Potential antibacterial and antifungal activities of novel sulfamidophosphonate derivatives bearing the quinoline or quinolone moiety

Article abstract of DOI:10.1002/ardp.202000291

A series of new α-sulfamidophosphonate/sulfonamidophosphonate (4a–n) and cyclosulfamidophosphonate (5a–d) derivatives containing the quinoline or quinolone moiety was designed and synthesized via Kabachnik–Fields reaction in the presence of ionic liquid under ultrasound irradiation. This efficient methodology provides new 1,2,5-thiadiazolidine-1,1-dioxide derivatives 5a–d in one step and optimal conditions. The molecular structures of the novel compounds 4a–n and 5a–d were confirmed using various spectroscopic methods. All these compounds were evaluated for their in vitro antibacterial activity against Gram-negative (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853) and Gram-positive (Staphylococcus aureus ATCC 27923) bacteria, in addition to three clinical strains (E. coli 1, P. aeruginosa 1, and S. aureus 1). Most of the tested compounds showed more potent inhibitory activities against both Gram-positive and -negative bacteria compared with the sulfamethoxazole reference. The following compounds, 4n, 4f, 4g, 4m, 4l, 4d, and 4e, are the most active sulfamidophosphonate derivatives. Furthermore, these molecules gave interesting zones of inhibition varying between 28 and 49 mm, against all tested bacterial strains, with a low minimum inhibitory concentration (MIC) value ranging from 0.125 to 8 μg/ml. All the synthesized derivatives were also evaluated for their in vitro antifungal activity against Fusarium oxyporum f. sp. lycopersici and Alternaria sp. The results revealed that all the synthesized compounds exhibited excellent antifungal inhibition and the compounds 4f, 4g, 4m, and 4i were the most potent derivatives with MIC values ranging from 0.25 to 1 μg/ml against the two tested fungal strains. The strongest inhibition of bacteria and fungi strains was detected by the effect of quinolone and sulfamide moieties.

Full text of DOI:10.1002/ardp.202000291

Received: 6 August 2020
Revised: 1 October 2020
Accepted: 6 November 2020
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DOI: 10.1002/ardp.202000291
F U L L P A P E R
Potential antibacterial and antifungal activities of novel
sulfamidophosphonate derivatives bearing the quinoline or
quinolone moiety
Ismahene Bazine1
| Samira Bendjedid2 | Abbes Boukhari1
1Laboratory of Organic Synthesis, Modeling
and Optimization of Chemical Processes,
Department of Chemistry, Badji
Abstract
A series of new α‐sulfamidophosphonate/sulfonamidophosphonate (4a–n) and cy-
closulfamidophosphonate (5a–d) derivatives containing the quinoline or quinolone
moiety was designed and synthesized via Kabachnik–Fields reaction in the presence
of ionic liquid under ultrasound irradiation. This efficient methodology provides new
1,2,5‐thiadiazolidine‐1,1‐dioxide derivatives 5a–d in one step and optimal condi-
tions. The molecular structures of the novel compounds 4a–n and 5a–d were con-
firmed using various spectroscopic methods. All these compounds were evaluated
for their in vitro antibacterial activity against Gram‐negative (Escherichia coli ATCC
25922 and Pseudomonas aeruginosa ATCC 27853) and Gram‐positive (Staphylococcus
aureus ATCC 27923) bacteria, in addition to three clinical strains (E. coli 1,
P. aeruginosa 1, and S. aureus 1). Most of the tested compounds showed more potent
inhibitory activities against both Gram‐positive and ‐negative bacteria compared
with the sulfamethoxazole reference. The following compounds, 4n, 4f, 4g, 4m, 4l,
4d, and 4e, are the most active sulfamidophosphonate derivatives. Furthermore,
these molecules gave interesting zones of inhibition varying between 28 and 49 mm,
against all tested bacterial strains, with a low minimum inhibitory concentration
(MIC) value ranging from 0.125 to 8 μg/ml. All the synthesized derivatives were also
evaluated for their in vitro antifungal activity against Fusarium oxyporum f. sp.
lycopersici and Alternaria sp. The results revealed that all the synthesized compounds
exhibited excellent antifungal inhibition and the compounds 4f, 4g, 4m, and 4i were
the most potent derivatives with MIC values ranging from 0.25 to 1 µg/ml against
the two tested fungal strains. The strongest inhibition of bacteria and fungi strains
was detected by the effect of quinolone and sulfamide moieties.
Mokhtar‐Annaba University, Annaba, Algeria
2Research Laboratory of Functional and
Evolutionary Ecology, Department of Biology,
Chadli Bendjedid University, El Taref, Algeria
Correspondence
Ismahene Bazine, Laboratory of Organic
Synthesis, Modeling and Optimization of
Chemical Processes, Department of
Chemistry, Badji Mokhtar‐Annaba University,
B.O. 12, Annaba 23000, Algeria.
Email: bazineismahane@gmail.com
K E Y W O R D S
antibacterial activity, antifungal, quinolone, sulfonamide, α‐sulfamidophosphonate
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1
INTRODUCTION
Every year millions of people are prone to infectious diseases and the
death rate is also getting fluctuated due to the intensity of the easily
Antimicrobial drugs have caused a remarkable change in the treat-
ment of infectious diseases.[1] There are many ways to get infectious
diseases and we are not able to prevent the infections that spread.
spreading characteristic of the microorganism.[2,3] Currently, anti-
microbial chemotherapy made sensational advances to develop new
potent antibiotics for combating antimicrobial resistance[4] because
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the microorganism is getting resistant with improvements in existing
antibiotic classes by mutation membrane permeability and spore
formation to the drugs by adapting themselves to withstand the
potency of the drug.[5] Therefore, because of the limiting factor to
the effectiveness of current drugs, the development of new treat-
ment approaches and the synthesis of novel, effective, and more
potent compounds to be used as chemotherapeutics is still in de-
mand to overcome these problems.[6,7] In this regard, sulfonamide
and cyclosulfamide derivatives have been the focus of attention for
chemists and biologists for a long time due to their wide range of
biological and physical properties,[8] such as antibacterial,[9,10]
anticonvulsant,[11] antihypoglycemic,[12] anticancer,[13] herbicidal,[14]
antifungal,[15] as well as their utility as synthetic intermediates.[16]
In search of some new antibiotics, we have focused on sulfona-
mide and cyclic sulfamide moieties, which have significance in the
area of medicinal chemistry[17–21] and drug development and are
used as a core substituent of antibacterial agents,[22] for example, the
sulfamethoxazole is an available sulfa drug acting as para‐
aminobenzoic acid competitive inhibitor.[23–25]
as more cost‐effective and more potent, pioneering antibacterial agents
with minimum adverse effects[45] (Figure 2).
Owing to such significance and keeping in view the wide range of
pharmaceutical activities of sulfonamide, quinoline, and aminopho-
sphonate scaffolds, in this report, we expect that the incorporation of
all these moieties in the same scaffold structure may lead to good
activities and potent antibacterial agents. Thus,
a series of
α‐sulfamidophosphonate, sulfonamidophosphonate, and cyclosulfa-
midophosphonate derivatives bearing quinoline or quinolone rings
was designed, synthesized, and evaluated for their antibacterial and
antifungal activities.
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2
RESULTS AND DISCUSSION
Chemistry
|
2.1
A
series of 18 novel α‐sulfonamidophosphonate (4a–c, 4h–k),
α‐sulfamidophosphonate (4d–g, 4l–n), and cyclosulfamidopho-
sphonate 5a–d (1,2,5‐thiadiazolidine‐1,1‐dioxide) derivatives con-
taining quinoline or quinolone moiety was designed and synthesized
under ultrasound irradiation.
Furthermore, a literature review revealed that the presence of
quinoline derivatives exhibits good antibacterial activity[26] for the
target compound and plays a significant role in the development of
new antibacterial agents (Figure 1).[27,28] The great attention paid by
researchers to the study of quinoline derivatives is explained by their
broad range of biological activities, such as antiviral,[29] antioxidant,
anti‐inflammatory,[30] antimicrobial,[31] anti‐atherothrombosis,[32]
antiemetic,[33] anxiolytic,[34] antimalarial, and antileishmanial,[35] and
recently, several reports have drawn attention to the use of chlor-
oquine and hydroxychloroquine (antimalarial drugs), as inhibitors of
SARS‐CoV‐2 virus.[36–38]
In the first stage, we started our study with the synthesis of
aldehyde derivatives and functionalized sulfonamides/sulfamides.
The sulfonamides/sulfamides presented in this study as starting
materials were obtained from a simple and efficient methodology
described in the literature.[46–49] 2‐Chloro‐quinoline‐3‐carbaldehyde
derivatives 2a–e were obtained via Meth–Cohn reaction,[50] which
included the condensation of acetanilide derivatives 1a–e with
Vilsmeier–Haack reagent. As
a
continuation, 2‐oxoquinoline
In contrast, the α‐aminophosphonate derivatives show great
interest in organic synthesis because of their biological and
pharmacological activities.[39] That is why the synthesis of new
α‐aminophosphonates is underway to find antibiotics,[40] enzyme
inhibitors,[41] antileishmanial,[42] antifungal,[43] or antitumoral[44] com-
pounds. The current work is an effort to develop novel formulations as
effective antibacterial agents against drug‐resistant bacterial strains. In
this regard, the combination of certain sulfamides/sulfonamides and
α‐aminophosphonates moiety are very suitable for further modifications
to obtain new α‐sulfamidophosphonates or α‐sulfonamidophosphonates
3‐carbaldehyde derivatives (3a–e) were then obtained in good
yields by the hydrolytic reaction of compounds 2a–e in the presence
of 70% acetic acid.[51]
In continuation of our program on the development and synth-
esis of novel compounds of α‐aminophosphonate derivatives and to
obtain these compounds in high yields and clean conditions, in this
study, we have used our previous strategy for the synthesis of new
α‐sulfonamidophosphonate (4a–c, 4h–k), α‐sulfamidophosphonate
(4d–g, 4l–n), and cyclosulfamidophosphonate 5a–d derivatives in
the presence of ionic liquid under ultrasound irradiation. It was
FIGURE 1 Structures of potent antimicrobial molecules containing quinoline and sulfonamide/sulfamide moieties

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FIGURE 2 Rational approach to the design of active compounds containing sulfonamide/sulfamide, quinoline, and phosphonate moieties
previously reported by our research group[52] that in the absence of
ionic liquid (triethylammonium acetate [TEAA]), the rates of the re-
action were remarkably slowed and the yields were very low. The
use of ionic liquid catalyst has gained importance in organic synthesis
due to several advantages, such as short reaction time, excellent
product yield, low cost, operational and simplicity of the reaction.
Owing to the numerous advantages associated with this methodol-
ogy, the application of ultrasonic irradiation to this reaction in-
creases the efficiency, which otherwise requires a long reaction time.
Moreover, ultrasound irradiations are believed to satisfy the de-
mands of “green chemistry” by minimizing waste and reducing
energy requirements, allowing for solvent‐free conditions to be
employed.
the same conditions and the desired products are obtained with a
significant improvement in yield (up to 75%). So, this new meth-
odology of multicomponent condensation reaction in one step is
able to promote the synthesis of 1,2,5‐thiadiazolidine‐1,1‐dioxide
in short reaction time and ecofriendly conditions. The obtained
results are summarized in Table 1.
The structures of target compounds were determined by their
spectral data (1H nuclear magnetic resonance [NMR], 13C NMR, 31P
NMR, heteronuclear single‐quantum coherence [HSQC], hetero-
nuclear multiple bond correlation [HMBC], and elemental analysis).
The spectra 1H NMR, 13C NMR, 31P NMR, HSQC, and HMBC 2D
NMR are available in the Supplementary Information Material; 1H
NMR spectra showed the characteristic signals of four principal types
of protons in each product (OCH2–CH3, P–*CHN, N–H and Ar–H). As
expected, in the spectrum, the introduction of phosphonate group is
confirmed by the presence of two triplets between 1.09 and
1.48 ppm and two multiplets between 2.81 and 4.52 ppm, re-
presenting the protons of CH3 and CH2, respectively, attributed to
two methoxy groups of the phosphonate, and the presence of
doublet signal characteristic of the proton related to asymmetric
carbon P*CHN between 4.9 and 5.6 ppm confirms the condensation
of sulfonamide/sulfamide with the quinoline/quinolone carbaldehyde.
Herein, we report a one‐pot synthesis of α‐sulfonamidophosphonate
(4a–c, 4h–k), α‐sulfamidophosphonate (4d–g, 4l–n) by condensa-
tion of quinoline/quinolone carbaldehyde (1 mmol), sulfonamide/
sulfamide (1 mmol), and triethylphosphite (1 mmol) catalyzed by
ionic liquid (TEAA) and under solvent‐free reaction using ultra-
sound irradiation. This method is an easy, rapid, one‐pot, and
good‐yielding reaction. Thus, this methodology is also suitable for
the synthesis of cyclosulfamidophosphonates 5a–d in one step
(Scheme 1). The intramolecular cyclization “in situ” is realized in

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SCHEME 1 One‐pot synthesis of novel α‐sulfamidophosphonate/sulfonamidophosphonate and cyclosulfamidophosphonate derivatives
under ultrasound irradiation
Since the peak of N–H protons appeared as two broad singlets,
ranged between 3 and 11 ppm only for compounds 4d–g and 4l–n,
which have two NH functions of sulfamide group (NH–SO2–NH).
Compounds 4a–c and 4h–k, on the contrary, have one NH function of
sulfonamide group (NH–SO2–R). While, the intramolecular cycliza-
tion and the formation of the cycle thiadiazolidine 1,1‐dioxide to
afford the compounds 5a–e is also confirmed by the absence of a
second NH peak and the presence of only broad singlet at 3–5 ppm.
Additionally, these compounds revealed a similar singlet signal at
2.80–3.2 ppm that can be assigned to 2NCH2 protons of the thia-
diazolidine scaffold, according to the literature.[53] However, the last
type of protons of aromatic rings is located between δ = 6.2
and 8 ppm.
The 13C NMR spectra of all compounds were characterized
by the presence of new signals of the carbon atoms characteristic
of the phosphonate group due to the expected doublets related

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TABLE 1 Synthesis of novel
α‐sulfamidophosphonates/
sulfonamidophosphonates (4a–n) and
cyclosulfamidophosphonates (5a–d) under
ultrasound irradiationa
Entry
4a
Aldehyde
Sulfonamide/sulfamide
Time (min)
Yield (%)
10
82
4b
4c
4d
13
9
79
85
88
8
4e
4f
15
14
9
76
87
84
90
4g
4h
7
4i
4j
13
10
92
78
4k
4l
12
84
95
8
(Continues)

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Entry
4m
Aldehyde
Sulfonamide/sulfamide
Time (min)
Yield (%)
11
90
4n
14
86
5a
5b
5c
15
16
12
79
75
81
5d
14
86
Abbreviation: IL[TEAA], triethylammonium acetate.
aConditions: aldehyde (1 mmol), amine (1 mmol), triethylphosphite (1 mmol), IL[TEAA], 40 kHz.
to the coupling of the carbon atoms with the phosphorus (JC‐P
couplings; P–O–CH2–CH3), which appear between 16 and
55 ppm and the peak of asymmetric carbon P*CH between 52
and 55 ppm. While, the appearance of peaks between 41 and
45 ppm, characteristic of the two methylene groups, confirmed
the formation of 1,2,5‐thiadiazolidine ring. In addition, the C
atoms of the aromatic ring, which was between the region of
δ = 113–130 ppm. Since, the carbonyl (CO) function of char-
acterized compounds containing quinolone moiety appeared at
162–168 ppm.
All these spectroscopic analyses confirm the obtaining of
α‐sulfamidophosphonates/sulfonamidophosphonates and cyclosulfa-
midophosphonates derivatives targeted in this study.
|
2.2
Biological evaluation
Combinations of two or more active moieties into one scaffold are a
common procedure for getting the synergistic effect to enhance the
drug activity with less dose of the drug.
In the 31P NMR spectrum, the phosphorus atom was resonated
as a single characterized between δ = 20 and 24 ppm approximately
in all the synthesized compounds.
Substituted 3‐formyl‐2‐quinoline and 3‐formyl‐2‐quinolones, used in
our study as starting materials, have been reported for their antimicrobial
and antifungal activities.[54] The literature reports reveal that the qui-
noline derivatives displayed good antibacterial activity against both
Gram‐negative and Gram‐positive bacterial strains[55] and have immense
potential to control methicillin‐resistant Staphylococcus aureus
infection.[56]
The relative attribution of proton–carbon has been determined
by a series of 2D NMR, HSQC, and HMBC experiments (400 MHz).
2D mode HSQC experiments confirm the vicinal relationship (C–H
correlation 1–2) and the HMBC mode indicates the C–H correla-
tion 1–3.
In contrast, the diverse biological activities of α‐aminophosphonates
and sulfamides moieties mentioned above prompted us to test the
antibacterial activities of the novel synthesized products. Hence, the
Elemental analysis furthermore confirms the assigned structures
of the synthesized compounds.

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TABLE 2 Diameters of the inhibition zone (DIZ) of α‐sulfonamidophosphonate/sulfamidophosphonate and cyclosulfamidophosphonate
derivatives
Diameters of inhibition zone (mm)
Gram‐negative strains
Gram‐positive strains
Pseudomonas
aeruginosa ATCC
27853
Escherichia coli
Escherichia
Pseudomonas
Staphylococcus aureus
Staphylococcus
Molecules
ATCC 25922
coli 1
aeruginosa 1
ATCC 27923
aureus 1
4a
4b
4c
4d
4e
4f
10
6
9
20
12
16
30
32
37
34
25
27
29
26
34
37
36
6
22
10
9
14
R
10
11
19
29
30
36
33
24
27
26
27
33
35
42
R
8
11
32
34
42
38
26
30
28
27
35
36
49
11
16
25
32
7
11
28
29
40
35
20
29
27
25
30
33
49
7
29
30
33
35
25
28
30
29
33
32
38
18
12
27
22
11
29
30
39
32
22
31
30
27
32
34
43
9
4
4h
4i
4j
4k
4l
4m
4n
5a
5b
5c
5d
10
23
25
9
R
R
R
19
27
6
9
7
13
R
10
R
Sulfamethoxazolea 12
Abbreviation: R, resistant.
aPositive reference.
18 newly synthesized compounds were screened for their in vitro anti-
microbial activity against selected strains of Gram‐positive and ‐negative
bacteria as well as two fungal strains.
evaluated by agar well diffusion assay[57] using a concentration of
512 μg/ml. Subsequently, the zone of inhibition was measured in
millimeters. The results are presented in Table 2.
To further determine the antibacterial effect of the tested
compounds, the minimum inhibitory concentration (MIC) values and
the minimum bactericidal concentration (MBC) against the above-
mentioned bacterial strains were measured by a broth dilution
method.[58–60] The MIC value is defined as the lowest concentration
of antibacterial agent that inhibits visible growth and the MBC value
is the higher antibiotic concentration that will kill the organisms. The
MIC and MBC values are summarized in Table 3.
|
2.2.1
In vitro antibacterial activity
The sulfamidophosphonate/sulfonamidophosphonate and cyclosulfami-
dophosphonate derivatives were evaluated for their in vitro anti-
bacterial activity against six bacterial strains causing several infectious
diseases, four strains are Gram‐negative: Escherichia coli (ATCC 25922),
E. coli 1, Pseudomonas aeruginosa (ATCC 27853), and P. aeruginosa 1, in
addition to two Gram‐positive strains, S. aureus (ATCC 25923) and
S. aureus 1. Dimethyl sulfoxide (DMSO) was used as a negative control
and the commercial antibiotic sulfamethoxazole as a positive control.
It is obviously observed from the obtained results that all the
newly synthesized compounds showed high antibacterial activity
compared with the sulfamethoxazole reference (positive control).
The diameters of inhibition zone (DIZ) values obtained with the
positive control sulfamethoxazole ranged between 6 and 12 mm
against Gram‐positive and ‐negative strains and with MIC value of
64 µg/ml against E. coli ATCC 25922 and 128 µg/ml against E. coli
Initially,
in
vitro
antibacterial
activity
of
the
α‐sulfonamidophosphonate (4a–c, 4h–k), α‐sulfamidophosphonate
(4d–g, 4l–n), and cyclosulfamidophosphonate 5a–e derivatives was

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TABLE 3 MICs and MBCs of sulfamidophosphonate/sulfonamidophosphonate (4a–n) and cyclosulfamidophosphonate (5a–d) derivatives
Gram‐negative strains
Gram‐positive strains
Pseudomonas
aeruginosa ATCC
27853
Escherichia coli
Staphylococcus aureus
Staphylococcus
Pseudomonas
ATCC 25922
Escherichia coli 1
ATCC 27923
aureus 1
aeruginosa 1
MIC
(µg/
MBC
(µg/
ml)
MIC
(µg/
MBC
(µg/
ml)
MIC
(µg/
MBC
(µg/
ml)
MIC
(µg/
ml)
MBC
(µg/
ml)
MIC
(µg/
MBC
(µg/
ml)
MIC
(µg/
ml)
MBC
(µg/
ml)
Molecules ml)
Ra ml)
Ra ml)
Ra
2
4
4
4
2
4
2
8
2
4
2
4
8
4
2
2
2
2
Ra ml)
Ra
2
‒
Ra
2
2
4
4
2
2
4
2
2
2
2
4
4
2
‒
4a
4b
4c
4d
4e
4f
128
128
64
256
256
128
4
2
2
2
4
4
8
8
4
2
4
2
2
8
8
2
2
4
4
64
32
128
0.5
2
128
64
256
2
2
2
2
4
8
8
4
8
4
4
2
8
4
2
2
2
8
2
256
128
64
1
512
512
256
4
64
256
128
2
128
512
512
8
2
2
4
4
4
8
4
2
8
2
8
2
4
8
4
‒
256
‒
512
‒
256
128
64
8
512
256
256
32
8
128
2
512
8
4
4
2
4
2
2
2
4
2
4
2
4
2
‒
1
0.5
0.125
0.5
8
2
16
1
1
2
1
4
2
4
4
1
0.125
0.25
4
0.25
0.5
16
2
1
0.25
0.25
8
2
0.5
0.5
64
8
2
1
2
4g
4h
4i
4
1
1
1
1
1
4
32
4
32
4
128
4
32
32
8
128
16
64
64
4
32
16
32
32
2
64
32
64
64
8
2
1
4
4j
2
8
4
16
4
2
8
4
16
32
1
4k
4l
4
8
2
4
8
8
64
2
0.5
0.5
0.125
128
256
32
1
1
8
0.5
1
2
1
4m
4n
5a
5b
5c
5d
4
0.5
2
8
0.5
0.125
128
‒
2
1
2
2
8
1
0.125 0.5
0.5
64
128
128
32
2
1
0.25
256
‒
1
1
2
256
512
128
64
128
256
64
256
512
512
16
128
256
256
64
512
‒
512
‒
‒
‒
‒
‒
‒
64
64
256
256
4
4
128
128
512
256
4
2
256
64
512
128
2
2
16
8
Abbreviations: MBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration; ‒, no inhibition (or concentration >512 μg/ml).
aR = MBC/MIC.
1, S. aureus ATCC 27923, and S. aureus 1. Whereas P. aeruginosa
ATCC 27853 and P. aeruginosa 1 strains were resistant toward sul-
famethoxazole standard. The negative control (DMSO) did not show
any antibacterial activity.
ranging from 1‒16 μg/ml and with DIZ values between 20 and
31 mm, whereas good‐to‐moderate activity against strains P. aer-
uginosa and P. aeruginosa 1 (8 μg/ml ≤ MIC ≤ 64 μg/ml). All these
compounds exhibited a higher inhibition zone than the standard
antibiotic sulfamethoxazole against all tested bacterial strains. 4i
was the most active among this series, probably due to the pre-
sence of para‐methyl substituent attached to the quinolone scaf-
fold. These derivatives showed better results than 4c, 4b, and 4a
(32 μg/ml ≤ MIC ≤ 256 μg/ml), which have a quinoline moiety. From
this point, it is noticeably evident that the antibacterial activity
was highly dependent on the nature of the ring substituent as well
as the chemical nature of the substituents and their positions on
the sulfamide or sulfonamide ring. In general, compounds con-
taining a sulfamide group possessed much higher activity than
those containing a sulfonamide group. However, the newly syn-
thesized sulfamidophosphonate derivatives bearing quinolone
moiety were the most active and demonstrated a high anti-
bacterial activity compared with those bearing quinoline moiety,
especially against Gram‐negative bacterial strains.
The results reveal that the compounds 4n, 4f, 4g, 4m, 4l, 4d, and
4e, respectively, showed the highest antibacterial activity and ex-
cellent inhibition against all bacterial strains with inhibition zone
(DIZ) values between 28 and 49 mm, and MIC values ranging from
0.125 to 8 μg/ml, for both clinical and reference strains. It can be
clearly seen that these derivatives contained a sulfamide function
(NH–SO2–NH) and had respectively ortho‐methoxyl, para‐bromo,
para‐fluoro, and para‐methyl substituents attached to the sulfamide
ring, which exhibited strong electron‐donating and/or electron‐
withdrawing properties,[25] which might have plausibly contributed
to the potent antibacterial activity of these compounds.
Another series of compounds, 4h–k, bearing sulfonamide
function (NH–SO2–R) and quinolone moiety, also showed ex-
cellent activity against Gram‐negative strains, E. coli ATCC 25922,
E. coli 1, S. aureus ATCC 27923, and S. aureus 1 with MIC values

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FIGURE 3 Comparison of antibacterial activity (minimum inhibitory concentration) of compounds 4a–n and 5a–d with sulfamethoxazole as
reference
While the last series is the cyclosulfamidophosphonate derivatives
5a–d, these compounds achieved good‐to‐moderate activity. The highest
activity was shown against Gram‐negative bacteria (E. coli and S. aureus)
with DIZ values varied within 19 and 32 mm, and MIC values ranged
between 8 and 128 μg/ml, only for compounds 5c and 5d that have a
quinolone moiety. Compounds 5a and 5b bearing quinoline scaffold ex-
hibited moderate activity against both Gram‐negative and ‐positive
bacteria (64 μg/ml ≤ MIC ≤ 256 μg/ml). This remark confirms our pre-
vious results about the effectiveness of quinolone moiety compared with
the quinoline ring. It is important to note that all sulfamidophosphonate
and sulfonamidophosphonate products 4a–n exhibit greater antibacterial
activity than the cyclosulfamidophosphonate derivatives 5a–d against
both Gram‐positive and ‐negative strains.
4n against E. coli ATCC 25922 and 4e, 4f, 4h, 4l, 5c against E. coli 1, in
addition to 4h, 4f toward S. aureus ATCC 27923, and 4f, 4i, 4k, and
4n versus S. aureus 1, these derivatives achieved a ratio MBC/
MIC = 8 ˃ 4.
It
could
be
concluded
that
the
presence
of
quinoline–aminophosphonate moiety in the same scaffold with sul-
famide/sulfonamide group significantly increases the antibacterial
activity against all tested bacterial strains. Subsequently, all the no-
vel synthesized compounds 4a–n and 5a–d exhibited a broad spec-
trum of antimicrobial activity and these derivatives can be
considered as promising antibacterial agents. Comparison of anti-
bacterial activity of all newly synthesized compounds with reference
antibiotic sulfamethoxazole is shown in Figure 3.
It is worth noting that high MIC values might be attributed to
the nature of the tested microbial strains as they were multidrug‐
resistant, particularly for sulfamethoxazole.
|
2.2.2
In vitro antifungal activity
However, the MBC of the tested molecules was determined to
define the action of an antibacterial on the bacterial strains using the
ratio MBC/MIC. If the ratio MBC/MIC ≤ 4, the effect was considered
as bactericidal, but if the ratio MBC/MIC > 4, the effect was defined
as bacteriostatic.[61,62]
Antifungal activity of 18 newly synthesized compounds was de-
termined in vitro against two phytopathogenic fungi strains, name-
ly Fusarium oxyporum. f. sp. lycopersici (FOL) and Alternaria sp. These
strains were tested for fungi toxicity by evaluating mycelia growth
inhibition of pathogenic agents. The inhibitory activity of the various
compounds, on the mycelium growth of the two phytopathogenic
agents, is determined by measuring the diameter growth of the
fungus on potato dextrose agar (PDA) medium containing the tested
product. DMSO was considered as negative control and amphoter-
icin B as a positive control. The negative control contains PDA and
DMSO without any other products.
Overall, the MBC values of all tested compounds were found to
be between 0.5 and 512 μg/ml and the bactericidal and bacteriostatic
effect of the tested compounds was determined using the ratio
MBC/MIC. Most of the synthesized molecules showed the ratio
MBC/MIC ≤ 4, which may be classified as bactericidal agents, espe-
cially for the compounds 4a, 4b, 4c, 4d, 4j, and 5d, which showed the
ratio MBC/MIC ≤ 4 on all tested bacterial strains, suggesting
that these molecules act as bactericidal agents against both
Gram‐positive and ‐negative strains. Also, we observed that all the
synthesized compounds have a bactericidal effect (R ≤ 4) against
Gram‐positive strains, and a minority of products that have de-
monstrated a bacteriostatic effect, such as the derivatives 4f, 4g, 4m,
The mycelial growth of the phytopathogenic agent is measured at a
millimetric scale after 7 days of incubation at 25°C. The results were
expressed as the percentage of growth inhibition of each fungus grown in
the control medium. Thus, the inhibition activity was expressed as a
percentage and was calculated according to the formula: Inhibition

10 of 14
BAZINE ET AL.
|
TABLE 4 In vitro antifungal activity results of
sulfamidophosphonate/sulfonamidophosphonate 4a–n,
cyclosulfamidophosphonate 5a–d derivatives
values ranged between 0.125 and 16 µg/ml and with inhibition per-
centages varied from 59.62 0.09 to 90.12 0.20% at the con-
centration of 64 µg/ml. Compounds 4f, 4g, 4m, and 4i were the most
potent derivatives with MIC value of 0.125 µg/ml against FOL and
with MIC values ranging from 0.25 to 1 µg/ml against Alternaria sp.
While, the compounds 4e, 4l, 4n, 4g, and 4d also showed excellent
inhibition and exhibited an MIC value between 0.5 and 2 µg/ml against
both tested fungal strains in this study.
Fusarium oxyporum f. sp. Alternaria sp.
lycopersici
Percentage
inhibition (%)a
MIC
Percentage
MIC
(µg/ml) inhibition (%)a
(µg/ml)
Molecules
4a
78.14 0.01
71.06 0.25
77.61 0.08
79.22 0.10
73.25 0.32
89.62 0.61
90.12 0.20
73.25 0.50
85.38 0.09
76.66 0.37
71.11 0.07
78.88 0.72
86.32 0.24
84.29 0.49
62.22 0.15
68.58 0.34
70.04 0.06
69.87 0.20
8
60.74 0.09
59.62 0.09
64.44 0.04
62.59 0.26
56.29 0.02
70.47 0.12
72.66 0.38
69.96 0.88
71.78 0.10
65.36 0.39
69.46 0.22
70.59 0.02
76.84 0.09
81.46 0.17
68.32 0.31
73.58 0.22
71.25 0.78
69.45 0.88
38 0.07
16
16
8
4b
4c
4d
4e
4f
4
In conclusion, the newly synthesized sulfamidophosphonate/
sulfonamidophosphonate 4a–n and cyclosulfamidophosphonate
5a–d derivatives bearing quinoline or quinolone heterocycle, showed
potent antibacterial activity against multidrug‐resistant strains of
Gram‐positive and Gram‐negative bacteria, and they are also effec-
tive against fungi FOL and Alternaria sp. These compounds could
attract the interest of researchers for the treatment of serious in-
fectious diseases caused by multidrug‐resistant microbial strains.
8
1
0.5
2
0.5
0.125
0.125
4
0.25
0.25
4
4g
4h
4i
0.125
1
1
4j
2
|
3
CONCLUSION
4k
4l
2
2
New sulfamidophosphonate, sulfonamidophosphonate, and cyclosulfa-
midophosphonate derivatives bearing quinoline or quinolone moiety
were synthesized and evaluated for their antibacterial and antifungal
activities. Therefore, these molecules presented a significant antibacterial
activity on Gram‐positive and Gram‐negative strains as compared with
the sulfamethoxazole control. Compounds 4n, 4f, 4g, 4m, 4l, 4d, and 4e,
respectively, containing a sulfamide function, showed the best inhibition
against clinical and reference strains with MIC values ranging from 0.125
to 8 µg/ml. Besides this, all sulfamidophosphonate and sulfonamidopho-
sphonate products 4a–n exhibited stronger activity than the cyclosulfa-
midophosphonate derivatives 5a–d against both Gram‐positive and
Gram‐negative strains and most of these new compounds presented a
bactericidal effect. In contrast, the antifungal assay revealed that all the
synthesized compounds 4a–n and 5a–d displayed excellent‐to‐good in-
hibition of the two phytopathogenic fungi strains, FOL and Alternaria sp.
with MIC values ranging between 0.125 and 16 µg/ml compared with the
amphotericin standard.
0.5
0.125
0.5
2
4
4m
4n
5a
5b
5c
5d
0.25
0.25
8
4
4
1
4
1
8
Amphotericinb 15 0.10
256
64
Abbreviation: MIC, minimum inhibitory concentration.
aValues are the means of three replicates SD.
bPositive control.
% = (C – T/C) × 100, where C is the colony diameter of a phytopathogenic
agent in millimeters on the PDA medium with DMSO (control), and T is
the colony diameter in millimeters, of the phytopathogenic agent on PDA
medium containing the tested compound. The inhibition zones of the test
compounds were compared with controls.
It can be concluded that all the synthesized compounds showed
potent antimicrobial activities against all tested pathogenic bacteria
and fungi strains. Subsequently, these results can help researchers to
look for new potent antimicrobial agents for therapeutic use.
The percentage of growth inhibition at 64 μg/ml concentration
of tested compounds and the MIC values of in vitro antifungal ac-
tivity was determined and is illustrated in Table 4.
|
According to the results (Table 3), the negative control did not
show any antifungal activity and the positive control amphotericin
showed weak‐to‐moderate activity against FOL and Alternaria sp. The
inhibition percentages and the MIC values of amphotericin reference
were in the range of 15 0.10 to 38 0.07% and 64–256 µg/ml
against both tested fungal strains. All tested compounds displayed
excellent antifungal activity against both fungi strains (FOL and
Alternaria sp.) compared with the amphotericin reference with MIC
4
EXPERIMENTAL
Chemistry
|
4.1
|
4.1.1
General
All starting materials and reagents used for synthesis were obtained
commercially from commercial sources Sigma‐Aldrich and Acros and

BAZINE ET AL.
11 of 14
|
were used without purification. Sonication was performed in a
Fungilab ultrasonic bath with a frequency of 40 kHz and output
power of 250 W. Melting points were measured using Buchi Melting
Point B‐545. All reactions were monitored by thin‐layer chromato-
graphy (TLC) carried out on 0.25‐mm Merck silica gel plates
(60F‐254) using ultraviolet light (254 nm) as the visualizing agent and
ninhydrin solution as developing agents. 1H NMR and 13C NMR
spectra were recorded at 25°C on Bruker spectrometers (400 MHz
for 1H, 101 MHz for 13C, and 162 MHz for 31P) using tetra-
methylsilane as internal standard and CDCl3 or DMSO‐d6 as solvent.
Elemental analysis (C, H, and N) were performed on a PerkinElmer
2400 CHN elemental analyzer model 1106. All reagents used for
biological activities were purchased from Sigma‐Aldrich Co.
The Supporting Information Data contains the 1H, 13C, 31P NMR,
HSQC, and HMBC 2D NMR spectra of all synthesized products and
their spectral data.
2‐Chloro‐3‐formyl‐6‐methylquinoline
C11H8ClNO; MW = 205.64; TLC Rf = 0.43 (CH2Cl2); yellow powder;
mp: 176–177°C; 75% yield; IR νmax (KBr) (cm−1) = 1645 (CO). 1H
NMR (400 MHz, DMSO‐d6) δ 10.57 (s, 1H, CHO), 8.58 (s, 1HAr), 7.97
(d, Jortho = 7.7 Hz, 1HAr), 7.75 (d, Jmetha = 2.3 Hz, 1HAr), 7.74 (dd,
J
ortho = 7.7, Jmetha = 2.4 Hz, 1HAr), 2.57 (s, 3H, CH3) ppm. 13C NMR
(101 MHz, DMSO‐d6) δ = 189.3, 149.2, 148.1, 139.5, 138.4, 135.9,
128.3, 128.1, 126.5, 126.2, 21.5 ppm.
|
4.1.4
General procedure for the preparation of
compounds 3a–f
2‐Chloro‐3‐formyl quinoline derivatives (2a–f) were treated with
70% acetic acid aqueous solution (200 ml) at 95°C for 10 h and then
the solution was cooled to room temperature to offer needle crystals
of compounds 3a–f.
|
4.1.2
General procedure for the synthesis of
6‐Methyl‐2‐oxo‐1,2‐dihydroquinoline‐3‐carbaldehyde (3b)
C11H9NO2; MW = 187.20; TLC Rf = 0.35 (CH2Cl2); yellow powder;
mp: 205–206°C; 92% yield. 1H NMR (400 MHz, DMSO‐d6) δ 12.11 (s,
1H, NH), 10.24 (s, 1H, CHO), 8.40 (s, 1HAr), 7.71–7.65 (m, 1HAr),
7.49 (dd, Jortho = 8.4, Jmetha = 2.0 Hz, 1HAr), 7.27 (d, Jortho = 8.4 Hz,
1HAr), 2.35 (s, 3H, CH3‐Ar) ppm. 13C NMR (101 MHz, DMSO‐d6):
δ = 190.25, 161.79, 142.52, 139.75, 135.57, 132.22, 130.47, 126.05,
118.55, 115.81, 20.73 ppm.
sulfamide derivatives
The sulfamide derivatives were prepared starting from chlor-
osulfonyl isocyanate (CSI) in three steps (carbamoylation, sulfamo-
lytion, and deprotection). To a stirred solution of CSI (1.62 g,
11.48 mmol) in 10 ml of anhydrous methylene chloride at 0°C was
added 0.85 g, 11.48 mmol of tert‐butanol in the same solvent. After a
period of 30 min, the resulting solution and 1.75 ml, 1.1 eq of trie-
thylamine was slowly added to a solution containing 1 eq of primary
amine (aromatic amine or 2‐chloroethylamine hydrochloride) in
10 ml of anhydrous methylene chloride at 0°C. The resulting reaction
solution was allowed to warm up to room temperature for over 2 h.
The reaction mixture was diluted with 30 ml of methylene chloride
and washed with HCl (0.1 N) and then with water. The organic layer
was dried over anhydrous sodium sulfate and concentrated in a va-
cuum, to give carboxylsulfamides in excellent yields. The deprotec-
tion reaction of carboxylsulfamide was carried out in distilled water,
the reaction mixture was refluxed for 15–30 min, and then it was
extracted 3 × (30 ml) with ethyl acetate. The organic layer was dried
over anhydrous sodium sulfate and concentrated under reduced
pressure to give sulfamides in good yields
|
4.1.5
General procedure for the preparation of
α‐sulfamidophosphonates/sulfonamidophosphonates
4a–n and cyclosulfamidophosphonates 5a–d
In a 10‐ml round‐bottom flask, a mixture of sulfamide/sulfonamide
(1 mmol) and aldehyde (1 mmol) was taken with 1 ml of ionic liquid at
room temperature, then triethylphosphite (1 mmol) was added. The
reaction mixture was subjected to ultrasonication for an appropriate
time. After completion of the reaction, as indicated by TLC, distilled
water was added. The product was finally filtered and dried and it
was purified by recrystallization using chloroform/diethyl ether to
yield pure α‐sulfamidophosphonates/sulfonamidophosphonates 4a–n
and cyclosulfamidophosphonates 5a–d.
|
4.1.3
General procedure for the synthesis of
Diethyl{(2‐chloroquinolin‐3‐yl)[(4‐methylphenyl)sulfonamide]methyl}-
phosphonate (4a)
quinoline derivatives
C21H24ClN2O5PS, MW = 482.92; TLC Rf = 0.51 (CH2Cl2/MeOH 7:3);
white powder; mp: 162–163°C; 82% yield. 1H NMR (400 MHz,
chloroform‐d6) δ 11.82 (s, 1H, NH), 8.02 (d, J = 3.6 Hz, 1HAr), 7.83
(dd, Jortho = 8.9, Jmetha = 2.8 Hz, 2HAr), 7.66–7.53 (m, 1HAr), 7.60 (td,
Place dimethylformamide (3 eq) in a flask equipped with a drying
tube cooled to 0°C temperature, then phosphorus oxychloride
(POCl3; 7 eq) was added dropwise with stirring to it. To this solution,
add acetanilide (1 mmol). After a few minutes, the reaction mixture
was refluxed for 6–8 h. After completion of the required time reac-
tion, the mixture was cooled and poured in ice‐cold water and stirred
for about half an hour, and then filtered to offer powdered
compound.
Jortho = 8.8, Jmetha = 2.3 Hz, 1H), 7.50 (td, Jortho = 7.9, Jmetha = 1.5 Hz,
1HAr), 7.38 (d, J = 8.3, 1HAr), 7.27 (s, 1HAr), 7.22 (td, Jortho = 7.5,
Jmetha = 2.1 Hz, 1HAr), 7.15 (t, J = 7.3 Hz, 1HAr), 4.79 (d, JH‐
P = 26.8 Hz, 1H, P*CH), 4.34–4.15 (m, 2H, OCH2CH3), 3.13–2.84
(m, 2H, OCH2CH3), 2.40 (s, J = 7.3 Hz, 3H, CH3–Ar), 1.32 (t,

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BAZINE ET AL.
|
J = 7.1 Hz, 3H, OCH2CH3), 1.22 (t, J = 7.2 Hz, 3H, OCH2CH3) ppm.
13C NMR (101 MHz, chloroform‐d6)
163.10, 143.32, 139.46,
139.28, 139.21, 137.52, 130.86, 129.61 (2CH), 128.20, 127.28,
126.39 (2CH), 123.13, 119.85 (d, C‐P = 2.7 Hz), 67.51 (d,
C‐P = 161.6 Hz), 63.48 (d, JC‐P = 7.0 Hz), 63.31 (d, JC‐P = 7.2 Hz),
chloroform‐d6) δ 10.77 (s, 1H, NH), 8.05 (d, J = 3.9 Hz, 1HAr), 7.69 (d,
J = 11.9 Hz), 7.45 (d, Jortho = 7.5 Hz, 1HAr), 7.35 (d, Jortho = 7.3 Hz,
2HAr), 7.28 (s, 1H, NH), 7.14 (t, Jortho = 7.5 Hz, 1HAr), 6.93 (ddd,
δ
J
Jortho = 9.3, 3.1, 1.6 Hz, 1HAr), 6.01 (s, 1H, NH), 5.40 (d,
J
JH‐P = 25.8 Hz, 1H, P*CH), 4.27–4.04 (m, 4H, OCH2CH3), 2.55 (s, 3H,
45.52, 21.47, 16.48 ppm. 31P NMR (162 MHz, CDCl3) δ 21.10 ppm.
Anal. calcd. for C21H24ClN2O5PS (482.92): C, 52.23; H, 5.01; Cl, 7.34;
N, 5.80; O, 16.57; P, 6.41; S, 6.64%; found: C, 52.41; H, 5.10; Cl, 7.30;
N, 5.81; O, 16.62; P, 6.25; S, 6.48%.
CH3–Ar), 1.35 (t, J = 7.0 Hz, 3H, OCH2CH3), 1.28 (t, J = 7.1 Hz, 3H,
OCH2CH3) ppm. 13C NMR (101 MHz, chloroform‐d6) δ 175.49,
162.81 (d,
JC‐P = 4.4 Hz), 139.84 (d, JC‐P = 7.3 Hz), 136.03 (d,
JC‐P = 1.8 Hz), 132.10, 127.22 (d, JC‐P = 1.5 Hz), 126.41 (2CH), 123.76,
122.84 (2CH), 121.54 (d, JC‐P = 7.7 Hz), 119.89 (d, JC‐P = 2.9 Hz),
115.38, 115.16, 66.65 (d, JC‐P = 161.4 Hz), 63.67 (d, JC‐P = 5.9 Hz),
61.84 (d, JC‐P = 5.5 Hz), 17.01, 16.28 (d, JC‐P = 6.6 Hz), 16.09 (d,
Diethyl((2‐chloro‐7‐methylquinolin‐3‐yl){[N‐(p‐tolyl)sulfamoyl]amino}-
methyl)phosphonate (4d)
C22H27ClN3O5PS; MW = 511.96; TLC Rf = 0.66 (CH2Cl2/MeOH 7:3);
yellow powder; mp: 170–171°C, 88% yield; 1H NMR (400 MHz,
DMSO‐d6) δ 9.57 (s, 1H, NH), 8.86 (dd, JH‐P = 11.3, J = 6.9 Hz, 1H, NH),
8.26 (d, J = 4.8 Hz, 1HAr), 7.63 (d, J = 2.2 Hz, 1HAr), 7.47 (dd, Jortho = 11.8,
J
C‐P = 7.0 Hz). 31P NMR (162 MHz, chloroform‐d6) δ 21.09 ppm. Anal.
calcd. for C21H25FN3O6PS (497.48): C, 50.70; H, 5.07; F, 3.82; N,
8.45; O, 19.30; P, 6.23; S, 6.44%; found: C, 50.77; H, 5.12; F, 3.81; N,
8.44; O, 19.34; P, 6.22; S, 6.43%.
Jmetha = 4.8 Hz, 1HAr), 7.42 (dd, J = 8.8, 1.7 Hz, 1HAr), 6.66 (d, Jortho
=
10.1 Hz, 2HAr), 6.51 (d, J = 10.1 Hz, 2HAr), 5.20 (dd, H‐P = 25.5,
J
Diethyl[(1,1‐dioxido‐1,2,5‐thiadiazolidin‐2‐yl)(2‐oxo‐1,2‐
J = 11.5 Hz, 1H, P*CH), 4.18–3.58 (m, 4H, OCH2CH3), 2.03 (s, 3H,
CH3–Ar), 1.80 (s, 3H, CH3–Ar), 1.21 (t, J = 7.1 Hz, 3H, OCH2CH3), 0.99 (t,
J = 7.0 Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, DMSO‐d6) δ 149.19,
146.79, 141.48, 141.35, 138.84, 135.63, 135.66, 131.25 (d, JC‐P = 2.6 Hz),
128.91, 128.90, 127.51 (d, JC‐P = 3.3 Hz), 124.81, 124.84, 124.87, 117.88,
117.85, 63.89, 63.09, 21.84, 20.32, 16.64 (d, JC‐P = 8.8 Hz), 16.36 (d,
J = 5.7 Hz). 31P NMR (162 MHz, DMSO‐d6) δ 18.72 ppm. Anal. calcd. for
dihydroquinolin‐3‐yl)methyl] phosphonate (5c)
C16H22N3O6PS, MW = 415,40; TLC Rf = 0.42 (CH2Cl2/MeOH 7:3);
white powder; mp: 126–127°C; 81% yield. 1H NMR (400 MHz,
chloroform‐d6) δ 12.22 (s, 1H, NH), 8.07 (d, J = 3.7 Hz, 1HAr), 7.57
(dd, Jortho = 7.9, Jmetha = 2.2 Hz, 1HAr), 7.48 (ddd, Jortho = 9.5, 7.7,
Jmetha = 2.4 Hz, 1HAr), 7.39 (d, Jortho = 7.7 Hz, 1HAr), 7.26–7.16 (m,
1HAr), 5.82 (s, 1H, NH), 5.67 (d, JH‐P = 12.6 Hz, 1H, P*CH), 4.34–4.04
(m, 4H, OCH2CH3), 2.04 (s, 4H, NCH2–CH2N), 1.30 (t, J = 7.5 Hz, 3H,
OCH2CH3), 1.23 (t, J = 7.1 Hz, 3H, OCH2CH3) ppm. 13C NMR
C22H27ClN3O5PS (511.96): C, 51.61; H, 5.32; Cl, 6.92; N, 8.21; O, 15.63;
P, 6.05; S, 6.26%; found: C, 51.74; H, 5.45; Cl, 6.90; N, 8.26; O, 15.68; P,
6.07; S, 6.22%.
(101 MHz, chloroform‐d6)
δ 163.18 (d, JC‐P = 4.4 Hz), 139.25
(d, JC‐P = 7.0 Hz), 137.56, 130.75, 128.20 (d, JC‐P = 11.7 Hz), 127.68 (d,
Diethyl{[(4‐methylphenyl)sulfonamide](2‐oxo‐1,2‐dihydroquinolin‐3‐
yl)methyl}phosphonate (4h)
J
C‐P = 6.2 Hz) 123.02, 119.88 (d, JC‐P = 2.9 Hz), 115.86, 66.20 (d,
C‐P = 163.2 Hz), 63.54 (d, JC‐P = 7.0 Hz), 63.42 (d, JC‐P = 7.3 Hz),
J
C21H25N2O6PS, MW = 464.47; TLC Rf = 0.51 (CH2Cl2/MeOH 7:3); white
powder; mp: 190–191°C; 90% yield. 1H NMR (400 MHz, DMSO‐d6) δ
11.90 (s, 1H, NH), 8.05 (d, JH‐P = 3.9 Hz, 1HAr), 7.73 (td, Jortho = 7.5, 6.9,
45.17, 21.91, 16.43, 16.37 ppm. 31P NMR (162 MHz, CDCl3) δ
21.35 ppm. Anal. calcd. for C16H22N3O6PS (415.40): C, 46.26; H,
5.34; N, 10.12; O, 23.11; P, 7.46; S, 7.72%; found: C, 46.28; H, 5.35;
N, 10.12; O, 23.13; P, 7.45; S, 7.71%.
Jmetha = 1.7 Hz, 2HAr), 7.50 (td, Jortho = 8.3, 7.2, Jmetha = 1.2 Hz, 2HAr),
7.36 (td, Jortho = 8.4, Jmetha = 2.1 Hz, 2HAr), 7.28 (d, Jmetha = 2.3 Hz, 1HAr),
7.19 (td, Jortho = 8.1, 7.4, Jmetha = 1.2 Hz, 1HAr), 6.20 (dd, JH‐P = 14.0,
J = 6.2 Hz, 1H, NH), 5.33 (dd, JH‐P = 13.4, J = 6.2 Hz, 1H), 4.40–3.99 (m,
4H, OCH2CH3), 2.37 (s, 3H, CH3‐Ar), 1.23 (t, J = 7.1 Hz, 3H, OCH2CH3),
1.17 (t, J = 7.1 Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, DMSO‐d6) δ
161.15 (d, JC‐P = 5.9 Hz), 142.28, 141.91, 138.47 (d, JC‐P = 1.8 Hz), 138.02
(d, JC‐P = 6.6 Hz), 131.17, 130.73, 129.72, 128.38, 126.09, 122.43, 119.47
|
4.2
Biological assays
|
4.2.1
Antibacterial activity
The in vitro antibacterial activity of all synthesized compounds was
assayed against Gram‐positive and ‐negative bacteria (S. aureus
(ATCC 25923), E. coli (ATCC 25922), and P. aeruginosa (ATCC
27853)), in addition to three clinical strains (E. coli 1, S. aureus 1, and
P. aeruginosa 1) according to agar disc diffusion method on solid
medium Mueller–Hinton.[57] DMSO was used as a negative control
and the antibacterial agent sulfamethoxazole as a positive control.
The DIZ of each product was measured in millimeters in accordance
with the recommendations of the Clinical and Laboratory Standards
Institute.[63]
(d,
JC‐P = 3.3 Hz), 115.39, 63.16 (d, JC‐P = 165.4 Hz), 62.79 (d,
JC‐P = 6.6 Hz), 62.61 (d, JC‐P = 7.0 Hz), 21.34, 16.81 (d, JC‐P = 5.9 Hz), 16.72
(d, JC‐P = 5.9 Hz) ppm. 31P NMR (162 MHz, DMSO‐d6) δ 21.54 ppm. Anal.
calcd. for C21H25N2O6PS (264.12): C, 54.30; H, 5.43; N, 6.03; O, 20.67; P,
6.67; S, 6.90%; found: C, 54.35; H, 5.46; N, 6.01; O, 20.70; P, 6.65;
S, 6.92%.
Diethyl({[N‐(4‐fluorophenyl)sulfamoyl]amino}(8‐methyl‐2‐oxo‐1,2‐
dihydroquinolin‐3‐yl)methyl)phosphonate (4m)
C21H25FN3O6PS; MW = 497.48; TLC Rf = 0.41 (CH2Cl2/MeOH 7:4);
white powder; mp: 187–188°C; 90% yield. 1H NMR (400 MHz,
Serial dilutions of the tested compounds were prepared in
DMSO in a concentration range from 0.125 to 512 µg/ml. All tests

BAZINE ET AL.
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were performed in triplicate. The MIC and the MBC values of tested
molecules were determined using broth dilution method after in-
cubation at 37°C and observed for bacterial growth after 24 h for
MIC and 96 h (4 days) for MBC determinations after inoculation
for 24 h.
[5] P. Forgacs, N. L. Wengenack, L. Hall, S. K. Zimmerman,
M. L. Silverman, G. D. Roberts, Antimicrob. Agents Chemother. 2009,
53(4789), 4793.
[6] M. P. Anthony, J. N. Burrows, S. Duparc, J. J. Moehrle,
T. N. C. Wells, Malaria J. 2012,11, 316.
[7] S. Alven, B. Aderibigbe, Molecules 2019, 24, 3601.
[8] M. Krátký, J. Vinšová, M. Volková, V. Buchta, F. Trejtnar,
J. Stolaříková, Eur. J. Med. Chem. 2012, 50, 433. https://doi.org/10.
1016/j.ejmech.2012.01.060
|
4.2.2
Antifungal activity
[9] (a) J. Y. Winum, A. Scozzafava, J. L. Montero, C. T. Supuran, Med.
Res. Rev. 2006, 26, 767; (b) M. L. Villalba, A. V. Enrique, J. Higgs,
R. A. Castaño, S. Goicoechea, F. D. Taborda, L. Gavernet, I. D. Lick,
M. Marder, L. E. Bruno Blanch, Eur. J. Pharmacol. 2016, 774, 55.
[10] A. Bouzina, K. Bechlem, H. Berredjem, B. Belhani, I. Becheker,
J. Lebreton, M. Le Borgne, Z. Bouaziz, C. Marminon, M. Berredjem,
Antifungal activity of 18 newly synthesized compounds was de-
termined in vitro against two phytopathogenic fungi strains (FOL and
Alternaria sp.). The inhibitory activity of the various compounds on
the mycelium growth of the two phytopathogenic agents is de-
termined by measuring the colony diameter of the fungus on PDA
medium, containing the tested product. Amphotericin B was con-
sidered as a positive control. The negative control contains the PDA
and DMSO without any other products. Experimentally, a disk of
5 mm in diameter is taken from a young fungal culture and is de-
posited in the center of the Petri dish containing the PDA medium
and the tested compound. The experiment is replicated three times
for each compound. After 7 days of incubation at 25°C, the colony
diameter of phytopathogenic agent is measured at a millimetric scale.
The results were expressed as the percentage of growth inhibition of
each fungus grown in the control medium. Thus, the inhibition ac-
tivity was expressed as a percentage and was calculated according to
the formula: Inhibition % = (C – T/C) × 100, where C is the colony
diameter of the phytopathogenic agent in millimeters on the PDA
medium with DMSO (control) and T is the colony diameter in
millimeters of the phytopathogenic agent on PDA medium containing
the tested compound. The inhibition zones of the test compounds
were compared with controls.
Molecules
2018, 23,
7, 1682. https://doi.org/10.3390/
molecules23071682
[11] A. B. Reitz, G. R. Smith, M. H. Parker, Expert Opin. Ther. Pat. 2009,
19, 1449.
[12] K. Suthagar, A. J. Fairbanks, Org. Biomol. Chem. 2016, 14, 1748.
[13] M. L. Villalba, A. V. Enrique, J. Higgs, R. A. Castaño, S. Goicoechea,
F. D. Taborda, L. Gavernet, I. D. Lick, M. Marder, L. E. Bruno Blanch,
Eur. J. Pharmacol. 2016, 774, 55.
[14] M. A. H. Fahmy, T. R. Fukuto, Eur. Pat. Appl. Ep. 1980, 0, 36.
[15] Y. T. Lee, C. J. Cui, E. W. L. Chow, N. Pue, T. Lonhienne, J. G. Wang,
J. A. Fraser, L. W. Guddat, J. Med. Chem. 2013, 56, 210. https://doi.
org/10.1021/jm301501k
[16] (a) P. Kafarski, B. Lejczak, Curr. Med. Chem. 2001, 1, 301; (b)
L. Berlicki, P. Kafarski, Curr. Org. Chem. 2005, 9, 1829.
[17] J. Y. Winum, A. Scozzafava, J. L. Montero, C. T. Supuran, Med. Res.
Rev. 2006, 26, 767.
[18] C. T. Supuran, Nat. Rev. Drug Discov. 2008, 7, 168.
[19] C. T. Supuran, A. Scozzafava, A. Casini, Med. Res. Rev. 2003, 23, 146.
[20] J. Zhong, Bioorg. Med. Chem. 2004, 12, 589.
[21] W. C. Groutas, S. He, R. Kuang, R. Ruan, J. Tu, H. K., Chan, Bioorg.
Med. Chem. 2001, 9, 1543.
[22] S. Alyar, N. Karacan, J. Enzyme Inhib. Med. Chem. 2009, 24, 4, 986.
https://doi.org/10.1080/14756360802561220
[23] A. Tačić, V. Nikolić, L. Nikolić, I. Savić, Adv. Technol. 2017, 6, 58
[24] P. Huovinen, Clin. Infect. Dis. 2001, 32, 1608.
To identify the lowest inhibitory concentration, the test was
repeated with serial dilutions of each product in a concentration
range from 0.125 to 512 µg/ml.[64,65]
[25] F. Naaz, R. Srivastava, A. Singh, N. Singh, R. Verma, V. K. Singh,
R. K. Singh, Bioorg. Med. Chem. 2018, 26, 12, 3414. https://doi.org/
10.1016/j.bmc.2018.05.015
[26] K. U. M. Rao, S. Swapna, D. M. Mahidhar, K. M. K. Reddy,
C. S. Reddy, Phosphorus, Sulfur Silicon Relat. Elem. 2015, 98, 232.
[27] S. Sabatini, F. Gosetto, N. Iraci, M. L. Barreca, S. Massari,
L. Sancineto, G. Manfroni, O. Tabarrini, M. Dimovska, G. W. Kaatz,
J. Med. Chem. 2013, 56, 4975.
ACKNOWLEDGMENTS
This study was supported by The General Directorate for Scientific
Research and Technological Development (DG‐RSDT), Algerian
Ministry of Scientific Research, Algeria.
[28] B. Garudachari, M. N. Satyanarayana, B. Thippeswamy,
C. K. Shivakumar, K. N. Shivananda, G. Hegde, A. M. Isloor, Eur.
J. Med. Chem. 2012, 54, 900.
CONFLICTS OF INTERESTS
The authors declare that there are no conflicts of interests.
[29] A. B. Velu, G. W. Chen, P. T. Hsieh, J. T. Horng, J. T. Hsu, H. P. Hsieh,
T. C. Chen, K. F. Weng, S. R. Shih, Antiviral Res. 2014, 112, 18.
[30] A. Zarghi, R. Ghodsi, Bioorg. Med. Chem. 2010, 18, 5855.
[31] (a) C. Challa, J. Ravindran, M. Konai, S. Varughese, J. Jacob,
B. Kumar, J. Haldar, R. S. Lankalapalli, ACS Omega 2017, 2, 5187; (b)
N. Dolan, D. P. Gavin, A. Eshwika, K. Kavanagh, J. McGinley,
J. C. Stephens, Bioorg. Med. Chem. Lett. 2016, 26, 630
ORCID
Ismahene Bazine
http://orcid.org/0000-0001-6772-8379
REFERENCES
[32] A. Huang, A. Moretto, K. Janz, M. Lowe, P. W. Bedard, S. D. L. Tam,
V. Clerin, N. Sushkova, B. Tchernychev, J. Med. Chem. 2010, 53, 6003.
[33] N. Kishibayashi, Y. Miwa, H. Hayashi, A. Ishii, S. Ichikawa,
H. Nonaka, T. Yokoyama, Suzuki, J. Med. Chem. 1993, 36, 3286.
[34] L. F. Vendruscolo, R. N. Takahashi, G. R. Brüske, A. Ramos,
Psychopharmacology 2003, 170, 287.
[1] F. Z. Akçam, D. Karaslan, M. Doğan, G. Yaylı, Med. Sci. Monit. 2006,
12(2), 81.
[2] S. J. Projan, P. A. Bradford, Curr. Opin. Microbiol. 2007, 10, 441.
[3] N. S. El‐Gohary, M. I. Shaaban, Eur. J. Med. Chem. 2017, 131, 255.
[4] P. A. Masters, T. A. O′Bryan, J. Zurlo, D. Q. Miller, N. Joshi, Arch.
Intern. Med. 2003, 163(402), 410.

14 of 14
BAZINE ET AL.
|
[35] A. N. Boa, S. P. Canavan, P. R. Hirst, C. Ramsey, A. M. Stead,
G. A. McConkey, Bioorg. Med. Chem. 2005, 13, 1945.
molecules24030548; (b) Y. Zheng, R. L. Du, S. Y. Cai, Z. H. Liu,
Z. Y. Fang, T. Liu, L. Y. So, Y. J. Lu, N. Sun, K. Y. Wong, Front.
[36] S. A. Baron, C. Devaux, P. Colson, D. Raoult, J. M. Rolain, Int.
J. Antimicrob. Agents 2020, 55, 105944. https://doi.org/10.1016/j.
ijantimicag.2020.105944
Microbiol.
2019,
24,
548.
https://doi.org/10.3389/fmicb.
201801937; (c) P. Teng, C. Li, Z. Peng, A. M. Vanderschouw,
A. Nimmagadda, M. Su, Y. Li, X. Sun, J. Cai, Bioorg. Med. Chem. 2018,
26, 12, 3573; (d) N. Sun, R. Du, Y. Zheng, B. Huang, Q. Guo,
R. Zhang, K. Wong, Y. Lu, Eur. J. Med. Chem. 2017, 135, 1; (e)
H. Yang, H. Wang, T. Zhu, L. Yu, J. Chen, L. Wang, L. Shi, D. Li, L. Gu,
Z. Huang L. An, Eur. J. Med. Chem. 2007, 127, 166.
[37] P. Gautret, J. C. Lagier, P. Parola, V. T. Hoang, L. Meddeb,
M. Mailhe, B. Doudier, J. Courjon, V. Giordanengo, V. E. Vieira,
H. T. Dupont, S. Honoré, P. Colson, E. Chabriere, B. La Scola,
J. M. Rolain, P. Brouqui, D. Raoult, Int. J. Antimicrob. Agents 2020,
56, 105949. https://doi.org/10.1016/j.ijantimicag
[56] P. Kumar, BMC. Chem. 2020, 14, 1. https://doi.org/10.1186/
s13065-020-00669-3
[38] J. M. Molina, C. Delaugerre, J. L. Goff, B. Mela‐Lima, D. Ponscarme,
L. Goldwirt, N. de Castro, Med. Mal. Infect. 2020, 50, 384. https://
doi.org/10.1016/j.medmal.2020.03.006
[57] (a) B. A. Arthington‐Skaggs, M. Motley, D. W. Warnock,
C. J. Morrison, J. Clin. Microbiol. 2000, 38, 2254; (b) N. T. Cong,
H. T. Nhan, L. Van Hung, T. D. Thang, P. C. Kuo, Molecules 2014, 19,
13577; (c) K. Mickevičienė, R. Baranauskait, K. Kantminien,
M. Stasevych, O. Komarovska‐Porokhnyavets, V. Novikov,
Molecules 2015, 20, 3170.
[39] X. J. Mu, M. Y. Lei, L. P. Zou, W. Zhang, Tetrahedron Lett. 2006, 47, 1125.
[40] P. P. Giannousi, P. A. Bartlett, J. Med. Chem. 1987, 30, 1603.
[41] M. C. Allen, W. Fuhrer, B. Tuck, R. Wade, J. M. Wood, J. Med. Chem.
1989, 32, 1652.
[42] M. V. N. Reddy, S. Annar, A. Balakrishna, G. C. S. Reddy, C. S. Reddy,
Org. Commun. 2010, 3, 39.
[58] A. K. Jordão, J. Novais, B. Leal, A. C. Escobar, H. M. dos Santos,
H. C. Castro, V. F. Ferreira, J. Med. Chem. 2013, 63, 196.
[59] (a) X. Lei, J. Li, B. Liu, N. Zhang, H. Liu, Molecules 2015, 20, 16375;
(b) Z. Z. Geng, J. J. Zhang, J. Lin, M. Y. Huang, L. K. An, H. B. Zhang,
P. H. Sun, W. C. Ye, W. M. Chen, Eur. J. Med. Chem. 2015, 100, 235.
[60] N. Suresh, H. N. Nagesh, J. Renuka, V. Rajput, R. Sharma, I. A. Khan,
C. S. Kondapalli Venkata Gowri, Eur. J. Med. Chem. 2014, 71, 324.
[61] P. Berche, J. L. Gaillard, M. Simonet, Ed. Flammarion Medicine
Sciences. Flammarion médecine‐sciences, Paris. 1988, 64.
[62] D. Gatsing, V. Tchakoute, D. Ngamga, J. R. Kuiate, J. D. D. Tamokou,
Iran J. Med. Sci. 2009, 34, 126.
[43] (a) Y. C. Guo, J. Li, J. L. Ma, Z. R. Yu, H. W. Wang, W. J. Zhu,
X. C. Liao, Y. F. Zhao, Chin. Chem. Lett. 2015, 26, 755;
(b) X. C. Huang, M. Wang, Y. M. Pan, X. Y. Tian, H. S. Wang,
Y. Zhang, Bioorg. Med. Chem. Lett. 2013, 23, 5283;
(c) A. K. Bhattacharya, D. S. Raut, K. C. Rana, I. K. Polanki,
M. S. Khan, S. Iram, Eur. J. Med. Chem. 2013, 66, 146.
[44] P. Kafarski, B. Lejczak, Phosphorus, Sulfur Silicon Relat. Elem. 1991,
63, 193.
[45] A. Bouzina, N. E. Aouf, M. Berredjem, Res. Chem. Intermed. 2016,
42, 5993.
[63] Clinical and Laboratory Standards Institute. Performance Stan-
dards for Antimicrobial Susceptibility Testing, 27th ed. Clinical and
Laboratory Standards Institute Antimicrobial Susceptibility Testing
Standards M02‐M07, Wayne, PA 2017.
[64] C. Dennis, J. Webster, Trans. Br. Mycol. Soc. 1971, 57(3), 363.
[65] W. Song, L. C. Yang, X. Cao, L. Zhang, X. Liu, Crop Prot. 2004, 23,
243. https://doi.org/10.1016/j.cropro.2003.08.007
[46] Z. Regainia, M. Abdaoui, N. E. Aouf, G. Dewynter, J. L. Montero,
Tetrahedron 2000, 56, 381.
[47] A. Bendjeddou, R. Djeribi, Z. Régainia, N. E. Aouf, Molecule 2005,
10, 1387.
[48] H. Cheloufi, M. Berredjem, W. Boufas, F. Bouchareb, N. E. Aouf,
Phosphorus, Sulfur Silicon Relat. Elem. 2014, 189, 1396.
[49] F. Bouchareb, M. Berredjem, S. Ait Kaki, A. Bouaricha, A. Bouzina,
B. Belhani, N. E. Aouf, J. Chem. Sci. 2016, 128, 1, 85.
[50] (a) O. Meth‐Cohn, B. Nadine, B. Tarnowsky, J. Chem. Soc. Perkin
Trans. 1981(0), 1520; (b) O. Meth‐Cohn, Heterocycle. 1993, 35, 539;
(c) O. Meth‐Cohn, D. L. Taylor, Tetrahedron Lett. 1995, 51, 1287.
[51] T. Tilakraj, S. Y. J. Ambekar, Indian J. Chem. 1985, 62, 251.
[52] I. Bazine, Z. Cheraiet, R. Bensegueni, C. Bensouici, A. Boukhari,
J. Heterocycl. Chem. 2020, 57, 2139. https://doi.org/10.1002/jhet.3933
[53] S. Hessainia, F. Bouchareb, H. Cheloufi, M. Berredjem, N. Aouf,
Rasayan J. Chem. 2013, 6(175), 48.
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How to cite this article: Bazine I, Bendjedid S, Boukhari A.
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quinolone moiety. Arch Pharm. 2020;e2000291.
[54] (a) M. Guo, C. Zheng, M. Song, Y. Wu, L. Sun, Y. Li, Y. Liu, H. Piao,
Bioorg. Med. Chem. Lett. 2013, 23, 4358; (b) C. S. Pinheiro, L. Feitosa,
M. Gandi, F. Silveira, N. Boechat, Molecules 2019, 24, 4095. https://
doi.org/10.3390/molecules24224095
https://doi.org/10.1002/ardp.202000291
[55] (a) H. G. Fu, Z. W. Li, X. Hu, S. Y. Si, X. F. You, S. Tang, Y. X. Wang,
D. Q. Song, Molecules 2019, 24, 548. https://doi.org/10.3390/