Synthesis, antioxidant and anticholinesterase activities of novel quinoline-aminophosphonate derivatives

Article abstract of DOI:10.1002/jhet.3933

A series of 20 novel α-aminophosphonate derivatives bearing quinoline or quinolone moiety was designed and synthesized via Kabachnik-Fields reaction in the presence of triethylammonium acetate as a solvent and catalyst under ultrasound irradiation. This procedure affords products in high yields and short reaction times. Molecular structures of the synthesized compounds 4a-g and 5a-m were confirmed using various spectroscopic methods. The antioxidant activity of these compounds was evaluated by eight complementary in vitro tests. The anticholinesterase activity (AChE, BChE) of these compounds were also evaluated. In addition, theoretical calculations of all compounds were investigated as corrosion inhibitors using density functional theory (DFT). The results revealed that 16 of these compounds exhibited high levels of antioxidant activities depending on the assay and that most compounds showed more potent inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).

Full text of DOI:10.1002/jhet.3933

Received: 4 December 2019
DOI: 10.1002/jhet.3933
Revised: 12 January 2020
Accepted: 28 January 2020
A R T I C L E
Synthesis, antioxidant and anticholinesterase activities of
novel quinoline-aminophosphonate derivatives
Ismahene Bazine1
| Zinelaabidine Cheraiet1,2 | Rafik Bensegueni3,4
|
Chawki Bensouici5 | Abbes Boukhari1
1Laboratoire de Synthèse Organique,
Abstract
Modélisation et Optimisation des Procédés
chimiques, Faculté des Sciences,
Université Badji Mokhtar d'Annaba,
Annaba, Algeria
2Ecole Supérieure de Technologies
Industrielles, Annaba, Algeria
3Université Mohamed Cherif Messaadia,
SoukAhras, Algeria
4Laboratoire de Chimie des Matériaux
Constantine, Université Frères Mentouri
Constantine 1, Constantine, Algeria
A series of 20 novel α-aminophosphonate derivatives bearing quinoline or
quinolone moiety was designed and synthesized via Kabachnik-Fields reaction
in the presence of triethylammonium acetate as a solvent and catalyst under
ultrasound irradiation. This procedure affords products in high yields and
short reaction times. Molecular structures of the synthesized compounds 4a-g
and 5a-m were confirmed using various spectroscopic methods. The antioxi-
dant activity of these compounds was evaluated by eight complementary
in vitro tests. The anticholinesterase activity (AChE, BChE) of these com-
pounds were also evaluated. In addition, theoretical calculations of all com-
pounds were investigated as corrosion inhibitors using density functional
theory (DFT). The results revealed that 16 of these compounds exhibited high
levels of antioxidant activities depending on the assay and that most com-
pounds showed more potent inhibitory activities against acetylcholinesterase
(AChE) and butyrylcholinesterase (BChE).
5Centre de Recherche en Biotechnologie,
Ali Mendjli Nouvelle Ville UV03,
Constantine, Algeria
Correspondence
Ismahene Bazine, Laboratoire de Synthèse
Organique, Modélisation et Optimisation
des Procédés chimiques, Faculté des
Sciences, Université Badji Mokhtar
d'Annaba B.P. 12, 23000 Annaba, Algeria.
Email: bazineismahane@gmail.com
Funding information
The General Directorate for Scientific
Research and Technological Development
(DG-RSDT), Algerian Ministry of
Scientific Research
1 | INTRODUCTION
oxidative damage[3]; also, these antioxidant agents have a
great effect to minimize the progress of Alzheimer's dis-
Currently, chemical researchers are striving for new safely
agents to prevent major health problems related to oxida-
tive stress. These problems including Alzheimer's diseases
affecting a large portion of the world population. From this
point, the development of new treatment strategies for
these diseases is one of the most remarkable topics in the
scientific area.[1,2] An antioxidant agent is defined as a
molecule that protects a biological target against oxidative
damage which causes many diseases. As a result, many
diseases have been treated with antioxidants to prevent
ease[4,5] by reacting with reactive oxygen species
(ROS).[6–9] In addition to their potential beneficial effects,
there has been an increasing research in pharmaceutical,
cosmetic and food industries for the discovery of antioxi-
dants to compare the bioactivities above mentioned with
those of commercial antioxidants, such as BHA (butylated
hydroxyanisole), BHT (butylated hydroxytoluene), TBHQ
(tertbutyl hydroquinone), PG (gallate), galantamine and
kojik acid which are commonly used in the food and phar-
maceutical industries.
J Heterocyclic Chem. 2020;1–11.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
BAZINE ET AL.
α-aminophosphonate constitutes a class of important
of 2-oxo-quinoline derivatives and α-aminophosphonate
motifs among the organophosphorus compounds with
variety of interesting and useful properties in medicinal
chemistry. compounds bearing this moiety have seen huge
development due to their expansive range of biological
and pharmaceutical properties,[10] such as catalyst
inhibitors,[11] antitumor, antimicrobial,[12] anti-inflamma-
tory, anticancer,[13] antimalarial,[14] peptidomimetics,[15]
antioxidant,[16] and inhibitors of protein tyrosine.[17]
On the other hand, quinoline and its analogs represent
privileged moieties with numerous derivatives widely dis-
tributed in nature.[18] Quinoline plays an important role in
the field of synthetic and medicinal chemistry, illustrated
by their extensive application as biologically and pharma-
cologically active compounds,[19,20] such as antitumor,[21]
anti-parasitic, antimalarial,[22] anti-hepatitis, antifungals,
antimicrobial,[23] anti-arrythmic,[24] antioxidant,[25] anti-
inflammatory[26] and anticancer properties.[27]
In order to increase the activity of these moieties, we
attempt to introduce the quinoline scaffold onto α-ami-
nophosphonate, using 2-chloro-3-formylquinoline deriva-
tives as starting material via simple and effective
procedure under ultrasound irradiation. In particular, the
objectives of this study were the investigation of the abil-
ity of compounds 4a-g and 5a-m to inhibit AChE and
BChE enzymes and the determination of the antioxidant
properties by using eight complementary in vitro tests,
such as β-carotene-linoleic acid, DPPH scavenging, ABTS
scavenging, reducing power, cupric-reducing antioxidant
capacity (CUPRAC), hydroxyl radical-scavenging,
phenanthroline and galvinoxyl scavenging assays,
followed by the assessment of theoretical antiradical
activity using DFT calculations. The theoretical part of
this study relates to the calculation of some thermody-
namic molecular descriptors of tested molecules, with the
density functional theory (DFT).
groups may lead to good antioxidant agents.
2 | RESULTS AND DISCUSSION
2.1 | Synthesis and identification
Series of 20 novel α-aminophosphonates 4a-g and 5a-m
containing quinoline or quinolone moiety was designed
and synthesized under ultrasound irradiation. A simple,
rapid, facile and highly efficient method has been
employed for the synthesis of α-aminophosphonate
derivatives via Kabachnik-Fields reaction starting from
quinoline or quinolone carbaldehyde and functionalized
amine using ionic liquid [TEAA] as a solvent and
catalysts.
Firstly, 2-chloro-quinoline-3-carbaldehyde derivatives
(2) were obtained via Meth-Cohn[29] reaction, which
included the condensation of acetanilide derivatives (1) with
Vilsmeir-Haack reagent. 2-Oxoquinoline 3-carbaldehyde
derivatives (3) were then obtained in good yields by the
hydrolytic reaction of (2) in the presence of 70% acetic
acid.[30] The target compounds 4a-g and 5a-m were synthe-
sized via Kabachnik-Fields reaction, under ultrasound irra-
diation in the presence of ionic liquid [TEAA], using
aminophenol or aminopyridine as starting materials
(Scheme 1). This method offers several advantages includ-
ing the easy, work-up reaction and giving pure product
without chromatography purification and high yield in
short reaction time. The structures of target compounds 4a-
g and 5a-m were confirmed using various spectroscopic
1
methods, including H NMR, 13C NMR, 31P NMR, HSQC,
HMBC, COSY, ESI-MS and elemental analysis.
(a): DMF, POCl3 (3/7), 70ꢀC, (b): CH3COOH (70%),
reflux, (c): PO(OEt)3, IL[TEAA], ultrasound irradiation.
It was found that ionic liquid [TEAA] has a large
effect on the rate of the reaction and yields of products;
the rates of the reaction were remarkable slowed without
It appears that the presence of 2-oxo-quinoline in the
scaffold lead to potent antioxidant activities according lit-
erature works[28]. It is thus to expect that the combination
SCHEME 1 One-pot synthesis
of novel α-aminophosphonate
derivatives under ultrasound
irradiations

BAZINE ET AL.
3
ionic liquid, and the yields were very low (about 30%).
The results were listed in Table 1. The great improvement
of the yield was achieved to afford α-aminophosphonates
containing quinolone moiety in the yield of 81-93% in
short reaction time; the obtained results were summa-
rized in Table 2.
initiation, decomposition of peroxides, prevention of con-
tinued hydrogen abstraction.[31] Moreover, inhibition
potential against acetylcholinesterase (AChE) and but-
yrylcholinesterase (BChE) key enzymes involved in com-
mon human pathologies neurodegenerative disorders[32]
was also evaluated.
2.2 | Biological evaluation
2.2.1 | Determination of the antioxidant
activity
Antioxidant capacity of all synthesized compounds was
evaluated by using eight complementary tests. These tests
were based on different mechanisms of action. It is
important to use many assays to prove the effectiveness
of each product and their mechanisms like the reductive
capacity and radical scavenging, prevention of chain
In this study, the antioxidant activity of 20 novel synthe-
sized compounds was tested using eight complementary
in vitro tests; namely, β-carotene-linoleic acid assay
according to the method of Marco[33] with slight modifi-
cations. Free radical-scavenging activity by DPPH scav-
enging assay according to the method described by Blois
1958[34]. ABTS scavenging assay according to the method
of Re et al.[35] with slight modifications. Cupric-reducing
antioxidant capacity (CUPRAC) was determined
according to the method of Apak et al.[36]. The reducing
power assay was carried out as described by Oyaizu[37]
with slight modifications. Measurement of the hydroxyl
radical-scavenging activity of the compounds was based
TABLE 1 Effect of IL (TEAA) on the yield of 4a, 4b, 4c
Compound
Yield without IL
Yield With ILa
4a
4b
4c
30
25
28
76
85
82
a1 mL IL (triethylammonium acetate): 1 mmol substrate.
on the method described by Smirnoff and Cumbes[38]
.
TABLE 2 Synthesis of novel
α-aminophosphonate under ultrasound
irradiation
Entry
R
Amine
Time (min)
Yield%
76
mpꢀC
4a
H
2-aminophenol
2-aminophenol
2-aminophenol
2-aminophenol
2-aminophenol
4-aminophenol
3-aminopyridine
2-aminophenol
2-aminophenol
2-aminophenol
2-aminophenol
2-aminophenol
4-aminophenol
4-aminophenol
4-aminophenol
4-aminophenol
4-aminophenol
3-aminopyridine
3-aminopyridine
3-aminopyridine
12
16
14
15
16
17
19
10
11
9
177-178
190-191
166-167
184-185
198-199
203-204
179-179.8
133-134
170-170.7
163-164.2
116-117
221-222
222-223
216-217
124-125
200-201
229-230
198-199
127-128
311-313
4b
4c
4d
4e
4f
6-Me
6-OMe
7-Me
8-Me
6-OMe
6-OMe
H
85
82
74
77
86
4g
5a
5b
5c
5d
5e
5f
79
92
6Me
6OMe
7Me
8Me
H
87
84
11
10
13
12
11
10
12
14
13
11
88
92
75
5g
5h
5i
6Me
6OMe
7Me
8Me
6Me
7Me
8Me
81
89
78
5j
71
5k
5l
83
93
5m
79
Note: Conditions: aldehyde (1 mmol), amine (1 mmol), triethylphosphite (1 mmol), LI, 40 kHz.

4
BAZINE ET AL.

BAZINE ET AL.
5
Phenanthroline activity was evaluated by the method of
Szydlowska-Czerniaka[39] and galvinoxyl scavenging
(GOR) assay was determined as previously method
described by Shi et al.[40]. BHA and BHT were used as
positive standards for comparison of the activity. The
tests were performed at different concentrations to calcu-
31.57 1.18 μM. Unfortunately, since these compounds,
cupric reducing antioxidant capacity of 4f (A0.50 = 1.86
0.01 μM),
5j
(A0.50
=
2.37 0.03 μM),
4e
(A0.50 = 12.73 0.03 μM) and 4b ≈ 4d (A0.50 = 13.36
0.02, 13.77 0.33 μM), respectively, were very higher
than that of both BHT (A0.50 = 43.65 0.87 μM) and
BHA (A0.50 = 20.19 0.19 μM). In the β-carotene-linoleic
acid assay, the antioxidants scavenge singlet oxygen caus-
ing radicals in lipids. The results suggested that all the
selected compounds showed remarkable lipid peroxida-
tion inhibition with IC50 values less than 12.6 μM. All
these compounds except 5g, 5d, 4d, 5m have a higher
antioxidant capacity than BHA (IC50 = 6.99 0.00 μM).
In this method, oxidation of linoleic acid was effectively
inhibited by 4f, 5b, 4c ≈ 5i ≈ 5j ≈ 5e (5.61 0.08; 5.71
0.08; 3.01 0.08; 3.26 0.07; 3.29 0.53; 3.79 0.09),
respectively. On the other hand, the best results were
obtained for compounds 4d (A0.50 = 13.06 0.04 μM), 4c
(A0.50 = 13.30 0.18 μM), 4b (A0.50 = 14.32 0.06 μM)
and 5d (A0.50 = 16.18 0.64 μM), respectively, with
reducing power assay. These derivatives have a higher
antioxidant capacity than the standard BHA
(A0.50 = 20.19 0.19 μM) and about three times higher
than BHT (A0.50 = 40.70 3.94 μM). In phenantroline
late the IC50 and A
values. Results were statistically
0.50
significant (P < 0.05) when compared with those of con-
trols in each test.
The results of all the tests expressed in term of IC50 or
A0.50 presented in Table 3. The effectiveness of antioxi-
dant properties is inversely correlated with their IC50
values. The product concentration providing 50% antioxi-
dant activity (IC50) was calculated from the graph of
antioxidant activity percentage against product con-
centration. The sample concentration producing 0.50
absorbance (A0.50) was calculated from the graph of the
absorbance against the sample concentration.
In general, the all tested compounds exhibited potent
antioxidant activity, except compounds 4g, 5k, 5l, 5m
which showed weak antioxidant activity with all tests. In
the DPPH and ABTS assays, all compounds except 5g
and 5d showed stronger antioxidant activities than BHT.
The highest DPPH activity was observed in the com-
pound 4f (IC50 = 2.01 0.02 μM) followed by 5j
(IC50 = 5.64 0.01 μM) and 5f (IC50 = 8.15 0.18 μM),
assay, the derivatives bearing
a quinoline moiety
exhibited a very high antioxidant capacity translated by
their low values of A0.50. The derivatives 4c (A0.50 = 1.84
0.81 μM), 4a (A0.50 = 1.99 0.20 μM), 4f (A0.50 = 2.87
0.16 μM), 4b (A0.50 = 3.61 0.05 μM), 4d (A0.50 = 4.36
0.75 μM), respectively, have a higher antioxidant
capacity than the standard BHA (A0.50 = 5.15 0.07 μM)
and BHT (A0.50 = 10.16 0.17 μM).
evidently, the same derivatives 4f (IC50
= 2.61
0.56 μM) and 5j (IC50 = 3.29 0.03 μM), exhibited the
best ABTS radical scavenging activity. For Galvinoxyl
assay, all selected compounds showed a very high antiox-
idant activity with IC50 values lower than 23.53
0.08 μM. All these compounds except 5c, 5d have a
higher antioxidant capacity than that of BHT
(IC50 = 15.06 0.18 μM). The highest inhibitory effect
was respectively exhibited by the derivatives 4f, 5i, 5j, 5h
and 4d (IC50 = 3.74 0.03, 4.73 0.08; 7.39 0.51; 7.70
0.22; 7.79 0.19 μM), their IC50 values about three
times lower than that of BHA (IC50 = 29.84 0.06 μM).
In the hydroxyl radical scavenging assay, the obtained
results demonstrate that all compounds except 4g, 5h, 5j,
5k, 5l, 5m had a moderate activity translated by a high
values of IC50 (169.66 0.53-1818.49 1.44 μM) which
was still much more than that of ascorbic acid
(IC50 = 32.33 1.17 μM).
Generally,
it
should
be
mentioned
that
α-aminophosphonate derivatives exhibited good antioxi-
dant activity, and it is worth noting that the presence of
quinoline and quinolone moiety significantly increases
their antioxidant activity[41]. In all studied methods, all
novel compounds showed excellent antioxidant activity
except 4g, 5k, 5l and 5m. It was observed that the most
effective compounds are those containing phenol due to
their power to give more atoms to stabilize free radi-
cals[42,43]. This explains the low antioxidant activity of 4g,
5k, 5l and 5m, which have a pyridine moiety replacing a
phenol groups in its structure.
Cupric reducing antioxidant capacity (CUPRAC) of
all compounds was also assayed. The results were given
as absorbance. In this method, copper (I) and
neocupronine give a stable complex, the formation of this
complex is carried out by reduction of copper (II) in the
presence of neocupronine. The results demonstrated that
all compounds exhibited higher antioxidant activity than
BHT (A0.50 = 43.65 0.87 μM) with A0.50 lower than
2.2.2 | DFT calculations
A molecular descriptors calculation was carried out on
all of our synthesized compounds, using the density func-
tional theory (DFT). Their structures geometries were
optimized at the B3LYP/6-311G++(d,p) level of the DFT

6
BAZINE ET AL.
theory. Solvation effects were considered using the
IEFPCM model[44]. Vibrational frequencies' calculations
were performed to check if the optimized geometries are
located at the minimum point of the corresponding
potential surface. All calculations were made with
GAUSSIAN 09 software[45], whereas GaussView 5.0.9[46]
was used for results visualization and analysis. Chem3D
Ultra software (version 8.0) was used to conduct a prelim-
inary molecular dynamics calculation with the molecular
mechanics force field MM2 (ChemOffice 2003, Cam-
bridge Soft Corporation). The calculated molecular
descriptors are: the bond dissociation enthalpy (BDE),
the ionisation potential (IP), the proton dissociation
enthalpy (PDE), the proton affinity (PA) of the anion and
the electron transfer enthalpy (ETE). The three possible
radical scavenging mechanisms, that may coexist are:
hydrogen atom transfer (HAT), single electron transfer-
proton transfer (SET-PT) and sequential proton loss elec-
tron transfer (SPLET)[47,48]. Each of these mechanisms is
distinguished by one or more molecular descriptors, as
illustrated in Equations (1) to (3). Therefore, BDE, IP and
PA are the three determinant molecular descriptors of
the thermodynamically preferred antiradical mechanism.
The higher is the scavenging activity, the lower are their
values[49] and the smallest descriptor corresponds to the
favored mechanism.
calculated at 298.15 K and 1 atm. The enthalpy values of
hydrogen atom (H•), proton (H+) and electron (e−) in
ethanol are equal to −1307.479[50], −1012.303 and
−102.154 kJ/mol, respectively. The two last values
were obtained from the corresponding solvation
enthalpies[51]
.
The geometries of the studied molecules were opti-
mized. The vibrational frequencies' calculations exhibited
no negative value, indicating indeed that the optimized
geometries are located on the global minimum point of
its potential energy surface. When comparing the deter-
minant molecular descriptors' values (Table 4), for each
molecule, it was found that PA was the lowest one.
Which mean that SPLET is thermodynamically the most
favored mechanism for the radical scavenging activity of
all studied molecules. However, a difference in the origin
of the transferred proton is noted between the tested
compounds. Some prefer to release the proton from the
hydroxyl group (4a, 4b, 4c, 4d, 4e, 4f, 5f, 5i and 5h) while
others favor the departure of the proton from the N-H
bond (5a, 5b, 5c, 5d, 5e, 5g, 5j, 5k, 5l, 5m and 4g). Notice
that a number of molecules have two N-H bonds (two
labile protons Ha and Hb), as shown in Figure 1. In this
case, the Ha proton transfer is always preferred to the Hb
one. Thus, molecules having a single N-H bond (4a, 4b,
4c, 4d, 4e, 4f) prefer the transfer of the O-H proton. For
molecules having two N-H bonds (5a, 5b, 5c, 5d, 5e), the
transfer of the Ha proton is preferred. The same thing is
observed for molecules having no O-H bond (5k, 5l,
5m, 4g). The rest of molecules show very close values of
PA with a slight preference to transfer the Ha proton, for
HAT : RX−H ! H: + RX: ½BDE = HðRX:Þ
+ HðH:Þ−HðRX−HÞꢁ,
ð1Þ
ꢂ
ꢀ
ꢁ
ꢃ
(
+ :
+ :
RX−H ! ðRX−HÞ + e− IP = H ðRX−HÞ
+ Hðe− Þ−HðRX−HÞ
SET−PT :
ð2Þ
ð3Þ
ꢂ
ꢀ
ꢁꢃ
+ :
+ :
ðRX−HÞ ! RX: + H+ PDE = HðRX:Þ + HðH+ Þ−H ðRX−HÞ
,
(
RX−H ! RX− + H+ ½PA = HðRX− Þ + HðH+ Þ−HðRX−HÞꢁ
SPLET :
RX− ! RX: + e− ½ETE = HðRX:Þ + Hðe− Þ−HðRX− Þꢁ:
For the generated radicals (RX• and RX-H+•), the
unrestricted open shell level UB3LYP/6-311G++(d,p)
was used to calculate their vibrational frequencies and
no significant change was noted when subjected to a
geometry optimization. Molecular descriptors are
5g and 5j, and to transfer the O-H proton, for 5f, 5i
and 5h.
A good correlation between the experimental results
of the DPPH scavenging activity (IC50) and the relevant
descriptors (PA)[52] is also observed (Figure 1).

BAZINE ET AL.
7
TABLE 4 Molecular descriptors (kJ/mol) calculated at the B3LYP/6-311G++(d,p) level of the DFT theory. Solvation effects (ethanol)
were considered using the IEFPCM model
Molecule
BDE(OH)
410.86
409.17
395.03
395.75
347.47
344.42
No OH
381.48
BDE(NH)
411.70
IP
PDE
PA(OH)
288.69
287.69
280.53
262.47
227.01
242.96
No OH
269.83
PA(NH)
320.82
ETE(OH)
315.19
314.50
307.52
326.30
313.48
294.48
No OH
304.67
ETE(NH)
283.90
4a
4b
4c
4d
4e
4f
482.14
480.39
474.83
499.71
465.34
434.16
483.02
462.27
121.74
121.80
113.22
89.06
411.75
321.93
282.84
399.25
323.72
268.56
418.74
317.51
294.25
347.47
75.16
313.35
227.14
374.11
103.28
No OH
112.23
321.37
245.76
4g
5a
390.09
298.73
284.39
435.07a
915.31b
420.63a
390.23b
413.26a
384.48b
429.15a
416.72b
426.02a
387.12b
387.19a
386.06b
416.17a
379.04b
408.67a
876.26b
428.66a
386.58b
424.78a
390.32b
423.97a
423.98b
431.44a
399.29b
425.33a
381.42b
222.32a
340.40b
241.15a
325.06b
224.40a
334.76b
236.61a
344.63b
254.02a
358.97b
237.60a
345.76b
233.59a
338.64b
242.89a
314.86b
240.85a
342.92b
236.25a
351.57b
232.81a
313.07b
231.19a
320.61b
236.70a
294.13b
405.77a
767.93b
372.50a
258.19b
381.88a
242.74b
385.56a
265.11b
365.02a
221.17b
242.61a
233.31b
375.60a
233.42b
358.81a
754.42b
380.83a
236.68b
381.55a
231.77b
384.18a
303.93b
393.27a
271.70b
381.65a
280.31b
5b
5c
5d
5e
5f
427.27
380.25
394.34
381.03
337.54
336.01
339.59
343.21
343.58
No OH
No OH
No OH
467.36
458.78
465.37
463.04
414.75
411.87
423.60
428.71
430.16
463.56
466.62
478.58
152.93
114.49
121.98
91.97
323.21
321.61
289.33
270.64
245.55
244.72
242.32
238.79
240.82
No OH
No OH
No OH
297.08
251.66
298.02
284.36
285.01
284.31
290.29
297.44
295.78
No OH
No OH
No OH
115.80
117.17
109.01
107.52
106.44
No OH
No OH
No OH
5g
5h
5i
5j
5k
5l
5m
aN-Ha
bN-Hb
2.2.3 | Determination of cholinesterase
(AChE, BChE) inhibitory activity
anticholinesterase activity of all synthesized products
which can lead to their possible uses as effect enzyme
inhibitors. Cholinesterase (ChE) inhibitory activity was
measured using Ellman's method, as previously
reported[56] with slight modification.
Inhibitors of acetylcholinesterase (AChE) and but-
yrylcholinesterase (BChE) are the most investigated and
commonly strategy used for the treatment of Alzheimer's
The IC50 values of all tested compounds against BChE
and AChE were summarized in Table 5. The obtained
disease[53–55]
.
In this context, we evaluated the

8
BAZINE ET AL.
FIGUR E 1 Correlation curve between the
IC50 of the DPPH scavenging activity and the
determinant molecular descriptor, PA in our
case, for the most active molecules
5e (IC50 = 52.55 1.07 μM) and 5a (IC50 = 55.23
0.38 μM), respectively, compared with Galantamine
standard (IC50 = 21.81 1.15 μM). In term of anti-BChE
activity, all tested compounds except 4a, 5e, 5l, 5k, 5m
(IC50 > 500 μM), showed good activities. The derivatives
5d, 5a, 5h, 5c and 5b (IC50 = 24.56 1.20; 29.35
TABLE 5 IC50 values of (AChE, BChE) inhibitory activity of
compounds 4(a-g) and 5(a-m)
IC50 (μM)a
Compound
AChE
BChE
4a
70.49 0.70
28.42 0.02
38.39 0.89
107.37 1.12
105.32 1.25
67.20 1.12
>500
>500
0.86;
33.49 2.25;
43.46 1.35-55.27 1.25 μM)
4b
73.38 1.99
186.79 1.99
65.30 1.42
169.40 1.99
79.22 1.86
429.55 2.01
29.35 0.86
55.27 1.25
43.46 1.35
24.56 1.20
>500
respectively, were the most potent compounds
against BChE compared with Galantamine standard
(IC50 = 120.93 1.99 μM).
4c
4d
4e
4f
3 | CONCLUSION
4g
5a
55.23 0.38
>500
In conclusion, we reported the synthesis, identification
and evaluation of antioxidant and anticholinesterase
activities of novel α-aminophosphonates derivatives. A
good correlation between the experimental results of the
DPPH scavenging activity (IC50) and the relevant descrip-
tors (PA) is also observed using DFT calculation.
The results suggested a potent antioxidant activity
with all tests of most products and showed a middle
inhibitory against AChE and important inhibition of
BChE, which may find the application of these novel
molecules as potential antioxidant agents and may be
useful as a moderate anticholinesterase agent, for treat-
ment of Alzheimer's diseases.
5b
5c
141.57 1.16
191.15 0.69
52.55 1.07
>500
5d
5e
5f
256.72 1.44
97.61 0.58
33.49 2.25
61.94 2.35
180.82 1.15
>500
5g
>500
5h
>500
5i
67.39 2.01
>500
5j
5k
91.73 0.49
>500
5l
>500
5m
96.92 1.12
21.81 1.15
>500
Galantamineb
120.93 1.99
4 | EXPERIMENTAL SECTION
4.1 | General information
aValues expressed are means SD of three parallel measurements.
bReference compounds.
IC50 values revealed that all tested compounds except 5b,
5f, 5g, 5i, 5h, 5l, 4g (IC50 > 500 μM) showed moderate
All starting materials and reagents used for synthesis
were obtained commercially from commercial sources
Aldrich and Acros and were used without purification.
Sonication was performed in a FUNGILAB ultrasonic
bath with a frequency of 40 kHz and an output power of
250 W. Melting points were measured using Buchi
inhibitory activity against AChE (IC50
=
28.42
0.02-191.15 0.96 μM). The highest inhibitory activity
against AChE was observed with derivatives 4b
(IC50 = 28.42 0.02 μM), 4c (IC50 = 38.39 0.89 μM),

BAZINE ET AL.
9
Melting Point B-545. All reactions were monitored by
thin-layer chromatography (TLC) carried out on
0.25-mm Merck silica gel plates (60F-254) using ultravio-
let light (254 nm) as the visualizing agent and ninhydrine
1HAr,H1), 7.37 (dd, Jortho = 8.5, Jmetha = 1.1 Hz,
1HAr,H6), 7.25 (td, Jortho = 8.1, 7.2, Jmetha = 1.1 Hz,
1HAr,H2). 13C NMR (101 MHz, DMSO-d6) δ 190.18,
190.15, 142.87, 134.08, 134.05, 131.29, 123.09, 123.07,
118.60, 115.89 ppm.
1
solution as developing agents. H NMR and 13C NMR
spectra were recorded at 30ꢀC on a Bruker spectrometers
1
(400 MHz for H, 101 MHz for 13C and 162 MHz for 31P)
using TMS as internal standard and CDCl3 or DMSOd-6 4.4 | General procedure for the
as solvent. Mass spectra were recorded with
a
preparation of α-aminophosphonate
MicrOTOF-Q Bruker spectrometer using electrospray
ionization (ESI) analysis. All reagents used for biological
activities were purchased from Sigma-Aldrich Co.,
St Lowis, MO. Measurements and calculations of the
antiradical activity were carried out on a 96-well micro-
plate reader, Perkin Elmer Multimode Plate Reader
EnSpire.
In a 10 mL round-bottom flask, a mixture of amine
(1 mmol) and aldehyde (1 mmol) was taken with 1 mL of
ionic liquid at room temperature and then triethyl phos-
phite (1 mmol) was added. The reaction mixture was sub-
jected to the ultrasonication for 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 chlo-
roform/diethyl ether to yield pure α-aminophosphonate.
diethyl(((2-hydroxyphenyl)amino)(−2-oxo-1,-
4.2 | General procedure for the
preparation of quinoline derivatives
2-dihydroquinolin 3yl)methyl)phosphonate 5a: C20H23N2
O5P; TLC Rf = 0.48 (CH2Cl2); yellow powder; 92% yield;
1H NMR (400 MHz, Chloroform-d6) δ 11.75 (s, 1H, OH),
9.74 (s, 1H, NH), 7.70 (d, JH-P = 3.5 Hz, 1H Ar, H7),
7.10-7.00 (m, 2H Ar, H1, H3,), 6.93 (dd, Jortho = 8.2,
Jmetha = 1.5 Hz, 1H Ar, H6), 6.88 (dd, Jortho = 7.8,
Jmetha = 1.4 Hz, 1H Ar, H17), 6.72 (td, Jortho = 7.7,
Jmetha = 1.9 Hz, 1H Ar, H2), 6.54 (td, Jortho = 7.6,
Place dimethyl formamide (DMF)(3 eq) in a flask
equipped with a drying tube cooled to 0ꢀC temperature,
then POCl3(Phosphorousoxychloride) (7 eq) was added
dropwise with stirring to it. To this solution add acetani-
lide (1 mmol). After few minutes the reaction mixture
was refluxed for 6-8 h. After completion of requiring time
reaction, the mixture was cooled and poured in ice-cold
water and stirred about half an hour then filtered to offer
powder of compound.
Jmetha = 1.4 Hz, 1H Ar, H18), 6.50 (dd, J
= 8.4,
ortho
Jmetha = 3.6 Hz, 1H Ar, H16), 5.92(d, J = 11.6 Hz, 1H,
NH), 5.89(dd, J ortho = 7.8, Jmetha = 1.7 Hz, 1H, H15), 5.77
(dd, JH-P = 25.0, 11.6 Hz, 1H, H12), 4.46-4.33 (m, 2H,
H27), 4.16-3.91 (m, 2H, H24), 1.20 (t, J = 7.0 Hz, 3H Ar,
H25), 1.09 (t, J = 7.1 Hz, 3H, H29) ppm. 13C NMR
2-Chloro-3-formyl-6-méthylquinoline: C10H7NO2; MW
= 173.17; TLC Rf = 0.35 (CH2Cl2); yellow powder; 96%
yield; IR νmax (KBr) (cm−1) = 1645 (CO). 1H NMR
(400 MHz, DMSO-d6) δ 10.57(s, 1H, CHO), 8.58 (s, 1H,
H4), 7.97 (d, J = 7.7, 1H, H8), 7.75 (d, J = 2.3, 1H, H5),
(101 MHz, Chloroform-d6) δ 163.10 (d, J
= 6.4 Hz),
C-P
7.74 (dd, J = 7.7, 2.4, 1H, H7), 2.57 (s, 3H, CH3) ppm. 13
C
145.22, 138.96, 137.17, 135.09 (d, J C-P = 16.2 Hz), 130.38,
128.53, 127.54, 122.05, 120.38, 119.39, 119.03, 115.16,
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.
115.03, 112.35, 64.65 (d, J
= 6.8 Hz), 63.75 (d, JC-
C-P
= 7.5 Hz), 45.46, 16.51 (d, JC-P = 5.8 Hz), 16.21 (d, JC-
P
= 5.6 Hz) ppm. 31P NMR (162 MHz, CDCl3) δ
P
4.3 | General procedure for the
preparation of compounds 3a-f
24.04 ppm. ESI-MS (m/z): 403.59 (M + H+). Anal. Calcd
for C20H23N2O5P (402.39): C, 59.70; H, 5.76; N, 6.96; O,
19.88; P, 7.70. Found: C, 59.75; H, 5.78; N, 6.92; O,
19.81; P, 6.90%.
2-Chloro-3-formyl quinoline derivatives were treated
with 70% acetic acid aqueous solution (200 mL) at 95ꢀC
for 10 h and then the solution was cooled to room tem-
perature to offer needle crystals of compounds 3a-f.
diethyl(((2-hydroxyphenyl)amino)(6-methyl-2-oxo-1,-
2-dihydroquinolin-3yl)methyl)phosphonate 5b: C21H25N2
O5P; TLC Rf = 0.43 (CH2Cl2);yellow powder; 87% yield;
1H NMR (400 MHz, Chloroform-d6) δ 10.99 (s, 1H, OH),
9.76 (s, 1H, NH), 7.52 (d, JH-P = 3.6 Hz, 1HAr, H7), 6.95
(d, Jortho = 7.7 Hz, 1HAr, H6), 6.85 (dd, Jortho = 7.8,
Jmetha = 1.4 Hz, 1HAr, H1), 6.81 (m, 3HAr, H15, H18, H3),
2-oxo-1,2-dihydroquinoline-3-carbaldehyde
(3a):
C10H7NO2; MW = 173.17; TLC Rf = 0.35 (CH2Cl2); yel-
1
low powder; 96% yield; H NMR (400 MHz, DMSO-d6) δ
12.11 (s, 1H, NH), 10.25 (s, 1H, CHO), 8.50-8.45 (m,
1HAr,H7), 7.90 (dd, Jortho = 7.9, Jmetha = 1.4 Hz,
1HAr,H3), 7.65 (ddd, Jortho = 8.5, 7.2, Jmetha = 1.5 Hz,
6.75 (td, J
= 7.1, Jmetha = 1.2 Hz, 1HAr, H16), 6.53
ortho
(td, J
= 7.6, Jmetha = 1.4 Hz, 1HAr, H17), 5.95 (dd,
ortho

10
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ACKNOWLEDGEMENTS
This work was supported financially by The General
Directorate for Scientific Research and Technological
Development (DG-RSDT), Algerian Ministry of Scientific
Research. Spectral data for the synthesis of novel
α-aminophosphonate prepared in this work are available
in the Supporting Information (Figures S1-S92).
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
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antioxidant and anticholinesterase activities of
novel quinoline-aminophosphonate derivatives.
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