Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives

Article abstract of DOI:10.1002/ardp.202000277

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66–5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66–3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC₅₀ value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.

Full text of DOI:10.1002/ardp.202000277

Received: 29 July 2020
Revised: 17 September 2020
Accepted: 23 September 2020
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DOI: 10.1002/ardp.202000277
F U L L P A P E R
Synthesis, antimicrobial evaluation, DNA gyrase inhibition,
and in silico pharmacokinetic studies
of novel quinoline derivatives
Mohamed H. El‐Shershaby1 | Kamal M. El‐Gamal1 | Ashraf H. Bayoumi1
|
Khaled El‐Adl2,3
| Hany E. A. Ahmed1,4
| Hamada S. Abulkhair1,5
1Pharmaceutical Organic Chemistry
Department, Faculty of Pharmacy, Al‐Azhar
University, Cairo, Egypt
Abstract
Herein, we report the synthesis and in vitro antimicrobial evaluation of novel qui-
noline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity
was assessed against a panel of pathogenic microbes including Gram‐positive bac-
teria (Streptococcus pneumoniae and Bacillus subtilis), Gram‐negative bacteria (Pseu-
domonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus,
Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds
that revealed the best activity were subjected to further biological studies to de-
termine their minimum inhibitory concentrations (MICs) against the selected pa-
thogens as well as their in vitro activity against the E. coli DNA gyrase, to realize
whether their antimicrobial action is mediated via inhibition of this enzyme. Four of
the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent anti-
microbial activity with MIC values in the range of 0.66–5.29 μg/ml. Among them,
compound 14 exhibited a particularly potent broad‐spectrum antimicrobial activity
against most of the tested strains of bacteria and fungi, with MIC values in the range
of 0.66–3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA
gyrase target enzyme revealed a significant potent inhibitory activity of quinoline
derivative 14, which can be observed from its IC50 value (3.39 μM). Also, a molecular
docking study of the most active compounds was carried out to explore the binding
affinity of the new ligands toward the active site of DNA gyrase enzyme as a pro-
posed target of their activity. Furthermore, the ADMET profiles of the most highly
effective derivatives were analyzed to evaluate their potentials to be developed as
good drug candidates.
2Pharmaceutical Medicinal Chemistry & Drug
Design Department, Faculty of Pharmacy,
Al‐Azhar University, Cairo, Egypt
3Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, Heliopolis University for
Sustainable Development, Cairo, Egypt
4Pharmacognosy and Pharmaceutical
Chemistry Department, Taibah University,
Al‐Madinah Al‐Munawarah, Saudi Arabia
5Pharmaceutical Chemistry Department,
Faculty of Pharmacy, Horus University,
New Damietta, Egypt
Correspondence
Hamada S. Abulkhair, Pharmaceutical Organic
Chemistry Department, Faculty of Pharmacy,
Al‐Azhar University, Nasr City, Cairo 11884,
Egypt.
Email: hamadaorganic@azhar.edu.eg
K E Y W O R D S
antimicrobial, DNA gyrase, molecular docking, quinoline, synthesis
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1
INTRODUCTION
management of global infectious diseases. The World Health
Organization has recognized this antimicrobial resistance and the
A wide‐ranging panel of infectious diseases including bacterial
and fungal infections is becoming resistant to commonly pre-
scribed drugs.[1] This resistance is the main obstacle to the
dwindling number of current potent antimicrobial drugs to be
alarming threats to human health.[2] Also, problems of
vancomycin‐resistant and methicillin‐resistant Staphylococcus
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Arch Pharm. 2020;e2000277.
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Rationale and aim of the work
aureus (VRSA and MRSA, respectively) and fluconazole‐resistant
Candida have reached a disturbing level worldwide.[3] Conse-
quently, it is essential to develop new antimicrobial agents with
improved potency.
1.1
On the basis of the aforementioned facts, inspired by the versatility of the
quinoline moiety mentioned above, and as a continuation of our recent
studies,[7,16,17] to identify new antimicrobial agents, the synthesis of three
novel series of 6‐methylquinoline‐3‐carbonitrile derivatives was carried
out to obtain new molecules with higher potency. The design of new
compounds depended on modifying structural aspects of the previously
reported fluoroquinolones to evaluate their activities against pathogenic
bacterial and fungal strains. The fluorine atom was replaced by the me-
thyl group, the carbonitrile group was attached to C‐3, and different
substitution patterns were introduced into C‐2 of the quinoline scaffold
to investigate the effect of such substitution pattern on the antimicrobial
activity of the designed compounds. All the synthesized compounds were
evaluated for their in vitro antimicrobial activity against a panel of pa-
thogenic microbes including two Gram‐positive bacteria (Streptococcus
pneumoniae and Bacillus subtilis), two Gram‐negative bacteria (Pseudomo-
nas aeruginosa and Escherichia coli), and four fungal strains (Aspergillus
fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida
albicans). In addition, the structure–activity relationship of the synthe-
sized compounds was discussed. Also, a molecular docking study of the
most active compounds was carried out to predict the binding affinity
toward the active site of DNA gyrase enzyme as a proposed target of
their activity. Furthermore, absorption, distribution, metabolism, excre-
tion, and toxicity (ADMET) profiles of the highest effective derivatives
were examined to evaluate the potentials of new compounds to be de-
veloped as good drug candidates.
DNA gyrase is a topoisomerase II that is vital in the DNA tran-
scription and replication processes in eukaryotes.[4] Quinolone anti-
microbials are the oldest, and still the only, existing class of agents
clinically used to inhibit bacterial DNA synthesis.[5] Nalidixic acid (1)
is a quinolone that forms the basis of the development of the
fluoroquinolone class of compounds. Fluoroquinolones and their
analogous naphthyridine antibiotics (Figure 1) work as DNA gyrase
poisons, as they could stabilize the covalent gyrase–DNA complex,[5]
thereby leading to protein‐stabilized DNA breaks and eventually cell
death. Nalidixic acid was first introduced into the market in the late
60s of the past century for the treatment of urinary tract
infections.[6] Subsequent novel generations of fluoroquinolones with
improved efficacy were afterward developed, namely norfloxacin (2),
ciprofloxacin (Cipro, 3), levofloxacin (Levaquin, 4), moxifloxacin
(Avelox, 5), gemifloxacin (Factive, 6), and delafloxacin (Baxdela, 7).
Over the last two decades, there were several reports on novel
quinoline derivatives as potential antimicrobial agents that target
DNA gyrase.[7,8] Currently, fluoroquinolones are being utilized in the
management of serious microbial infections such as bacterial pneu-
monia. However, bacterial resistance to such antimicrobials with no
novel medications in the antimicrobials pipeline has driven intensive
research in this area.
However, pathogenic fungi are one of the most harmful parasitic
organisms and can cause serious health problems. Fungal infections
also produce various toxins that can seriously compromise food
safety.[9] Over the last few decades, the use of a huge number of
antifungal agents has resulted in resistance to eradicate fungi, thus
leading to a decrease in the efficacy of traditional fungicides. Con-
sequently, it is also essential to develop novel effective fungicides to
control these fungal diseases. Quinoline is a vital pharmacophore ring
system present in a number of antifungal agents.[8,10] Quinoline
derivatives possess diverse pharmacological activities, particularly
antibacterial,[7,8] antifungal,[8,11–13] and antimalarial.[14,15]
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2
RESULTS AND DISCUSSION
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2.1
Chemistry
Synthetic approaches adopted for the synthesis of the starting
2‐mercapto‐6‐methylquinoline‐3‐carbonitrile and final target com-
pounds are illustrated in Schemes 1 and 2. The starting material,
2‐mercapto‐6‐methylquinoline‐3‐carbonitrile (11), was prepared by
FIGURE 1 Fluoroquinolones and their analogous naphthyridine antibiotics

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SCHEME 1 The synthetic protocol of the starting quinoline
the Vilsmeier–Haack reaction[18] of p‐methylacetanilide with
dimethylformamide (DMF) and phosphorus oxychloride, followed by
treatment of the produced quinoline‐3‐carbaldehyde derivative with
hydroxylamine hydrochloride to give 2‐chloro‐6‐methylquinoline‐3‐
carbonitrile (10). Treating the latter with thiourea gave 6‐methyl‐2‐
mercaptoquinoline‐3‐carbonitrile,[19] which was used as a starting mate-
rial in the synthesis of final compounds. In the present work, the
Vilsmeier–Haack method was selected to prepare the first intermediate,
9, due to the availability of starting materials and accessible reaction
conditions. Briefly, DMF and POCl3 were allowed to react at 0°C for 2 hr,
and then p‐methylacetanilide was added to the reaction mixture. The
overall reactant ratio was found to be a critical issue to obtain the desired
product in a good yield. Different ratios have been tried and the optimum
one was 1:3:12 (8/DMF/POCl3). Compound 10 was obtained in a high
yield, 80%, using a Bell and Ackerman modified protocol, where
compound 9 was treated with hydroxylamine hydrochloride at 70°C for
2 hr. Then, the in situ formed oxime was directly heated up to 110°C to
lose a molecule of water and give the desired quinoline‐3‐carbonitrile
product. The starting quinoline derivative 11 was prepared following the
reported procedure in an 80% yield. Briefly, compound 10 was allowed to
react with thiourea, followed by treating the reaction mixture with so-
dium hydroxide. The reaction mechanism involves the formation of an
isothiuronium salt, which is converted to the mercapto‐containing com-
pound upon the addition of sodium hydroxide. Both the melting point and
infrared (IR) spectrum confirmed the structure of the compound, where a
characteristic SH broad absorption band was observed at 2,624 cm−1
.
As depicted in Scheme 2, our convergent synthesis approach to the
final compounds started with the preparation of N‐aryl‐2‐
chloroacetamides and N‐aryl‐3‐chloropropionamides by the reaction of
substituted anilines with 2‐chloroacetyl chloride or 3‐chloropropionyl
chloride in the presence of triethylamine.[20,21,22] Similarly, α‐
chloroacetate and α‐chloropropionate esters were obtained by the ac-
tion of α‐chloroacetyl chloride or α‐chloropropionyl chloride against the
appropriate alcohol.[23,24] Final target quinolines of the current work
were achieved by the electrophilic substitution of starting 2‐mercapto‐6‐
methylquinoline‐3‐carbonitrile with different electrophiles including the
(a)
(c)
(b)
hr, 70–85%;
hr, 70–85%;
hr, 92%
SCHEME 2 The synthetic route of the new quinoline derivatives

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above‐prepared 2‐chloro‐N‐arylacetamide, 3‐chloro‐N‐arylpropanamide,
α‐chloroactate, and α‐chloropropionate ester derivatives in the presence
of potassium carbonate to neutralize the effect of HCl side product.[25,26]
The progress of the chemical reactions was validated by thin‐layer
chromatography (TLC) methodology and the final products were pur-
ified by the column chromatography method. Structures and purities of
new derivatives were confirmed on the basis of their IR, liquid
chromatography–mass spectrometry, 1H nuclear magnetic resonance
(NMR), and 13C NMR spectral data. In all cases, the characteristic thiol
stretching band disappeared and typical amide or ester carbonyl
stretching bands were observed between 1,660 and 1,725 cm−1, as
revealed by all IR spectra. Collectively, these observations confirm
tethering of the acetanilide moiety with the quinoline nucleus of
compounds 12–19 via S‐linkage. The NH group revealed a D2O‐
exchangeable singlet, equivalent to one proton, around 10.40 ppm. The
1H NMR spectra of compounds 12–19 showed, in addition to quinoline
aromatic protons, aromatic signals equivalent to aromatic acetanilide
protons and one D2O‐exchangeable singlet signal equivalent to one
proton, around 10.30 ppm due to NH. The aliphatic S–CH2 protons
appeared as a singlet signal at about 4.20 ppm, a singlet signal
equivalent to three protons at 2.50 ppm due to quinoline‐CH3. Also, IR
spectra of all compounds showed stretching bands in the range of
3,419 and 3,460 cm−1, representing the secondary amide NH func-
tionality. In addition, typical amidic carbonyl stretching bands between
1,665 and 1,681 cm−1 were observed. The 13C NMR spectra of acet-
amide derivatives 12–19 are characterized by the presence of a
minimum of two peaks in the aliphatic region at ~34 ppm due to SCH2
and ~19 ppm due to CH3. The most predominant features in the IR
spectra of the isolated ester derivatives 20–22 were the disappearance
of the thiol‐characteristic band at 2,624 cm−1
, which reflects
S‐substitution, and the appearance of a distinctive carbonyl ester
stretching band around 1,730 cm−1. In addition, the protons of added
alkyl ester moieties were revealed in the 1H NMR spectra between
4.60 and 1.30 ppm. The ethyl acetate moiety of compound 21 showed
a singlet signal equivalent to two protons at 3.30 ppm due to S–CH2, a
quartet signal of two protons at 4.30 ppm, and a triplet of three pro-
tons at 1.30 ppm, with the same coupling constant, due to ethoxy
group. The 1H NMR spectrum of the propionate analog 22 showed two
distinctive signals, that is, a doublet equivalent to the methyl group at
1.15 ppm and a quartet signal at 4.10 ppm, equivalent to a methine
proton, with the same J value. Both signals confirm the presence of
ethyl propionate moiety substituted at carbonyl carbon. The 1H NMR
spectra of hydrazide 23 is characterized by the presence of a singlet
signal at 8.86 ppm, which is corresponding to one proton of NH. The
presence of a signal at 4.30 ppm indicates two protons of NH2. Besides,
the presence of a singlet signal at 4.0 ppm indicates two protons of
S–CH2. Mass spectra of all the new structures are characterized by the
presence of distinctive molecular ion peaks at the expected m/z value.
All the newly synthesized triazoles gave elemental analysis data con-
sistent with that calculated for assigned structures.
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2.2
Evaluation of biological activity
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2.2.1
Antibacterial activity
All the newly synthesized compounds were evaluated for their in
vitro antibacterial activities against the four bacterial pathogens:
TABLE 1 Antibacterial activity of the
new compounds against Gram‐positive and
Gram‐negative pathogens
Inhibition zone (mm)a
Streptococcus
pneumoniae
Bacillus
subtilis
Pseudomonas
Escherichia
coli
Compound no.
aeruginosa
12
18.1 0.72
17.4 .58
19.3 0.58
NA
20.2.1 0.58
19.1 0.63
20.8 0.67
NA
NA
16.6 0.72
15.2 0.58
19.2 0.63
NA
13
NA
14
NA
15
NA
16
17.1 0.44
19.3 0.58
NA
17.9 0.63
21.2 0.72
NA
NA
16.7 2.1
18.3 0.63
NA
17
NA
18
NA
19
13.6 1.2
20.3 0.58
15.7 2.1
18.3 .63
20.7 0.72
23.8 0.2
NT
15.2 1.5
21.4 1.2
16.1 0.58
20.4 0.63
21.8 0.63
32.4 0.58
NT
NA
12.4 .58
20.3 0.58
15.2 0.63
17.5 2.1
20.9 0.58
NT
20
NA
21
NA
22
NA
23
NA
Ampicillin
Gentamicin
NT
17.3 0.63
21.3 0.58
Abbreviations: NA, no activity; NT, not tested.
aMean zone of inhibition in millimeters standard deviation for at least three experiments.

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S. pneumoniae and B. subtilis as examples of Gram‐positive bacteria;
P. aeruginosa and E. coli as examples of Gram‐negative bacteria.
Results of the antibacterial activity of new compounds are presented
in Table 1. Agar diffusion method[27,28] was used for the preliminary
evaluation of antibacterial activity and results were listed as the
average diameter of inhibition zones (IZs) of bacterial growth around
the discs in millimeters. Ampicillin and gentamycin (1 mg/ml)
were used as standard references for Gram‐positive and Gram‐
negative bacteria, respectively.
significant antimicrobial activity against most of the tested bacterial
and fungal pathogens. Results of antimicrobial screening showed that
most of the studied compounds displayed variable growth inhibitory
effects on the tested Gram‐positive and Gram‐negative bacterial
strains and fungal strains. In general, most of the tested quinolines
revealed a higher activity against the Gram‐positive strains than
Gram‐negative strains. It was also observed that there is no sig-
nificant variation between the antimicrobial activity of amide deri-
vatives 12–19 and both of ester derivatives 20–22 and hydrazide 23.
As expected, a clear difference in the activity is noted between de-
rivatives within the same series, pointing to the strengthening and
fading effects of substitution at C‐2 of the quinoline scaffold. The
diameter of IZs of the antifungal activity revealed almost the same
trend as the antibacterial activity. Concerning the effect of sub-
stitution at the terminal phenyl ring in amide derivatives 12–19, it is
evident that the change of such a substituent may have a remarkable
effect on the antimicrobial activity, which may be improved or de-
creased, depending on the electronic nature of such a substituent.
The type of the substitutions on the terminal phenyl ring is im-
portant. Except for compound 18, amide derivatives with electron‐
withdrawing substituents (12, 14, and 17) showed better activity
than other derivatives with electron‐donating substituents. The di-
minished activity of 18 may be attributed to the presence of three
bulky bromine atoms, which may interfere with the binding of such
compounds with the receptor site. Elongation of the linker moiety of
these amides, as in compound 19, revealed a negative impact on the
antimicrobial activity. Regarding esters 20–22, it was concluded that
the acetate derivatives 20 and 21 showed much better activity than
that of the propionate derivative 22. The hydrazide derivative 23
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2.2.2
Antifungal activity
The synthesized compounds were tested in vitro for their antifungal
activity against four human pathogenic strains: A. fumigatus, S. race-
mosum, G. candidum, and C. albicans. The agar diffusion method[27,28]
was also used for the evaluation of the initial screening of antifungal
activities. Amphotericin B (1 mg/ml) was used as a positive control.
Results for each test compound were recorded as the average dia-
meter of IZs, in millimeters, of fungal growth around the discs. IZ
diameters, attributed to the tested original concentration (5 mg/ml)
as a preliminary test, are shown in Table 2.
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2.2.3
Structure–activity relationship study
From the above‐mentioned data, the following observation can be
made: The mean values of the inhibitory zone diameter obtained for
the new compounds suggest that all the new derivatives possess a
TABLE 2 Antifungal activity of the new
compounds
Inhibition zone (mm)a
Aspergillus
fumigatus
Syncephalastrum
racemosum
Geotrichum
candidum
Candida
albicans
Compound no.
12
13
14
15
16
17
18
19
20
21
22
23
19.3 2.1
17.3 1.2
20.1 1.2
NA
17.2 0.25
16.2 0.44
18.3 0.58
NA
19.9 1.5
18.3 2.1
20.1 2.1
NA
NA
NA
NA
NA
NA
NA
NA
NA
18.3 1.2
NA
19.3 0.58
NA
20.4 2.1
NA
NA
NA
NA
NA
NA
NA
19.3 0.63
NA
19.9 2.1
NA
20.6 0.58
NA
NA
NA
17.3 2.1
19.5 1.2
16.4 0.58
20.1 0.63
19.7 0.72
19.1 1.5
21.3 2.1
28.7 0.58
NA
NA
Amphotericin B 23.7 0.63
Abbreviation: NA, no activity.
aMean zone of inhibition in millimeters standard deviation for at least three experiments.
25.4 0.63

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obtained with compounds 20 and 23, which gave very promising
results with activity ≥85% in comparison to the standard drugs. Also,
the same two compounds showed the best activity against B. subtilis
and the Gram‐negative strain E. coli, which gave 66% and 96% effi-
cacy, respectively, relative to those of ampicillin and gentamicin. No
activity was observed against P. aeruginosa with any of the tested
compounds.
Regarding the antifungal activity, the highest potent compound
against A. fumigatus was 14 with 84.8% efficacy in comparison to the
standard drug. The best activities against S. racemosum and G. can-
didum were observed in the case of compound 23, with 95.12% and
74.2% efficacy, respectively, in comparison to amphotericin B. No
activity was observed against Candida albicans with any of the tested
compounds. A summary of the structure–activity relationship of the
most active derivatives, compared with standard antimicrobial
agents, is presented in Figures 2 and 3.
14
20
23
FIGURE 2 The comparison between the inhibition zones of
compounds 14, 20, and 23, and standard drugs against three tested
Gram‐positive and Gram‐negative bacterial strains
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2.2.4
Minimum inhibitory concentration (MIC) and
in vitro enzyme assay
Compounds that revealed the highest potent activity in the pre-
liminary antimicrobial evaluation (14, 17, 20, and 23) were subjected
to further biological studies to determine their MICs[29] against the
selected bacterial and fungal pathogens as well as their in vitro ac-
tivity against the E. coli DNA gyrase. The in vitro capability of se-
lected compounds to inhibit DNA gyrase enzyme was evaluated using
the DNA gyrase supercoiling assay[30] to realize whether their effect
is mediated via inhibition of this enzyme. Novobiocin was used as a
positive control. The obtained MIC values, together with the IC50
values, of these compounds as DNA gyrase inhibitors and reference
drugs are presented in Table 3. The tabulated results revealed that
the amide derivatives 14 and 17 showed low MIC values as com-
pared with the ester and hydrazide derivatives 20 and 23. In parti-
cular, the compound with two halogen substituents (14) was the
highest potent compound with MIC values of 0.98, 0.74, 3.98, 0.79,
14
23
FIGURE 3 The comparison between the inhibition zones of
compounds 14 and 23 and standard drug against three tested fungal
strains
showed promising activities against all the selected bacterial and
fungal strains, except P. aeruginosa and C. albicans.
In particular, the antibacterial activity of the synthesized com-
pounds revealed that the highest activity against S. pneumoniae was
TABLE 3 Minimum inhibitory concentrations (MIC in μg/ml) and DNA gyrase activity (IC50 in μM) of new compounds
Minimum inhibitory concentrations (MIC in μg/ml)
Gram‐positive bacteria
Gram‐negative bacteria
Fungi
DNA gyrase
activity
Streptococcus
pneumoniae
Bacillus
subtilis
Pseudomonas
aeruginosa
Escherichia Aspergillus
Syncephalastrum
racemosum
Geotrichum
candidum
Candida
albicans
Compound no.
coli
fumigatus
0.79
1.35
1.49
1.28
NT
(IC50 in μM)
14
0.98
1.15
2.15
1.95
0.96
NT
0.74
0.98
1.82
1.95
0.47
NT
NT
3.98
4.21
5.49
4.49
NT
3.80
3.93
4.65
4.07
NT
0.66
0.98
1.04
0.98
NT
NT
NT
NT
NT
NT
NT
0.51
NT
3.39 0.25
7.10 1.50
26.50 1.32
18.52 1.05
NT
17
NT
20
NT
23
NT
Ampicillin
Gentamicin
NT
15.38
NT
3.70
NT
NT
NT
NT
NT
Amphotericin B NT
NT
0.92
NT
3.96
NT
0.51
NT
NT
Novobiocin
NT
NT
NT
NT
1.84 0.11
Abbreviation: NT, not tested.

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Molecular Operating Environment (MOE) software, utilizing the
flexible docking protocol implemented in the MOE software, and
using the 4DUH complex retrieved from Protein Data Bank. The
latter complex was prepared by the removal of solvent molecules and
the internal ligand, followed by protonation of protein. Initially, a
flexible docking of the original ligand (RLI) was carried out to validate
the reliability of this enzyme model. Next, one of the four most active
compounds was added for computational analysis. At the end of
the molecular docking procedure, docking poses were scored and
selected, depending on the calculated energy of binding. The binding
mode of the original co‐crystallized ligand, RLI[31] with the pocket of
DNA gyrase enzyme, exhibited a binding energy of −13.85 kcal/mol.
There are two main interactions between RLI and the binding site of
the receptor (Figure 4): (a) two hydrogen‐bonding interactions be-
tween the terminal carboxylate group of RLI and Arg76 and Arg136
residues; (b) two hydrogen‐bonding interactions between the NH and
S atom of the thiazole ring of RLI and the Gly101 residue. Free
energies of binding, hydrophobic interaction, and hydrogen bonding
interactions of selected compounds and that of the original ligand are
presented in Table 4.
FIGURE 4 Three‐dimensional interactions of RLI with the active
site of DNA gyrase
3.80, and 0.66 μg/ml against S. pneumoniae, B. subtilis, E. coli,
A. fumigatus, S. racemosum, and G. candidum, respectively, compared
with 0.96, 0.47, 3.70, 0.92, 3.96, and 0.51 μg/ml of reference drugs.
Also, the same compound revealed the best activity as a DNA gyrase
inhibitor with an IC50 value of 3.39 μM as compared with 1.84 μM of
novobiocin.
The behavior of the new compounds in the pocket of DNA gyr-
ase is summarized in Figure 5, which is almost similar to the RLI drug.
The binding mode of compound 14 exhibited an affinity value of
−13.59 kcal/mol, which is much better than that of the internal li-
gand. Adhering to almost the same interaction pattern of RLI with the
binding site of DNA gyrase, the carbonyl oxygen of 14 formed a
hydrogen bond with the Arg136 residue. The sulfur atom formed one
more hydrogen bond with the Glu50 residue. An additional hydro-
phobic interaction is formed between the quinoline ring scaffold and
the Arg136 residue (Figure 5). These three desirable interactions of
compound 14 might explain the good activity of such derivative as an
antimicrobial agent. Independently, compound 17 revealed an affinity
value of −10.49 kcal/mol and exhibited a different virtual binding
|
2.3
Molecular docking study
To rationalize the mechanism of action of the four most active
compounds, a molecular docking study was conducted to give gui-
dance concerning their molecular binding modes inside the pocket of
DNA gyrase enzyme. The in silico docking study was performed using
TABLE 4 In silico docking results of the
most active compounds with the binding
Hydrogen bonding interactions
Hydrophobic
ΔG
Compound no.
14
(kcal/mol)
Distance (Å)
Residue
interaction
site of DNA gyrase
−13.59
3.16
3.12
3.28
Arg136
Glu50
Arg136
Gly101
17
20
23
−10.49
−12.68
−11.10
3.68
2.61
Asn46
–
Lys103
3.35
2.94
Asp73
Gly77
Lys103
Lys103
3.01 bidirectional
Asp73
Asp73
Gly77
3.40
2.94
RLI
−12.23
3.06
Arg76
–
3.15
Arg136
Gly101
Gly101
3.63 bidirectional
2.81

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EL‐SHERSHABY ET AL.
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FIGURE 5 Three‐dimensional interactions of compounds 14 (upper left panel), 17 (upper right panel), 20 (lower left panel), and 23 (lower
right panel) with the active site of DNA gyrase enzyme
mode with the DNA gyrase enzyme. The nitrile nitrogen formed a
hydrogen bond with Lys103 residue, whereas the sulfur atom formed
another hydrogen bond with the Asn46 residue. The ester derivative
20 also exhibited a different virtual binding mode with that of 14.
The ester derivative 20 revealed an affinity value of −10.98 kcal/mol
and showed three different interaction patterns with the binding site
of DNA gyrase receptor. These interactions involve two hydrogen
bonds between the sulfur atom and nitrile nitrogen in the target
compounds with Asp73 and Gly77 residues, respectively. The third
interaction is the form of arene–H hydrophobic interaction between
the benzene of quinoline ring scaffold and the Lys103 residue. The
obtained docking result for the hydrazide derivative 23 is virtually
the same as that of compound 20. With −11.10 kcal/mol free energy
of binding, the binding mode of 23 involves two hydrogen bonds
between the sulfur atom and nitrile nitrogen in the target compounds
with Asp73 and Gly77 residues, respectively. A bidirectional hydro-
gen bond is also formed between the NH fragment of 23 and the
Asp73 residue. The last interaction is similar to that of 20, an
arene–H hydrophobic interaction between the benzene of quinoline
ring scaffold and the Lys103 residue.
directions of the Lipinski's rule of five.[32] Lipinski proposed that the
absorption of an orally administered compound is more likely to be
good enough if the molecule obeys at least three rules of the following:
(a) molecular weight <500; (b) H‐bond donors (OH, NH, and SH) ≤ 5;
(c) H‐bond acceptors (N, O, and S atoms) ≤ 10; (d) logP < 5. The bioa-
vailability of molecules that violate more than one of these rules is
expected to be not good. Whereas the reference compound drugs
gentamicin and amphotericin B violated two or more of Lipinski's rules,
all the highest active derivatives in this study satisfied all the Lipinski's
rules, except compound 14, which only violated logP. All derivatives
own a limited number of hydrogen bond acceptors (between 4 and 6)
and only two or less hydrogen bond donor groups. These numbers of
H‐bond acceptors and donors in the new compounds agree satisfacto-
rily with Lipinski's rules. In addition, ADMET profiles of the new qui-
noline derivatives were preliminary evaluated to determine their
possibility to be developed as good oral drug candidates. The pharma-
cokinetic profile of a compound detects how it would be absorbed,
distributed, metabolized, and excreted (ADME). Although the ideal
binding of a drug to the protein target is critical, making sure that it will
arrive at this therapeutic target in a relatively adequate concentration is
also essential to produce the biological effect. ADMET profiles have
been predicted using the pkCSM descriptors algorithm protocol.[33] Two
main structural aspects correlate properly with pharmacokinetic prop-
erties, the 2D polar surface area (PSA_2D) and the lipophilicity levels
(logP). The absorption of a drug depends on several factors including
intestinal absorption, membrane permeability, skin permeability, and
P‐glycoprotein substrate or inhibitor. Drug distribution depends on the
|
2.4
Pharmacokinetic study
In the present study, an in silico computational analysis of compounds
with a promising antimicrobial activity was conducted to determine
their surface areas and other physicochemical properties according to

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EL‐SHERSHABY ET AL.
|
TABLE 5 ADMET profile of the four most active compounds and reference drugs
Parameter
14
17
20
23
Ampicillin
Gentamicin
Amphotericin B
Molecular properties
Molecular weight
LogP
402.306
378.413
272.329
272.333
349.412
477.603
924.091
0.7117
3
5.4525
4.0539
2.68
1.4969
0.3181
−3.3275
Rotatable bonds
H‐bond acceptors
H‐bond donors
Surface area
4
5
3
3
4
7
4
6
5
5
5
12
17
1
1
0
2
3
8
12
164.683
158.730
114.948
114.330
143.121
194.977
380.536
Absorption
Water solubility
−5.713
0.618
91.751
−2.822
Yes
−4.922
0.899
95.038
−2.769
Yes
−3.418
1.062
97.334
−2.642
No
−2.638
−0.105
84.168
−3.069
Yes
−2.396
0.395
43.034
−2.735
No
−2.56
−0.164
13.46
−2.735
Yes
−2.937
−0.597
0
Caco2 permeability
Intestinal abs. (human)
Skin permeability
−2.735
Yes
P‐glycoprotein substrate
P‐glycoprotein I inhibitor
P‐glycoprotein II inhibitor
Yes
Yes
No
No
No
No
No
Yes
Yes
No
No
No
No
No
Distribution
VDss (human)
0.09
−0.076
0.022
−0.175
0.196
−0.178
0.247
−1.23
−0.967
0.94
−0.37
Fraction unbound (human)
BBB permeability
CNS permeability
0.027
0.072
−1.554
0.752
0.541
−0.648
−1.996
−0.26
−0.474
−2.939
−0.767
−3.166
−1.593
−5.49
−2.058
−3.718
−2.853
Metabolism
CYP2D6 substrate
CYP3A4 substrate
CYP1A2 inhibitor
CYP2C19 inhibitor
CYP2C9 inhibitor
CYP2D6 inhibitor
CYP3A4 inhibitor
No
No
No
No
Yes
Yes
No
No
No
No
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No
Yes
Yes
Excretion
Total clearance
Renal OCT2 substrate
0.307
Yes
0.139
No
0.427
No
0.082
No
0.337
No
0.722
No
−1.495
No
Toxicity
Ames toxicity
Yes
Yes
Yes
Yes
No
No
No
Max. tolerated dose (human)
hERG I inhibitor
hERG II inhibitor
0.281
No
0.038
No
0.513
No
0.338
No
0.952
No
0.694
No
0.292
No
Yes
No
No
No
No
No
No
Oral rat acute toxicity (LD50
Oral rat chronic toxicity (LOAEL)
Hepatotoxicity
)
2.424
0.711
No
2.721
1.346
Yes
2.336
0.743
Yes
2.582
1.447
Yes
1.637
2.398
Yes
2.016
3.506
No
2.518
2.049
No
Skin sensitization
No
No
No
No
No
No
No
Tetrahymena pyriformis toxicity
Minnow toxicity
1.515
−2.85
0.857
−2.108
1.073
−0.327
0.584
2.279
0.285
4.232
0.285
5.959
0.285
11.261
Abbreviations: BBB, blood–brain barrier; CNS, central nervous system; VDss, volume of distribution.
volume of distribution (VDss), the blood–brain barrier permeability
(logBB), and central nervous system (CNS) permeability. Metabolism is
predicted depending on the CYP models for substrate or inhibition.
Excretion is predicted on the basis of the total clearance and the renal
OCT2 substrate. Toxicity of the drugs is predicted on the basis of Ames
toxicity, hERG inhibition, hepatotoxicity, and skin sensitization. These
parameters were calculated for the four highest potent quinoline deri-
vatives, 14, 17, 20, and 23, as well as for reference marketed anti-
microbial agents. After evaluation of the ADMET properties (Table 5),
we can propose that these derivatives have the advantage of better

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EL‐SHERSHABY ET AL.
|
intestinal absorption in humans over all the reference drugs
(84.168–97.334), with zero in the case of amphotericin and
revealed a significant potent inhibitory activity of compound 14 with an
IC50 value of 3.39 μM. In addition, the structure–activity relationship of
the synthesized compounds was discussed. Also, a molecular docking
study of the most active compounds was carried out to predict the
binding affinity toward the active site of DNA gyrase enzyme as a
proposed target of their activity. Furthermore, ADMET profiles of the
highest effective derivatives were examined to evaluate the potentials
of the new compounds to be developed as good drug candidates. This
study led to the identification of four novel quinoline derivatives with an
interesting antimicrobial activity and DNA inhibitory potentials at re-
latively low micromolar concentrations.
B
13.46–43.034 in the case of ampicillin and gentamicin, respectively. This
advantage may be attributed to the superior lipophilicity of the new
ligands, which would make it easier to pass through the biological
membranes.[34] Therefore, they may have a good bioavailability after
the oral administration. The analysis of the CNS permeability revealed
that the amide derivative 14 displayed the highest ability to penetrate
the CNS (CNS permeability = −1.55), whereas the reference anti-
microbials displayed lower abilities to penetrate (CNS permeability ≤
−3.16). Additionally, it was clear that in contrast to the three reference
drugs, all the new compounds, except 20, could inhibit the main cyto-
chrome involved in drug metabolism, cytochrome P3A. This may also
attribute to the higher lipophilicity of our newly synthesized quinolines.
Excretion was evaluated in the terms of total clearance, a parameter
that is associated with bioavailability and is taken into account while
deciding dose timing intervals. Observed data demonstrated that the
ester derivative 20 and gentamicin revealed the highest total clearance
values (0.427 and 0.722, respectively), compared with other ligands,
especially 17, and amphotericin B, which showed the lowest total
clearance value (0.139 and −1.495, respectively). Thus, 17 is expected to
be excreted faster and consequently needs shorter dosing intervals. The
last parameter studied in the ADMET profile of our newly synthesized
quinolines is the toxicity. As shown in Table 5, ampicillin and all the new
ligands, except 14, share the disadvantage of hepatotoxicity. One critical
disadvantage of the new quinolines is the probability of Ames toxicity,
which means that the new ligands are expected to be mutagenic and
hence may act as a carcinogen. Our designed compound 20 sa-
tisfactorily showed comparable tolerability (0.513) with that of ampi-
cillin and gentamicin and better tolerability than that of amphotericin B
|
4
EXPERIMENTAL
|
4.1
Chemistry
|
4.1.1
General
Melting points were measured using an Electrothermal (Stuart
SMP30) apparatus and were uncorrected. Infrared spectra were
recorded on a Pye Unicam SP1000 IR spectrophotometer at the
Pharmaceutical Analytical Unit, Faculty of Pharmacy, Al‐Azhar Uni-
versity. 1H NMR and 13C NMR spectra were recorded in dimethyl
sulfoxide (DMSO)‐d6 at 300 and 100 MHz, respectively, on a Varian
Mercury VXR‐300 NMR spectrometer at NMR Lab, Faculty of Sci-
ence, Cairo University. Chemical shifts were related to that of the
solvent, and tetramethylsilane was used as an internal standard.
Coupling constant and chemical shift values are mentioned in Hz and
ppm, respectively. Mass spectra and elemental analyses were carried
out at the Regional Center for Mycology and Biotechnology,
Al‐Azhar University, Cairo, Egypt. The progress of reactions was
monitored with Merck silica gel IB2‐F plates (0.25 mm thickness) and
was visualized under a UV lamp using different solvent systems as
mobile phases. Reagents and starting p‐toluidine, phosphorus
oxychloride, chloroacetyl chloride, chloropropionyl chloride, and aniline
derivatives were purchased from Sigma‐Aldrich chemical company and
were used as received. 2‐Chloro‐N‐arylacetamides and 3‐chloro‐N‐
arylpropanamides were prepared following the reported
procedures.[21,35] Compound 11 was synthesized according to
directions of previously reported procedures.[8,13]
(0.292). Finally, the oral acute toxic doses of the new compounds (LD50
)
are also close to that of gentamicin and amphotericin B, which are
higher than that of ampicillin.
|
3
CONCLUSION
The present study reports the synthesis and in vitro antimicrobial
evaluation of novel quinoline derivatives as potential DNA gyrase in-
hibitors. The preliminary antimicrobial activity was assessed against a
panel of pathogenic microbes including two Gram‐positive bacteria
(S. pneumoniae and B. subtilis), two Gram‐negative bacteria (P. aeruginosa
and E. coli), and four fungal strains (A. fumigatus, S. racemosum, G. can-
didum, and C. albicans). The highest active compounds were subjected to
further biological studies to determine their MICs against the selected
pathogens as well as their in vitro activity against the E. coli DNA gyrase
to realize whether their effect is mediated via inhibition of this enzyme.
Four of the new derivatives (14, 17, 20, and 23) displayed a relatively
potent antimicrobial activity with MIC values ranging between 0.66 and
5.29 μg/ml. Among them, compound 14 exhibited a particularly potent
broad‐spectrum antimicrobial activity against the majority of the tested
strains, with MIC values ranging from 0.66 to 3.98 μg/ml. A subsequent
in vitro investigation against the bacterial DNA gyrase target enzyme
The InChI codes of the investigated compounds, together with
some biological activity data, are provided as Supporting Information.
|
4.1.2
General procedures for the synthesis of 2‐
[(3‐cyano‐6‐methylquinolin‐2‐yl)thio]‐N‐
arylacetamides and 3‐[(3‐cyano‐6‐methylquinolin‐
2‐yl)thio]‐N‐(m‐tolyl)propanamides 12–19
As displayed in Scheme 2, 2‐mercapto‐6‐methylquinoline‐3‐carbonitrile
(0.20 g, 0.001 mol) was suspended in a solution of potassium
carbonate (0.025 mol) in DMF (30 ml). An appropriate quantity of

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EL‐SHERSHABY ET AL.
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2‐chloro‐N‐arylacetamide
or
3‐chloro‐N‐arylpropanamide
(s, 1H, quinoline‐H4), 7.90 (d, 1H, J = 9 Hz, quinoline‐H8), 7.72 (d, 2H,
J = 6 Hz, phenyl‐H3, H5), 7.43 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.31
(t, 1H, J = 6 Hz, phenyl‐H4) 7.50 (s, 1H, quinoline‐H5), 4.31 (s, 2H,
S–CH2), 2.5 (s, 3H, CH3). 13C NMR (DMSO‐d6, 100 MHz) δ (ppm):
18.06 (CH3), 34.70 (S–CH2), 104.51, 115.85, 126.48, 127.27, 127.48,
127.57, 134.99, 135.25, 135.62, 135.78, 143.46, 146.41, and 156.12
(aromatic carbons), 123.82 (C≡N), and 165.52 (C═O). MS (m/z): 403
(C19H13Cl2N3OS, 2.1%, M+2), 401 (C19H13Cl2N3OS, 3.8%, M+), 241
(C13H9N2OS, 100%), 199 (C11H7N2S, 13.9%), 167 (C11H7N2, 34.7%).
Anal. calc. for C19H13Cl2N3O2S (M.W. = 401): C, 56.73; H, 3.26;
N, 10.45%; found: C, 56.91; H, 3.39; N, 10.66%.
derivative[36–38] (0.011 mol) was added, and the reaction mixture was
heated to 120°C for 7 hr with continuous stirring. After the reaction was
completed (monitored by TLC), the mixture was allowed to stand
overnight. Later, after adding distilled cold water (100 ml), the obtained
solid products were collected through filtration, washed with three
repetitive portions of cold water (100 ml each) to remove the side salt
product triethylammonium chloride, dried, crystallized from ethanol, and
finally purified by using the column chromatography technique using
hexane ethyl acetate as an eluent to afford the pure amide derivatives
(12–29) in reasonable yields.
N‐(4‐Chlorophenyl)‐2‐[(3‐cyano‐6‐methylquinolin‐2‐yl)thio]-
acetamide (12)
Yellowish white solid. Yield: 85%; m.p. 230°C. IR (KBr) cm−1: 3,295
2‐[(3‐Cyano‐6‐methylquinolin‐2‐yl)thio]‐N‐(2,6‐dimethylphenyl)-
acetamide (15)
White solid. Yield: 70%; m.p. 270°C. IR (KBr) cm−1: 3,249 (NH), 3,028
(CH aromatic), 2,984 (CH aliphatic), 2,222 (C≡N), 1,660 (C═O). 1H
NMR (DMSO‐d6) δ ppm: 9.6 (s, 1H, NH, D2O‐exchangeable), 8.9 (s, 1H,
quinoline‐H4), 7.91 (d, 1H, J = 9 Hz, quinoline‐H8), 7.83 (d, 2H, J = 6 Hz,
phenyl‐H3, H5), 7.72 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.02 (t, 1H,
J = 6 Hz, phenyl‐H4), 7.54 (s, 1H, quinoline‐H5), 4.33 (s, 2H, S–CH2),
2.50 (s, 3H, quinoline‐CH3), 2.08 (s, 6H, phenyl‐2CH3). 13C NMR
(DMSO‐d6, 100 MHz) δ (ppm): 18.06, 20.26, 33.71 (aliphatic carbons),
104.52, 115.86, 126.49, 127.28, 127.49, 127.58, 135.00, 135.26,
135.63, 136.78, 143.47, 146.42, and 156.13 (aromatic carbon atoms),
123.83 (C≡N), and 165.53 (C═O). MS (m/z), 361 (C21H19N3OS, .85%,
M+), 241 (C13H9N2OS, 90.6%), 213 (C12H9N2S, 100%), 199 (C11H7N2S,
18.3%). Anal. calc. for C21H19N3OS (M.W. = 361): C, 69.78; H, 5.3;
N, 11.63%; found: C, 69.91; H, 5.39; N, 11.76%.
(NH), 3,051 (CH aromatic), 2,904 (CH aliphatic), 2,221 (C≡N), 1,689
(C═O). 1H NMR (DMSO‐d6)
δ ppm: 9.89 (s, 1H, NH, D2O‐
exchangeable), 8.9 (s, 1H, quinoline‐H4), 7.8 (d, 1H, J = 9.0 Hz,
quinoline‐H8), 7.5 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.4 (d, 2H,
J = 9.6 Hz, phenyl‐H2, H6), 7.1 (d, 2H, J = 9.6 Hz, phenyl‐H3, H5), 7.3
(s, 1H, quinoline‐H5), 4.37 (s, 2H, S–CH2), 2.49 (s, 3H, CH3). 13C NMR
(DMSO‐d6, 100 MHz) δ (ppm): 18.11 (CH3), 34.75 (S–CH2), 104.56,
115.90, 126.53, 127.32, 127.53, 127.62, 135.04, 135.30, 135.67,
135.83, 143.51, 146.45, and 156.17 (aromatic carbons), 123.84
(C≡N), and 165.57 (C═O). MS (m/z): 369 (C19H14ClN3OS, 1.53%, M
+2), 367 (C19H14ClN3OS, 4.17%, M+), 241 (C13H9N2OS, 100%), 213
(C12H9N2S, 46.37%), 199 (C11H7N2S, 1.52%), 167 (C11H7N2, 15.69%),
90 (C7H6, 4%). Anal. calc. for C19H14ClN3OS (M.W. = 367): C, 62.04;
H, 3.42; N, 11.42%; found: C, 62.16; H, 3.91; N, 11.53%.
2‐[(3‐Cyano‐6‐methylquinolin‐2‐yl)thio]‐N‐(4‐methoxyphenyl)-
acetamide (16)
Greyish white solid. Yield: 85%; m.p. 225°C. IR (KBr) cm−1: 3,257
2‐[(3‐Cyano‐6‐methylquinolin‐2‐yl)thio]‐N‐(m‐tolyl)acetamide (13)
Yellowish solid. Yield: 85%; m.p. 210°C. IR (KBr) cm−1: 3,254 (NH),
3,043 (CH aromatic), 2,976 (CH aliphatic), 2,223 (C≡N), 1,662 (C═O).
1H NMR (DMSO‐d6) δ ppm: 10.30 (s, 1H, NH, D2O‐exchangeable),
8.81 (s, 1H, quinoline‐H4), 7.82 (d, 1H, J = 9.0 Hz, quinoline‐H8), 7.77
(d, 1H, J = 9.0 Hz, quinoline‐H7), 7.53 (s, 1H, phenyl‐H2), 7.44 (s, 1H,
quinoline‐H5), 7.32 (d, 1H, J = 7.8 Hz, phenyl‐H6), 7.25 (t, 1H,
J = 10.80 Hz, phenyl‐H5), 6.80 (d, 1H, J = 6 Hz, phenyl‐H4), 4.29
(s, 2H, S–CH2), 2.26 (s, 3H, quinoline‐CH3), 2.26 (s, 3H, phenyl‐CH3).
13C NMR (DMSO‐d6, 100 MHz) δ (ppm): 18.09 (CH3), 19.17 (CH3),
34.73 (S–CH2), 104.54, 115.90, 126.51, 127.30, 127.54, 127.60,
135.05, 135.32, 135.69, 135.85, 143.51, 146.43, and 156.16 (aro-
matic carbons), 123.86 (C≡N), and 165.55 (C═O). MS (m/z): 347
(C20H17N3OS, 9.6%, M+), 241 (C13H9N2OS, 100%), 213 (C12H9N2S,
70.6%), 199 (C11H7N2S, 2.5%), 167 (C11H7N2, 28.1%), 90 (C7H6,
2.8%). Anal. calc. for C20H17N3OS (M.W. = 347): C, 69.14; H, 4.93;
N, 12.09%; found: C, 69.36; H, 5.1; N, 12.26%.
(NH), 3,049 (CH aromatic), 2,922 (CH aliphatic), 2,223 (C≡N), 1,662
(C═O). 1H NMR (DMSO‐d6)
δ ppm: 10.26 (s, 1H, NH, D2O‐
exchangeable), 8.82 (s, 1H, quinoline‐H4), 7.85 (d, 1H, J = 9.0 Hz,
quinoline‐H8), 7.7 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.51 (d, 2H,
J = 9.6 Hz, phenyl‐H2, H6), 6.82 (d, 2H, J = 9.6 Hz, phenyl‐H3, H5),
7.43 (s, 1H, quinoline‐H5), 4.24 (s, 2H, S–CH2), 3.34 (s, 3H, phenyl‐
OCH3), 2.40 (s, 3H, quinoline‐CH3). 13C NMR (DMSO‐d6, 100 MHz)
δ (ppm): 18.19 (CH3), 34.83 (S–CH2), 57.26 (OCH3), 104.64, 115.98,
126.61, 127.40, 127.64, 127.70, 135.15, 135.42, 135.79, 135.95,
143.61, 146.53, and 156.26 (aromatic carbons), 123.88 (C≡N), and
165.65 (C═O). MS (m/z): 363 (C20H17N3O2S, 9.4%, M+), 241
(C13H9N2OS, 21.54%), 213 (C12H9N2S, 14.9%), 123 (C7H9NO, 100%).
Anal. calc. for C20H17N3O2S (M.W. = 363): C, 66.10; H, 4.71; N,
1.56%; found: C, 66.19; H, 4.74; N, 11.61%.
2‐[(3‐Cyano‐6‐methylquinolin‐2‐yl)thio]‐N‐(4‐nitrophenyl)-
acetamide (17)
Yellowish white solid. Yield: 85%; m.p. 230°C. IR (KBr) cm−1: 3,227
2‐[(3‐Cyano‐6‐methylquinolin‐2‐yl)thio]‐N‐(2,6‐dichlorophenyl)-
acetamide (14)
White solid. Yield: 85%; m.p. 250°C. IR (KBr) cm−1: 3,241 (NH), 3,022
(CH aromatic), 2,957 (CH aliphatic), 2,226 (C≡N), 1,673 (C═O). 1H
NMR (DMSO‐d6) δ ppm: 10.20 (s, 1H, NH, D2O‐exchangeable), 8.9
(NH), 3,043 (CH aromatic), 2,929 (CH aliphatic), 2,221 (C≡N), 1,675
(C═O). 1H NMR (DMSO‐d6)
exchangeable), 8.9 (s, 1H, quinoline‐H4), 8.21 (d, 1H, J = 9.0 Hz,
δ ppm: 11.02 (s, 1H, NH, D2O‐

12 of 14
EL‐SHERSHABY ET AL.
|
quinoline‐H8), 7.80 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.71 (d, 2H,
J = 9.6 Hz, phenyl‐H2, H6), 7.13 (d, 2H, J = 9.6, phenyl‐H3, H5), 7.36
(s, 1H, quinoline‐H5), 4.37 (s, 2H, S–CH2), 2.46 (s, 3H, CH3). 13C NMR
(DMSO‐d6, 100 MHz) δ (ppm): 18.15 (CH3), 34.79 (S–CH2), 104.60,
115.95, 126.57, 127.36, 127.63, 127.68, 135.11, 135.38, 135.75,
135.98, 143.63, 146.47, and 156.21 (aromatic carbons), 123.85
(C≡N), and 165.62 (C═O). MS (m/z): 378 (C19H14N4O3S, 3.26%, M+),
241 (C13H9N2OS, 100%), 199 (C11H7N2S, 2.86%), 167 (C11H7N2,
27.8%). Anal. calc. for C19H14N4O3S (M.W. = 378): C, 60.31; H, 3.73;
N, 14.81%; found: C, 60.39; H, 3.75; N, 14.89%.
(30 ml). An appropriate quantity of α‐chloroester derivative (0.011 mol)
was added, and the reaction mixture was heated to 90°C for 7 hr with
continuous stirring. After the reaction was completed (monitored by
TLC), the mixture allowed to stand overnight. Later, after adding dis-
tilled cold water (100 ml), the obtained solid products were collected
through filtration, washed with three repetitive portions of cold water
(100 ml each) to remove the side salt product triethylammonium
chloride, dried, crystallized from ethanol, and finally purified by using
column chromatography technique using hexane ethyl acetate as an
eluent to afford the pure amide derivatives (12–29) in reasonable yields.
2‐[(3‐Cyano‐6‐methylquinolin‐2‐yl)thio]‐N‐(2,4,6‐tribromophenyl)-
acetamide (18)
Methyl 2‐[(3‐cyano‐6‐methylquinolin‐2‐yl)thio]acetate (20)
Yellow solid. Yield: 85%; m.p. 135°C. IR (KBr) cm−1: 3,069 (CH aro-
matic), 2,953 (CH aliphatic), 2,222 (C≡N), 1,729 (C═O). 1H NMR
(DMSO‐d6) δ ppm: 9.12 (s, 1H, quinoline‐H4), 7.93 (d, 1H, J = 9.0 Hz,
quinoline‐H8), 7.60 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.54 (s, 1H,
quinoline‐H5), 3.82 (s, 2H, S–CH2), 3.32 (s, 3H, CO2CH3), 2.50 (s, 3H,
CH3). 13C NMR (DMSO‐d6, 100 MHz) δ (ppm): 20.09 (CH3), 30.73
(S–CH2), 51.17 (OCH3), 104.53, 122.50, 126.30, 128.93, 134.61,
138.54, 140.97, 144.68, 159.85 (aromatic carbons), 121.80 (C≡N),
and 169.56 (C═O). MS (m/z): 272 (C14H12N2O2S, 28.8%, M+), 241
(C13H9N2OS, 8.63%), 213 (C12H9N2S, 100%). Anal. calc. for
Yellow white solid. Yield: 75%; m.p. 285°C. IR (KBr) cm−1: 3,216 (NH),
3,045 (CH aromatic), 2,989 (CH aliphatic), 2,226 (C≡N), 1,663 (C═O), 636
(C–Br). 1H NMR (DMSO‐d6) δ ppm: 10.27 (s, 1H, NH, D2O‐exchangeable),
8.92 (s, 1H, quinoline‐H4), 7.98 (d, 1H, J = 9.0 Hz, quinoline‐H8), 7.91
(s, 2H, phenyl‐H3, H5), 7.75 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.78 (s, 1H,
quinoline‐H5), 4.36 (s, 2H, S–CH2), 2.36 (s, 3H, quinoline‐CH3). 13C NMR
(DMSO‐d6, 100 MHz) δ (ppm): 18.25 (CH3), 34.87 (S–CH2), 104.71,
116.06, 126.67, 127.46, 127.63, 127.78, 135.21, 135.47, 135.66, 136.09,
143.72, 146.56, and 156.30 (aromatic carbons), 123.87 (C≡N), and
165.71 (C═O). MS (m/z): 570 (C19H12Br3N3OS, 2.97%, M+2), 568
(C19H12Br3N3OS, 2.97%, M+), 241 (C13H9N2OS, 100%), 213 (C12H9N2S,
44.4%). Anal. calc. for C19H12Br3N3OS (M.W. = 570): C, 40.04; H, 2.12; N,
7.37%; found: C, 40.29; H, 2.33; N, 7.49%.
C14H12N2O2S (M.W. = 272): C, 61.75; H, 4.44; N, 10.29%; found:
C, 61.87; H, 4.49; N, 10.38%.
Ethyl 2‐[(3‐cyano‐6‐methylquinolin‐2‐yl)thio]acetate (21)
Yellow solid. Yield: 85%; m.p. 129°C. IR (KBr) cm−1: 3,060 (CH aro-
matic), 2,980 (CH aliphatic), 2,222 (C≡N), 1,731 (C═O). 1H NMR
(DMSO‐d6) δ ppm: 9.12 (s, 1H, H4), 7.9 (d, 1H, J = 8.4 Hz, quinoline‐
H8), 7.6 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.5 (s, 1H, H5), 4.3 (q, 2H,
J = 21 Hz, OCH2), 3.3 (s, 2H, S–CH2), 2.49 (s, 3H, CH3), 1.3 (t, 3H,
J = 15 Hz, –CH3). 13C NMR (DMSO‐d6, 100 MHz) δ (ppm): 15.12
(CH3), 20.09 (CH3), 30.72 (S–CH2), 58.17 (OCH2), 104.52, 122.50,
126.28, 128.86, 134.59, 138.54, 140.95, 144.66, 159.84 (aromatic
carbons), 121.81 (C≡N), and 169.58 (C═O). MS (m/z): 286
(C15H14N2O2S, 10.9%, M+), 241 (C13H9N2OS, 7.35%), 213 (C12H9N2S,
100%). Anal. calc. for C15H14N2O2S (M.W. = 286): C, 62.92; H, 4.93;
N, 9.78%; found: C, 62.45; H, 4.56; N, 9.78%.
3‐[(3‐Cyano‐6‐methylquinolin‐2‐yl)thio]‐N‐(m‐tolyl)-
propanamide (19)
Pale yellow solid. Yield: 85%; m.p. 230°C. IR (KBr) cm−1: 3,256 (NH),
3,021 (CH aromatic), 2,920 (CH aliphatic), 2,223 (C≡N), 1,647 (C═O).
1H NMR (DMSO‐d6) δ ppm: 9.30 (s, 1H, NH, D2O‐exchangeable), 8.86
(s, 1H, quinoline‐H4), 7.80 (d, 1H, J = 9.0 Hz, quinoline‐H8), 7.73 (d,
1H, J = 9.0 Hz, quinoline‐H7), 7.44 (s, 1H, phenyl‐H2), 7.31 (s, 1H,
quinoline‐H5), 7.20 (d, 1H, J = 7.8 Hz, phenyl‐H6), 7.1 (t, 1H, J = 15 Hz,
phenyl‐H5), 7.01 (d, 1H, J = 6 Hz, phenyl‐H4), 3.68 (t, 2H, S–CH2), 2.8
(t, 2H, CH2–C═O), 2.49 (s, 3H, quinoline‐CH3), 2.19 (s, 3H, phenyl‐
CH3). 13C NMR (DMSO‐d6, 100 MHz) δ (ppm): 20.09 (CH3), 19.17
(CH3), 34.73 (S–CH2), 32.73 (CH2CO), 104.53, 115.90, 126.50,
127.30, 127.53, 127.61, 135.04, 135.33, 135.68, 135.85, 143.51,
146.42, and 156.14 (aromatic carbons), 123.84 (C≡N), and 165.56
(C═O). MS (m/z): 361 (C21H19N3OS, 14.07%, M+), 255 (C14H11N2OS,
16.48%), 227 (C13H11N2S, 80.46%), 200 (C11H7N2S, 11.36%). Anal.
calc. for C21H19N3OS (M.W. = 361): C, 69.78; H, 5.30; N, 11.63%;
found: C, 69.96; H, 5.39; N, 11.76%.
Ethyl 2‐[(3‐cyano‐6‐methylquinolin‐2‐yl)thio]propanoate (22)
Yellow solid. Yield: 85%; m.p. 160°C. IR (KBr) cm−1: 3,052 (CH aro-
matic), 2,977 (CH aliphatic), 2,221 (C≡N), 1,729 (C═O). 1H NMR
(DMSO‐d6) δ ppm: 8.89 (s, 1H, quinoline‐H4), 7.90 (d, 1H, J = 9.0 Hz,
quinoline‐H8), 7.61 (d, 1H, J = 9.0 Hz, quinoline‐H7), 7.54 (s, 1H,
quinoline‐H5), 4.61 (q, 1H, J = 12 Hz, S–CH), 4.12 (q, 2H, J = 10.8 Hz,
OCH2), 2.36 (s, 3H, CH3), 1.62 (d, 3H, J = 12 Hz, S–CH–CH3), 1.15
(t, 3H, J = 15 Hz, CH2–CH3). 13C NMR (DMSO‐d6, 100 MHz) δ (ppm):
14.09 (CH3), 17.23 (CH3), 24.89 (CH3), 32.34 (S–CH), 60.04, (OCH2),
104.18, 115.67, 127.10, 131.23, 135.32, 143.50, 146.24, 147.11,
158.90 (aromatic carbon atoms), 123.74 (C≡N), and 168.48 (C═O).
MS (m/z): 300 (C16H16N2O2S, 7.17%, M+), 255 (C14H11N2OS, 4.59%),
227 (C13H11N2S, 100%). Anal. calc. for C16H16N2O2S (M.W. = 300):
C, 63.98; H, 5.37; N, 9.33%; found: C, 63.92; H, 5.46; N, 9.41%.
|
4.1.3
General procedures for the synthesis of alkyl
2‐[(3‐cyano‐6‐methylquinolin‐2‐yl)thio]acetate/
propanoate 20–22
2‐Mercapto‐6‐methylquinoline‐3‐carbonitrile (0.20 g, 0.001 mol) was
suspended in a solution of potassium carbonate (0.025 mol) in DMF

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4.1.4
Synthesis of 2‐[(3‐cyano‐6‐methylquinolin‐
Antimicrobial Susceptibility Testing: 11th Informational Supplement;
National Committee for Clinical Laboratory Standards.[29] The MIC
values were defined as the lowest concentration of each compound
that results in an inhibition of the visible growth of bacteria after
incubation at 37°C for 18–24 hr, as detected by unaided eye.
2‐yl)thio]acetohydrazide (23)
A mixture of 21 (10 mmol) and hydrazine hydrate 80% (0.5 ml,
10 mmol) in absolute ethanol (50 ml) was refluxed for 4 hr. The re-
action mixture was cooled in an ice bath and diluted with water
(50 ml). The produced precipitate was filtered off and recrystallized
from ethanol as transparent plates. Yield: 90%; m.p. over 290°C. IR
(KBr) cm−1: 3,418 (NH2), 3,125 (NH), 3,046 (CH aromatic), 2,983 (CH
aliphatic), 2,224 (C≡N), 1,666 (C═O). 1H NMR (DMSO‐d6) δ ppm:
8.86 (s, 1H, NH, D2O‐exchangeable), 9.38 (s, 1H, quinoline‐H4), 7.82
(d, 1H, J = 9.0 Hz, quinoline‐H8), 7.73 (d, 1H, J = 9.0 Hz, quinoline‐H7),
7.45 (s, 1H, quinoline‐H5), 4.30 (s, 2H, NH2), 4.07 (s, 2H, S–CH2), 2.55
(s, 3H, quinoline‐CH3). 13C NMR (DMSO‐d6, 100 MHz) δ (ppm): 14.09
(CH3), 39.89 (S–CH2), 104.18, 115.67, 127.10, 131.23, 135.32,
143.50, 146.24, 147.11, 158.90 (aromatic carbon atoms), 123.74
(C≡N), and 168.48 (C═O). MS (m/z): 272 (C13H12N4OS, 4.2%, M+),
240 (C13H9N2OS, 100.11%), 213 (C12H9N2S, 40.13%), 200
(C11H8N2S, 25.3%). Anal. calc. for C13H12N4OS (M.W. = 272):
C, 57.34; H, 4.44; N, 20.57%; found: C, 57.41; H, 4.41; N, 20.61%.
|
4.2.3
DNA gyrase supercoiling inhibition assay
IC50 values were determined using high‐throughput assay[30] on
black streptavidin‐coated 96‐well microtiter plates. Novobiocin was
used as a positive control. IC50 values were calculated using the
GraphPad Prism software and they represent the concentration of a
compound where the residual enzyme activity is 50%, as observed in
three independent tests. Results are given as their average values in
μM (see Supporting Information Data).
|
4.3
Docking studies
Molecular docking experiments were conducted by MOE builder
within the MOE software suite (MOE2014, https://www.chemcomp.
com/Products.htm) to evaluate the binding free energy and to dis-
cover the binding mode toward DNA gyrase enzyme (PDB: 4DUH,
resolution: 2.70 Å, https://www.rcsb.org/structure/4DUH), which is
considered as a target for docking simulation.[31] The crystal struc-
ture of the protein was first prepared by removing water molecules
and retaining the essential chain and the internal co‐crystallized
ligand (RLI). Next, hydrogen atoms were added to the structure, the
energy was minimized, and the binding pocket of the protein was
defined. The 3D structures of new quinolines were sketched using
ChemDraw3D 15.0, their energies were minimized, and finally saved
in molfile format. Molecular docking of the four most active quinoline
derivatives was performed by the default protocol against the target
receptor. In each case, 20 docked poses were generated using ge-
netic algorithm searches, and Affinity dG and London dG were used
for Scoring 1 and Scoring 2, respectively. The London dG scoring
function predicts the free energy of binding of the ligand from a given
pose. The functional form is a sum of terms:
|
4.2
In vitro antimicrobial evaluation
The agar diffusion method[39,40] was used for the determination of
antibacterial and antifungal activity. The microorganisms were
spread uniformly using sterile cotton swabs on a sterile malt extract
agar Petri dish for fungi and nutrient agar for bacteria. A volume of
100 cm3 of each sample was added to each well (10‐mm‐diameter
holes were cut in the agar gel, 20 mm apart from one another). The
systems were incubated for 24–48 hr at 37°C for bacteria and at
28°C for fungi. After the incubation period, microorganism growth
was observed, and the IZs of the bacterial and fungal growth were
measured in millimeters. Tests were performed in triplicate.
|
4.2.1
Determination of the IZs
Here, 75 μl from a solution of each test compound (1 mg/ml in DMF) was
put in a 6‐mm‐diameter well in an agar plate seeded with the appro-
priate test pathogen in triplicates. Ampicillin (5.0 μg/disc), gentamicin
(5.0 μg/disc), and amphotericin B (100.0 μg/disc) were used as standards
for Gram‐positive, Gram‐negative antibacterial, and antifungal agents,
respectively. DMF as a negative control showed no IZ. Plates were in-
cubated at 37°C for 24 hr. Samples that showed IZ ≥ 19 mm were se-
lected for further biological evaluation to measure their MIC.[39]
ΔG = C + Eflex
+
CHBFHB
+
CMFM
∑
m−lig
+
atom iΔDi,
∑
∑
h−bond
where C is the average gain or loss of rotational and translational
entropy; Eflex represents the energy upon loss of flexibility of the
ligand; CHB and FHB are the energy of an ideal hydrogen bond and the
geometric imperfections of hydrogen bonds, respectively; CM and FM
represent the energy of an ideal metal ligation and the measure of
geometric imperfections of metal ligations, respectively; and Di is the
desolvation energy of an atom i.
|
4.2.2
Determination of the MIC
The MICs of derivatives that showed IZ ≥ 19 mm and reference drugs
were determined as described by the Performance Standards for
CONFLICTS OF INTERESTS
The authors declare that there are no conflicts of interests.

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ORCID
[23] A. A. El‐Helby, H. Sakr, I. H. Eissa, H. Abulkhair, A. A. Al‐Karmalawy,
K. El‐Adl, Arch. Pharm. 2019, 352, 1900113. https://doi.org/10.1002/
ardp.201900113
Khaled El‐Adl
http://orcid.org/0000-0002-8922-9770
http://orcid.org/0000-0001-8898-8452
Hany E. A. Ahmed
[24] S. Ihmaid, H. E. A. Ahmed, A. Al‐Sheikh Ali, Y. E. Sherif, H. M. Tarazi, S.
M. Riyadh, M. F. Zayed, H. S. Abulkhair, H. S. Rateb, Bioorg. Chem.
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[25] H. Abul‐Khair, S. Elmeligie, A. Bayoumi, A. Ghiaty, A. El‐Morsy, M. H.
Hassan, J. Heterocycl. Chem. 2013, 50, 1202. https://doi.org/10.1002/
jhet.714
Hamada S. Abulkhair
http://orcid.org/0000-0001-6479-4573
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How to cite this article: El‐Shershaby MH, El‐Gamal KM,
Bayoumi AH, El‐Adl K, Ahmed HEA, Abulkhair HS. Synthesis,
antimicrobial evaluation, DNA gyrase inhibition, and in silico
pharmacokinetic studies of novel quinoline derivatives. Arch
Pharm. 2020;e2000277.
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Arch. Pharm. 2020, e2000170. https://doi.org/10.1002/ardp.
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Divers. 2020, https://doi.org/10.1007/s11030-020-10131-0
[22] K. El‐Adl, A.‐G A. El‐Helby, H. Sakr, R. R. Ayyad, H. A. Mahdy, M.
Nasser, H. S. Abulkhair, S. S. A. El‐Hddad, Arch. Pharm. 2020,
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https://doi.org/10.1002/ardp.202000277