheikh, Synthesis and evaluation of antimicrobial
activity of novel oxazine derivatives using Betti’s protocol, Lett. Drug Des.
Discov. 10 (2013) 283e288.
€
Zn(II)
based
on
1-(5-bromo-2-hydroxybenzylidene)-4-
[9] A. Krizsan, D. Volke, S. Weinert, N. Strater, D. Knappe, R. Hoffmann, Insect-
phenylthiosemicarbazide: synthesis, structural characterization, theoretical
studies and antibacterial activity, J. Mol. Struct. 1134 (2017) 126e134.
[28] M. Azarkish, A. Akbari, T. Sedaghat, J. Simpson, Ternary complexes of Zn(II)
derived proline-rich antimicrobial peptides kill bacteria by inhibiting bacterial
protein translation at the 70S ribosome, Angew. Chem. Int. Ed. 53 (2014)
12236e12239.
and
Cu(II)
with
1-((2-hydroxynaphthalen-1-yl)methylene)-4-
[10] H.N. Chopde, J.S. Meshram, C.P. Pandhurnekar, R. Pagadala, S.B. Jonnalagadda,
Efficient synthesis, characterization, in vitro antibacterial and antifungal ac-
tivity study and computational tool for prediction of molecular properties of
some novel Schiff’s base via Betti’s protocol and azetidinones, J. Heterocycl.
Chem. 53 (3) (2016) 824e831.
[11] K. Al-Sabti, C.D. Metcalfe, Fish micronuclei for assessing genotoxicity in water,
Mutat. Res. 343 (1995) 121e135.
[12] M. Hollstein, J. McCann, F.A. Angelosanto, W.W. Nichols, Short-term tests for
carcinogens and mutagens, Mutat. Res. Rev. Genet. Toxicol. 65 (3) (1979)
133e226.
phenylthiosemicarbazide in the presence of heterocyclic bases as auxiliary
ligands: synthesis, spectroscopic and structural characterization and anti-
bacterial activity, J. Mol. Struct. 1156 (2018) 34e42.
[29] F. Tumer, S. Goksu, H. Secen, First synthesis of (þ/-)-vertilecanin A, Russ.
Chem. Bull. 54 (2005) 2466e2467.
€
€
[30] M. Karabork, H. Kirpik, K. Sayin, M. Kose, New diazo-containing phenolic
oximes: structural characterization, computational studies, and solvent
extraction of Cu(II), Ni(II), and Zn(II) ions, Turk. J. Chem. 43 (2019) 197e212.
[31] A.P.E.X.2 Bruker, Saint, Bruker AXS Inc., 1998;
b) Bruker, Bruker Sadabs, AXS Inc., Madison, WI, 2009.
[32] a) G.M. Sheldrick, A short history of SHELX, ActaCrystallogr. Sect. A 64 (2008)
112e122;
[13] N.J. van Sittert, G. de Jong, Biomonitoring of exposure to potential mutagens
and carcinogens in industrial populations, Food Chem. Toxicol. 23 (1985)
23e31.
b) G.M. Sheldrick, SHELXTeIntegrated space-group and crystal-structure
determination, Acta Crystallogr. 71 (2015) 3e8.
[33] X.J. Du, Q. Bian, H.X. Wang, S.J. Yu, J.J. Kou, Z.P. Wang, Z.M. Lia, W.G. Zhao,
Design, synthesis, and fungicidal activity of novel carboxylic acid amides
represented by N-benzhydrylvalinamode carbamates, Org. Biomol. Chem. 12
(2014) 5427e5434.
[34] CLSI, Performance standards for antimicrobial disk susceptibility tests
approved standard, in: CLSI Document M02-A11, seventh ed., Clinical and
Laboratory Standards Institute, Wayne, Pennsylvania 19087, USA, 2012, 950
West Valley Road, Suite 2500.
[35] M. Balouiri, M. Sadiki, S.K. Ibnsouda, Methods for in vitro evaluating antimi-
crobial activity: a review, J. Pharmaceut. Biomed. Anal. 6 (2016) 71e79.
[36] A.W. Bauer, W.M. Kirby, J.C. Sherris, M. Turck, Antibiotic susceptibility testing
by a standardized single disk method, Am. J. Clin. Pathol. 45 (1966) 493e496.
[37] P.R. Murray, E.J. Baron, M.A. Pfaller, F.C. Tenover, R.H. Yolken, Manual of
Clinical Microbiology, seventh ed., ASM, Washington DC, 1999.
[38] A.P. David, J.P. McCuen, Manual of BBL Products and Laboratory Procedures,
sixth ed., U.S.A, 1988, pp. 67e72.
[14] P.T. Henderson, R.V. Doorn, C.M. Leıjdeker, R.P. Bos, Excretion of thioethers in
urine after exposure to electrophilic chemicls, IARC Sci. Publ. 59 (1984)
173e187.
[15] A.D. Dayan, Monitoring human exposure to carcinogenic and mutagenic
agents, J. Clin. Pathol. 39 (3) (1986) 347.
[16] S. Mahato, A. Singh, L. Rangan, C.K. Jana, Synthesis, in silico studies and in vitro
evaluation for antioxidant and antibacterial properties of diarylmethyl-
amines: a novel class of structurally simple and highly potent pharmaco-
phore, Eur. J. Pharmaceut. Sci. 88 (2016) 202e209.
[17] V. Summa, A. Petrocchi, V.G. Matassa, C. Gardelli, E. Muraglia, M. Rowley,
O.G. Paz, R. Laufer, E. Monteagudo, P. Pace, 4,5-Dihydroxypyrimidine car-
boxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent,
selective HIV integrase inhibitors with good pharmacokinetic profiles in
preclinical species, J. Med. Chem. 49 (2006) 6646e6649.
[18] M. Gerlach, C. Maul, Substituted 1 and 2-naphthol Mannich Bases, 2004,
US20040147570.
ꢀ
ꢀ
ꢀ
ꢀ
€
ꢀ
[19] N. Gyemant, H. Engi, Z. Schelz, I. Szatmari, D. Toth, F. Fülop, J. Molnar,
P.A.M. de Witte, In vitro and in vivo multidrug resistance reversal activity by a
Betti-base derivative of tylosin, Br. J. Canc. 103 (2010) 178e185.
[39] L.J. Bradshaw, Laboratory microbiology, in: Acta Crystallographica Section A
Foundations and Advances, fourth ed., 1992, p. 435. Printed in U.S.A.
[20] a) S. Mahato, A. Singh, L. Rangan, C.K. Jana, Synthesis, in silico studies and