Antibacterial activities and DNA-cleavage properties of novel fluorescent imidazo-phenanthroline derivatives

Article abstract of DOI:10.1016/j.bioorg.2020.103885

Design and biological activities of fluorescent imidazo-phenanthroline derivatives; (E)-5-((4-((4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenoxy)methyl)benzylidene)amino)- isophthalicacid, 2 and 2-(4-(((5-chloroquinolin-8-yl)oxy)methyl)phenyl)-1H-imidazo[4,5f] [1,10]phenanthroline, 3, have been reported. Their characterizations were performed by spectroscopic techniques. Their promising photophysical behaviours were observed in absorbance and fluorescence studies. The antibacterial activities of the compounds were determined against seven different microorganisms; Bacillus subtilis ATCC 6633(G + ), Pseudomonas aeruginosa ATCC 29853(G-), Escherichia coli ATCC 35,218 (G-), Enterococcus faecalis ATCC 292,112 (G + ), Salmonella typhimurium ST-10 (G-), Streptococcus mutans NCTC 10,449 (G + ), and Staphylococcus aureus ATCC 25923(G + ). MIC values of 3 was determined as 156,25 μM on all tested bacteria. A preliminary study of the structure–activity relationship (SAR) also revealed that the antimicrobial activity depended on the substituents on the phenyl ring. The electron withdrawing Cl-substitued compound 3 most favour for antimicrobial activity even at lowest concentration compared to other compounds. DNA-cleavage activities of the compounds were also investigated. The interactions of the compounds with supercoiled pBR322 plasmid DNA were obtained by agarose gel electrophoresis. All imidazo-phenanthroline derivatives were found to be highly effective on DNA, even at the lowest concentrations because of their planar nature which provides ease of bind to the helix structure of DNA.

Full text of DOI:10.1016/j.bioorg.2020.103885

Bioorganic Chemistry 100 (2020) 103885
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Antibacterial activities and DNA-cleavage properties of novel fluorescent
imidazo-phenanthroline derivatives
a,⁎
b
c
c
Aslıhan Yılmaz Obalı , Sedef Akçaalan , Emine Arslan , İhsan Obalı
b
a
Department of Chemistry, Faculty of Science, Selcuk University, Turkey
Department of Molecular Biology and Genetics, Faculty of Science, Necmettin Erbakan University, Turkey
c
Department of Biology, Faculty of Science, Selcuk University, Turkey
A R T I C L E I N F O
A B S T R A C T
Keywords:
Design and biological activities of fluorescent imidazo-phenanthroline derivatives; (E)-5-((4-((4-(1H-imidazo
[4,5-f][1,10]phenanthrolin-2-yl)phenoxy)methyl)benzylidene)amino)-
Imidazo-phenanthroline
Schiff base
isophthalicacid, 2 and 2-(4-(((5-chloroquinolin-8-yl)oxy)methyl)phenyl)-1H-imidazo[4,5f] [1,10]phenan-
throline, 3, have been reported. Their characterizations were performed by spectroscopic techniques. Their
promising photophysical behaviours were observed in absorbance and fluorescence studies. The antibacterial
activities of the compounds were determined against seven different microorganisms; Bacillus subtilis ATCC
Chloro-quinoline
Antimicrobial activity
DNA cleavage activity
6
633(G + ), Pseudomonas aeruginosa ATCC 29853(G-), Escherichia coli ATCC 35,218 (G-), Enterococcus faecalis
ATCC 292,112 (G + ), Salmonella typhimurium ST-10 (G-), Streptococcus mutans NCTC 10,449 (G + ), and
Staphylococcus aureus ATCC 25923(G + ). MIC values of 3 was determined as 156,25 μM on all tested bacteria. A
preliminary study of the structure–activity relationship (SAR) also revealed that the antimicrobial activity de-
pended on the substituents on the phenyl ring. The electron withdrawing Cl-substitued compound 3 most favour
for antimicrobial activity even at lowest concentration compared to other compounds. DNA-cleavage activities
of the compounds were also investigated. The interactions of the compounds with supercoiled pBR322 plasmid
DNA were obtained by agarose gel electrophoresis. All imidazo-phenanthroline derivatives were found to be
highly effective on DNA, even at the lowest concentrations because of their planar nature which provides ease of
bind to the helix structure of DNA.
1
. Introduction
Heterocyclic organic molecules such as imidazoles, imidazo-phe-
of DNA [12,13]. These features tend to increase the attention and use of
imidazo-phenanthrolines in extensive sensor designs for ions or DNA
and as agents for anticancer, antibacterial, antifungal, antitumour and
antiflammatory drugs [14,15]. To increase the effect of biological ac-
tivities or photophysical properties, derivation of those imidazole
compounds with Schiff base or chloro-quinoline groups becomes an
important issue.
nanthrolines, phenanthro-imidazoles and their derivatives bearing
polar heteroatoms such as N, O in their aromatic π-conjugated rings
were preferable in photophysical and biological studies [1–5]. Imidazo-
phenanthrolines act as an electron acceptor in systems with their
electron density deficiency on C atoms in aromatic ring. Donating/
withdrawing substitutions to the imidazole-phenanthrolines increase
the hyperpolarizability and effects their photophysical properties with
the increase of intensity or shift of bands [6–9]. Hence, beside their
considerable photophysical, pharmacological properties, imidazo-phe-
nanthrolines exhibit also biological activity and DNA binding/cleavage
properties, as well. To compare with other heterocylic molecules, imi-
dazo-phenanthrolines have structural similarity with the amino acid
histidine, vitamin B12, DNA base in living systems [10,11]. Further-
more, their planar nature provides ease of binding to the helix structure
Schiff bases with azomethine linkages which also exist in living
systems can be used to understand the relationships between biomo-
lecules and drug molecules and are very vital for improving the
bioactive drugs. The effects of the quinolines in biological studies can
be explained by the fact that they can penetrate bacterial cells and to
inhibit DNA gyrase [16–32]. In this work, the design and synthesis of
the Schiff base and quinoline based heterocylic imidazo-phenanthroline
derivatives were designed for biological activity and photophysical
studies. 2 was obtained by Schiff base condensation reaction and 3 was
obtained by nucleophilic substitution of bromine-substitued imidazo-
⁎
Corresponding author.
E-mail address: aslihanyilmaz@selcuk.edu.tr (A.Y. Obalı).
https://doi.org/10.1016/j.bioorg.2020.103885
Received 15 February 2020; Received in revised form 23 March 2020; Accepted 23 April 2020
Available online 03 May 2020
0045-2068/ © 2020 Elsevier Inc. All rights reserved.

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
phenanthroline and 5-chloro-8-quinolinol. Their structures were well
characterized.
and 4-((4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenoxy)methyl)-
benzaldehyde (0.1 g, 0.23 mmol) were carried out in 30 mL methanol
medium under reflux for 72 h. The reaction was monitored by TLC by
2
. Experimental section
using methanol/NH (4: 1) as the eluent. The crude dark yellow residue
3
was collected by filtration and washed with methanol and dried under
−
1
2.1. Materials and instrumentation
vacuum (yield %86). M.P. > 300 °C (decomp.). FT-IR υ(cm ): 3393
(
OH), 3055 (NH), 2870 (CH), 1683 (C]N), 1611 (C]O), 1248
1
The reagents and chemicals were purchased from Merck and Sigma-
(CeOeC). H NMR (DMSO‑d
6
) δ(ppm): 13.80 (b, s, 1H, NH), 13.12 (b,
Aldrich and used without further purification. Melting points were
s, 2H, OH), 8.92 (s, 1H, HC = N), 9.1–7.3 (m, 17H, aromatic-CH), 5.45
1
13
13
determined by Büchi Melting Point B-540 instrument. H NMR and
C
(s, 2H, O-CH
2
). C NMR (DMSO‑d
6
): δ (ppm) = 168, 167, 161, 160,
NMR spectra were recorded on a Varian 400-MHz Spectrometer and
Bruker Biospin 300-MHz Spectrometer, respectively. Infrared spectra
were measured using a Bruker Fourier Transform-Infrared (FT-IR)
Spectrometer. Elemental analyses were carried out using a LECO-CHNS-
153, 152, 151, 149, 148, 145, 136, 134, 133, 131, 130, 129, 127, 124,
119, 118, 116, 69. Elemental analysis (C35
H
23
N
5
5
O ), Calculated
(Found) %: C: 70.82 (70.74), H: 3.91 (3.89), N: 11.80 (11.73).
2-(4-(((5-chloroquinolin-8-yl)oxy)methyl)phenyl)-1H-imidazo[4,5-
f][1,10]phenanthroline, 3. 5-Chloro-8-quinolinol (0.046 g, 0.25 mmol)
was dissolved in 30 mL methanol and then added dropwise to the me-
thanol solution of 2-(4-(bromomethyl)phenyl)-1H-imidazo[4,5-f][1,10]-
phenanthroline (0.1 g, 0.25 mmol) and triethylamine (0.034 mL,
0.25 mmol). The mixture was refluxed for 48 h. The reaction was mon-
9
32 elemental analyzer. High-Resolution Mass Spectroscopy was re-
corded on Waters SYNAPT G1 MS at positive mode (ES + )50–1000 Da.
UV–vis spectra were recorded on Perkin Elmer Lambda 25 UV–Vis
Spectrometer. Fluorescence data were obtained by using a Perkin Elmer
LS 55 Luminescence Spectrometer. All measurements were carried out
at 298 K. Thin layer chromatography (TLC) plates were supplied from
merck (silica gel 60 F254 on aluminum.
itored by TLC by using methanol/NH (4: 1) as the eluent. After the re-
3
action completed, evaporation of the solvents were performed. Light
yellow solid residue was washed with water. Then dried under vacuum.
−1
2.2. Synthesis procedures
(yield %90). M.P. > 300 °C (decomp.). FT-IR υ(cm ): 3151 (NH), 2921
1
(
CH), 1651 (C]N), 1279 (CeOeC), 550 (C-Cl). H NMR (DMSO‑d
6
)
1
,10-Phenantroline-5,6-dione, 4-(1H-imidazo[4,5–f][1,10]phenan-
δ(ppm): 13.66 (b, s, 1H, NH), 9.2–7.3 (m, 15H, aromatic-CH), 4.85 (s, 2H,
13
throline-2-yl)phenol (1), 2-(4-(bromomethyl)phenyl)-1H-imidazo[4,5-f]
O-CH
2
). C NMR (DMSO‑d ): δ (ppm) = 157, 153, 152, 150, 148, 145,
6
[
1,10]phenanthroline, 4-((4-(1H-imidazo-[4, 5-f][1,10]phenanthrolin-2-
142, 135, 134, 133, 129, 128, 127, 124, 123, 118, 116, 115, 107, 71.
yl)-phenoxy)methyl)benzaldehyde were synthesized via the literature
Elemental analysis (C29
H18ClN
5
O), Calculated (Found) %: C: 71.38
+
methods [33,34].
(71.34), H: 3.72 (3.64), N: 14.35 (14.28). HRMS (ESI) (m/z) (M + H) :
1
,10-Phenantroline-5,6-dione. 1,10-Phenanthroline (0.54 g, 3 mmol)
488.12.
was added into a solution of 60% sulfuric acid (7 mL). After the solid
compound was dissolved, potassium bromate (0.55 g, 3.3 mmol) was
added in batches over a period of half an hour. The mixture was stirred at
room temperature for 20 h. Then, the mixture was poured over ice and
was carefully neutralized to pH:7 using a saturated solution of sodium
hydroxide. The solution was then filtered, extracted with di-
chloromethane and evaporated to dryness. The crude product was re-
crystallized from methanol to provide the desired product.
2.3. Antimicrobial activities
In antimicrobial activity studies, the minimum inhibitory con-
centration values of compounds were determined by using broth mi-
crodilution method. Antibacterial activity of compound individually
tested against different microorganisms [Bacillus subtilis ATCC
6633(G + ), Pseudomonas aeruginosa ATCC 29853(G-), Escherichia coli
ATCC 35,218 (G-), Enterococcus faecalis ATCC 292,112 (G + ),
Salmonella typhimurium ST-10 (G-), Streptococcus mutans NCTC 10,449
(G + ), and Staphylococcus aureus ATCC 25923(G + )]. Gram positive
and gram negative bacteria were grown on Mueller-Hinton agar plates
and incubated at 37 °C for 24 h.
4
-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)phenol, 1. 1,10-
Phenanthroline-5,6-dione (0.1 g, 0.46 mmol) and ammonium acetate
0.58 g, 13.3 mmol) were dissolved in 10 mL of hot glacial acetic acid.
While the mixture was stirred, a solution of 4-hydroxybenzaldehyde
(
(
0.056 g, 0.46 mmol) in 10 mL of glacial acetic acid was added drop-
wise to the mixture. The mixture was heated at 90 °C for 3 h and was
then poured in 200 mL of water. The solution was neutralized with
ammonia to pH:7 and was then cooled to room temperature. The pre-
cipitate was filtered off and washed with large portions of water. The
product was dried for 48 h in a vacuum at 50 °C.
MIC value was determined by using microplate. The bacterial sus-
8
pensions were adjusted to 0.5 McFarland standard turbidity (10 CFU/
5
ml). Finally, these suspensions used as inoculums were prepared at 10
CFU/ml by diluting fresh cultures at McFarland 0.5 density. Mueller-
Hinton Broth (100 µl) was placed into each 96 wells of microplates.
Compound solutions initially prepared at a concentration of 10000 µM
were added into first wells of microplates and two fold dilutions of the
compounds (2500–2,44 µM) were made by dispensing the solutions to
the remaining wells. Then, 100 µl of culture suspensions were in-
oculated to each well. Chloramphenicol (2500–2,44 µM) was used as
control. The sealed microplates were incubated at 37 °C for 24 h.
Microbial growth was determined by adding 200 µl of 2,3,5-Triphenyl-
tetrazolium chloride (0.5%) after incubation to each well and in-
cubating for 30 min at 37 °C. The lowest concentration of the com-
pounds that completely inhibit macroscopic growth was determined as
minimum inhibitory concentrations (MICs).
2-(4-(bromomethyl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthro-
line. A mixture of 1,10-phenanthroline-5,6-dione (0.25 g, 1.2 mmol),
ammonium acetate (2.6 g, 1.2 mmol), 4-(bromomethyl)benzaldehyde
(
0.25 g, 0.46 mmol) and 30 mL glacial acetic acid were refluxed for
4
8 h and then poured in 200 mL of water. The solution was neutralized
with ammonia to pH:7 and cooled to room temperature. The precipitate
was collected and washed with water. The crude yellow product was
dried under vacuum.
4-((4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)-phenoxy)me-
thyl)benzaldehyde. To the solution of 4-(bromomethyl)benzaldehyde in
mL DMF, 4-(1H-imidazo[4,5-f][1,10] phenanthroline-2-yl)phenol
3
0
(
0.15 g, 0.5 mmol) and K
2
CO (0.13 g, 1 mmol) were added. The
3
mixture was stirred for 36 h at 90 °C. Then cooled to room temperature
and 50 mL water as added to the solution. The resulting crude product
were filtered and washed with cold water.
2.4. DNA cleavage activity
The interactions of the compounds with supercoiled pBR322
plasmid DNA were studied by agarose gel electrophoresis. The com-
plexes were incubated with pBR322 DNA in the dark at 37 °C for 24 h
and electrophoresed in 1% agarose gel electrophoresis. The gel was
(
E)-5-((4-((4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phe-
noxy)methyl)benzylidene) amino)isophthalic acid, 2. Schiff base
condensation reaction of 5-aminoisophthalic acid (0.04 g, 0.23 mmol)
2

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
1
13
electrophoresed for 1 h at 100 V in 1XTAE buffer. After electrophoresis,
the gel was stained in ethidium bromide, then, DNA viewed with UV-
transilluminator.
measurements and FT-IR, H NMR,
C NMR, HRMS techniques.
Melting points of the compounds were determined at room tempera-
ture. The melting point differences between the starting compounds
and target compounds primarily can prove the synthesis of target
compounds. FT-IR spectra of the compounds are given in Figs. 1–2. For
2.5. BamH I and Hind III restriction enzyme digestion
−
1
the Schiff base compound 2, the bands appeared at 3462 cm
,
−1
−1
The compound-DNA mixtures were first incubated for 24 h and then
3056 cm , 1683 cm
can be attributed to υ(OH, carboxylic acid),
restricted with restriction enzyme BamH I and Hind III for 1 h at 37 °C.
BamH I and Hind III are known to recognize the sequence G/GATCC and
A/AGCTT respectively. pBR322 plasmid DNA contains a single re-
striction site for each enzyme which convert supercoiled form I DNA
and singly nicked circular Form II DNA to linear form III DNA. After one
hour incubation, the restricted DNA was electrophoresed in 1% agarose
gel for 1 h at 100 V in TAE buffer. The gel was stained with ethidium
bromide and then viewed with UV-transilluminator.
υ(NH) and υ(C]N), respectively. The azomethine band is the most
specific band for 2. For the chloro-quinoline based compound 3, the
−1
−1
−1
−1
bands at 3151 cm , 1651 cm , 1279 cm , 551 cm
can be as-
signed to υ(NH), υ(C]N), υ(CeOeC), υ(C-Cl), respectively. The dis-
appears of υ(OH) band of 5-chloro-8-quinoline and formation of
1
υ(CeOeC) etheric band proves the synthesis of target compound 3. H
NMR spectra of the compounds are given in experimental part (Figs. 3
and 5). The broad singlet peak at 13.12 ppm is assigned for the car-
boxylic acid OH protons of 2. Another important singlet that appears at
3
. Results and discussion
8.92 ppm is the proof of CH = N azomethine protons of the Schiff base
1
2
. For 3, the most specific peak appears on H NMR spectra at 4.85 ppm
3.1. Synthesis and characterizations
is of O-CH protons. Absence of the aldehyde peak and amine peak of
13
2
the initial compounds proves the target compound 3. Specific C NMR
Herein we report the synthesis and characterization of imidazo-
signals for 2 appeared at 69 ppm for oxy-bonded aliphatic carbon (O-
phenanthroline derivatives. 1,10-phenantroline-5,6-dione and 4-(1H-
imidazo[4,5-f][1,10]phenanthroline-2-yl)phenol, 1 were synthesized
via the literature method (and also given in experimental part) and
obtained for the next steps. 2 was obtained by the Schiff base con-
densation reaction between 4-((4-(1H-imidazo[4,5-f][1,10]-phenan-
throlin-2-yl)-phenoxy)methyl)benzaldehyde and 5-aminoisophthalic
acid. It precipitated in 1 h with good yields. Because of the difficulties
in purifying Schiff bases in column chromatography, 2 was purified by
washing with methanol several times. The reactions of the starting
compounds and target compounds are demonstrated in Scheme 1. The
reaction of 5-chloro-8-quinolinol and 2-(4-(bromomethyl)-phenyl)-1H-
imidazo[4,5-f][1,10]-phenanthroline in the presence of triethylamine
gave chloro-quinoline based imidazo-phenanthroline derivative, 3
CH ), 152 ppm for the carbon which connects NH and N groups of
2
imidazole unit, 160 ppm for imine carbon of Schiff base and 169 ppm
1
3
for carboxylic acid carbons (Fig. 4). C NMR signals for 3 are appeared
at 71 ppm for oxy-bonded aliphatic carbon (O-CH ), 152 ppm for the
2
carbon which connects NH and N groups of imidazole unit, 118 ppm for
chloro-bonded aromatic quinoline carbon and 156 ppm for the oxy-
bonded aromatic quinoline carbon (Fig. 6). HRMS (ESI) was also re-
corded for 3 to determine the molecular weight (Fig. 7). The molecular
ion peak was observed at m/z 488.12 confirming the formula weight of
3 which is the same as the calculated value.
3.2. Photophysical properties
-
5
-5
-4
(
Scheme 2).
Absorption data of 1 (1x10 M), 2 (1x10 M) and 3 (1x10 M) were
The structures of the compounds were confirmed by melting point
determined in acetonitrile. To explain the different concentration
Scheme 1. Synthesis route of Schiff base imidazo-phenanthroline derivative, 2. The reaction conditions were as i) ammonium acetate, glacial acetic acid, 118 °C. ii)
CO , DMF, 90 °C, iii) Methanol, 65 °C.
K
2
3
3

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
Scheme 2. Synthesis route of chloro-quinoline based imidazo-phenanthroline derivative, 3. The reaction conditions were as i) ammonium acetate, glacial acetic acid,
1
18 °C, ii) triethylamine, methanol, 65 °C.
Fig. 1. FT-IR spectrum of (E)-5-((4-((4-(1H-imidazo[4,5–f][1,10]phenanthrolin-2-yl)phenoxy)methyl)benzylidene)-amino)isophthalic acid, 2.
preference of 3, it should be noted that at lower concentrations (such as
338–369 nm for 3 were observed. While recording the samples with
-
5
-2
1
x10 M) very low absorbance data were recorded. Hence, higher
more concentrated (as 1x10 M) solutions, we observed the scala was
-
4
concentration (1x10 M) was preferred to see the double shoulders
clearly for 3. All the compounds show absorbances in UV–vis region.
The spectra of 1, 2 and 3 exhibit double shoulder bands at λ:
passed over with noise so we couldn’t record more concentrated solu-
tions. Red-shifts might be occurred due to the intermolecular associa-
tion of the molecule–molecule dimer aggregate formation in the ground
state at high concentrations of solute. It was discovered that increasing
the concentration of a dye molecule, band arises and red-shifted and
aggregates formed. To form the simplest aggregate, a dimer, the
dye–dye interaction must be strong enough to overcome any other
forces which would favor solvation of the monomer [36,37]. And also
the delocalization of electrons between π-conjugated the imidazo-phe-
nanthroline rings may give rise to form a charge cloud above and below
this plane along the conjugated chain and may cause red-shift in
fluorescence band [38,39].
2
80–324 nm, 280–324 nm and 280–314 nm, respectively (Fig. 8). These
bands correspond to phenanthroline-centered spin-allowed π → π*
transitions [35]. Molar absorptivities, ε, were calculated as
−
1
−1
−1
−1
−1
−1
1
20.000 M .cm , 80.000 M .cm and 18.000 M .cm for the
compounds 1, 2, and 3 (respectively) at their maximum absorbances
and λmax: 280 nm for each.
Fluorescence studies of 1, 2 and 3 in acetonitrile medium (both
-
4
-5
1
x10 M and 1x10 M) were also reported at the excitation of λ:
70 nm. When excitated at 270 nm, exhibited fluorescence bands for all
2
the compounds are displayed in Fig. 9. The effects of concentration
increases on fluorescence intensities were also observed. The solutions
3.3. Antimicrobial activity
-
4
of three compounds were prepared with concentrations of 1x10 M and
-
5
1
x10 M. Red-shifts from λ: 329–370 nm to 372–460 nm for 1, from λ:
31–370 nm to 361–460 nm for 2 and from λ: 323–370 nm to
The antibacterial activities of OH-substitued (1), COOH-substitued (2)
3
and Cl-substitued (3) imidazo-phenanthroline derivatives were
4

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
Fig. 2. FT-IR spectrum of 2-(4-(((5-chloroquinolin-8-yl)oxy)methyl)phenyl)-1H-imidazo[4,5f][1,10]phenanthroline, 3.
Fig. 3. 1H NMR spectra of Schiff base imidazo-phenanthroline derivative compound 2.
determined against B.subtilis, P.aeruginosa, E.coli, E.faecalis, S.typhimurium,
S.mutans and S.aureus microorganisms. The antimicrobial activities with
minimum inhibitory concentrations (MIC) of the compounds are given in
Table 1.
relationships of OH–, COOH– and Cl- substitued imidazo-phenanthro-
line derivatives (Fig. 10) against microorganisms indicated that in-
troduction of electron-withdrawing Cl boosted the antimicrobial ac-
tivity and this leads compound 3 more potent than other compounds
[40–41].
The minimal inhibitory concentration (MIC) values of the com-
pounds were studied further, and these values are in the range of
1
56,25–1250 µM. Chloramphenicol was used as a control. As it is
3.4. DNA cleavage activity; interaction with pBR322 plasmid DNA
shown in Table 1, it can be seen that the most effective compound on
the microorganisms was 3. According to the results, the MIC values of 3
was determined as 156,25 μM on all tested bacteria. It is generally
known that the existence of electron-donating groups on the phenyl
ring such as OH reduce, electron-withdrawing groups such as Cl, COOH
increase the antimicrobial activities. Hence, the results of this study
were compatible with that knowledge that OH– substitued compound 1
has less antimicrobial activity at lower concentrations. Comparing the
derivatives 1, and 2, even at lowest concentration 3 shows most anti-
bacterial activity among them. According to the structure–activity
At the highest two concentrations (10000 and 5000 μM) of 1, both
Form I and Form II bands disappear because of degradation of pBR322
plasmid DNA. In Fig. 11(C), the mobility of Form I has increased and all
of the concentrations of 1 were decreased intensity of Form I band
compared with Form II but when further dilutions of this compound are
made starting from the 7th concentration Fig. 12(C), it has become
closer to untreated plasmid in the decreasing concentrations of 1. 1
clearly accelerated the migration of the open circular form (FormII)
because of the condensation and cross-linking of DNA (shown in both
5

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
Fig. 4. 13C NMR spectra of Schiff base imidazo-phenanthroline derivative compound 2.
Fig. 11(C) and Fig. 12(C)) [42–43].
In the highest first 7 concentrations of 3-DNA interaction, the DNA has
been completely degenerated. At the 8th and 9th concentrations, DNA
may appear to be cleavaged while bands are invisible. Compared to
other compounds, further dilutions were made an addition to con-
centrations which were less than these 7 concentrations and were found
to be very effective even at the lowest concentrations (0.152 μM). The
gel photo shows concentrations that decrease from 156.25 μM to
0.152 μM (Fig. 12(B)). Both Forms I and II were not detectable at the
highest two concentrations of 3 (156.25 μM and 78.125 μM) when the
plasmid DNA interacted with 3. This shows that 3 may be caused de-
gradation of pBR322 plasmid DNA. The electrophoretic mobility of
both Form I and Form II was increased according to the control plasmid.
All of the concentrations of 3 were decreased the intensity of Form I
band.
In Fig. 11(A), plasmid DNA bands are not visible at the first 6
concentrations at which the serial dilutions starting from 10000 μM are
made. Therefore additional dilutions were made starting from the 7th
concentration. As shown in Fig. 12(A), the untreated plasmid was used
a positive control and plasmid DNAs which incubated with 2 at con-
centrations between 156.25 and 1.220 μM were run. At the highest
concentration (156.25) of 2, both Form I and Form II bands disappear.
This shows that 2 may be caused degradation of pBR322 plasmid DNA.
All of the concentrations of 2 were decreased intensity of Form I band
compared with Form II and 2 accelerated the migration of both the
supercoiled form (Form I) and the open circular form (FormII). This is
due to the condensation of DNA [42–43]. The intensity of the Form II
band increased with decreasing concentrations.
Fig. 11(B) shows the electrophoretic mobility of the 3-DNA mixture.
All the three imidazo-phenanthroline derivative compounds studied
Fig. 5. 1H NMR spectra of chloro-quinoline based imidazo-phenanthroline derivative compound 3.
6

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
Fig. 6. 13C NMR spectra of chloro-quinoline based imidazo-phenanthroline derivative compound 3.
were found to be highly effective on DNA, even at the lowest con-
centrations. But if we compare three of them, it was found to be the
most effective 3, since the DNA is degenerate as shown in Fig. 11(B).
observe that endonuclease activity is inhibited in the presence of
complexes by binding or blocking the recognition sites in plasmid DNA
[43–45].
The highest first 4 concentrations of 1, All three forms of plasmid
DNA forms were observed, though Form I and II were faint. 1 binds to
G-G bases at these high doses and relatively inhibits the cleavage of
Form I and II. However, at decreasing concentrations (last 4 con-
centrations), the compound was unable to inhibit to cut off with BamHI
both open circular and supercoil forms of plasmid DNA. The highest
first 5 concentrations of 1, all three forms of plasmid DNA forms were
observed, though Form I and II were faint. But in the other decreasing
concentrations, it was only observed Form III (Fig. 13(C)).
Digestion with BamH I and Hind III of 2-DNA interaction disappear
since at the highest first concentration of 2 was not detectable as to be
3
.5. BamH I and Hind III restriction enzyme digestion of compound-plasmid
DNA
In order to assess whether the 1, 2 and 3 show affinity toward
guanine-guanine (GG) and/or adenine-adenine (AA) regions, the re-
striction endonuclease analysis of the compound-pBR322 plasmid DNA
adducts was carried out by BamH I and Hind III enzymes and the
electrophoretograms are shown in Fig. 13(A), (B) and (C). BamH I and
Hind III enzymes bind at the recognition site G-GATCC and A-AGCTT
and cleave these sequences just after 5′-guanine and 5′-adenine sites,
respectively, and, as a result, convert Form I and Form II DNA to linear
Form III DNA. Therefore, the restriction enzymes have been used to
2
-DNA interaction test. Although the intensity of linear DNA (Form III)
band increased in decreasing concentrations, intensity Form I and Form
Fig. 7. HRMS spectra of chloro-quinoline based imidazo-phenanthroline derivative compound 3.
7

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
Fig. 8. The absorption spectra of 4-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)phenol, 1, (E)-5-((4-((4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenoxy)
methyl)benzylidene)-amino)isophthalic acid, 2 and 2-(4-(((5-chloroquinolin-8-yl)oxy)methyl)phenyl)-1H-imidazo[4,5f][1,10]phenanthroline, 3 in acetonitrile
medium.
II bands decreased but not completely lost. This shows that the com-
pound does not allow the BamH I enzyme to completely digest because
it binds to G-G bases in DNA. Hind III completely cut off by targeting
supercoil form (Form I) and convert it into Form III. At the highest 3rd,
concentrations. Form I is seen at the lowest last 4 concentrations,
though very faint. Here we can say that the compound binds to by
targeting G-G bases in DNA in supercoil form (Form I) at low con-
centrations. The Hind III restriction enzyme completely cut off Form I
and Form II at the last 4 concentrations and convert to Form III. This
indicated that the compound did not bind to A-A bases (Fig. 13(B)).
In case decreasing concentrations of 1, 2 and 3, only linear Form III
band was observed in the presence of Hind III indicating that all of the
plasmid DNA is doubly nicked at A-A region. In case decreasing con-
centrations of only 1, only linear Form III band was observed in the
presence of BamH I indicating that all of the plasmid DNA is doubly
nicked at G-G region.
4
th, and 5th concentrations, it mostly digested Form II, but cut at all
concentrations except these. This shows that 2 was unable to cleave
because it binds to A-A bases in plasmid DNA, which is the open cir-
cular form (Form II) (Fig. 13(A)).
It wasn’t observed any bands in the highest five concentrations of 3.
It was already quite effective compared to other compounds even at
decreasing concentrations of 3. Since the compound did not bind to
open circular plasmid DNA, BamH I completely cut off Form II. After the
6
th concentrate, the intensity of Form III increased at decreasing
Fig. 9. The fluorescence spectra of 4-(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)phenol, 1, (E)-5-((4-((4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenoxy)
methyl)benzylidene)-amino)isophthalic acid, 2 and 2-(4-(((5-chloroquinolin-8-yl)oxy)methyl)phenyl)-1H-imidazo[4,5f][1,10]phenanthroline, 3 with the con-
-
4
-5
centrations of 1x10 M and 1x10 M in acetonitrile medium at λext: 270 nm.
8

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
Table 1
The minimum inhibition concentration (µM) of imidazole-phenanthroline derivatives 1, 2 and 3 (Antibiotic; C: chloramphenicol).
Compound/Bacteria B.subtilis ATCC
P.aeruginosa ATCC
E.coli ATCC
E.faecalis ATCC
S.typhimurium S.mutans NCTC
S.aureus ATCC
25,923
6633
29,853
35,218
292,112
ST-10
10,449
1
2
3
C
625
625
625
625
625
1250
625
1250
1250
156,25
9,76
625
1250
156,25
312,5
1250
156,25
9,76
1250
1250
156,25
2,44
156,25
78,125
156,25
9,76
156,25
156,25
Fig. 10. Chemical structures and structure–activity relationships (SAR) of imidazo-phenanthroline derivatives (1, 2 and 3) showed potent antibacterial activities.
Fig. 11. Electrophotograms applying to the interaction of pBR322 plasmid DNA with decreasing concentrations of 2 (A), 3 (B) and 1 (C). Line P applied untreated
plasmid DNA to use as a control. Lines 1–9 applied to plasmid DNA interacted with decreasing concentrations of compounds (10000 μM, 5000 μM, 2500 μM,
1
250 μM, 625 μM, 321.5 μM, 156.25 μM, 78.125 μM, 39.062 μM).
4
. Conclusion
results, MIC values of 3 was determined as 156,25 μM on all tested
bacteria. Compared with the compounds, standard antibiotic was more
effective on the bacteria. According to the DNA-cleavage study results,
all imidazole-phenanthroline derivatives were found to be highly ef-
fective on DNA, even at the lowest concentrations.
As a summary, fluorescent imidazo-phenanthroline derivatives have
been designed, prepared and characterized by various spectroscopic
techniques. Their biological activities were investigated. Antibacterial
activities of the compounds were determined against seven different
microorganisms. The minimal inhibitory concentration (MIC) values of
the compounds were studied, and these values are in the range of
Declaration of Competing Interest
1
56,25–1250 µM. As it is shown in Table 1, it can be seen that the most
effective compound on the microorganisms was 3. According to the
The authors declared that there is no conflict of interest.
9

A.Y. Obalı, et al.
Bioorganic Chemistry 100 (2020) 103885
Fig. 12. Electrophotograms applying to the interaction of pBR322 plasmid DNA with decreasing concentrations of 2 (A), 3 (B) and 1 (C). Line P applied untreated
plasmid DNA to use as a control. Lines 1–11 applied to plasmid DNA interacted with decreasing concentrations of compounds (156.25 μM, 78.125 μM, 39.062 μM,
1
9.531 μM, 9.765 μM, 4.882 μM, 2.441 μM, 1.220 μM, 0.61 μM, 0.305 μM, 0.152 μM).
Fig. 13. Electrophoretogram applying to incubated mixtures of plasmid DNA and compounds 2 (A), 3 (B) and 1 (C) followed by digestion with BamH I or Hind III.
Lane P: the untreated and undigested plasmid DNA. Lines BamH I and Hind III: digestions of plasmid DNA-compounds mixtures to use as a control. Lines 1–11:
digestions of plasmid DNA interacted with decreasing concentrations of compounds (156.25 μM, 78.125 μM, 39.062 μM, 19.531 μM, 9.765 μM, 4.882 μM, 2.441 μM,
1
.220 μM, 0.61 μM, 0.305 μM, 0.152 μM).
Acknowledgment
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We thank the Scientific Research Projects Foundation (BAP) of
Selcuk University (Konya/TURKEY) for financial support of this work.
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