Synthesis and potent antimicrobial activity of novel coumarylthiazole α-aminophosphonates derivatives

Article abstract of DOI:10.1007/s11030-021-10242-2

Abstract: Herein, we reported a novel series of?α-aminophosphonates derivatives (IV)a–m bearing an important pharmacophore coumarylthiazole moiety. All the new compounds have been synthesized?via?Kabachnik–Fields reaction under ultrasonic irradiation. The products were obtained in good yield with a simple workup and were confirmed using various spectroscopic methods. All these compounds (IV)a–m were screened for their in vitro for antimicrobial activity against thirteen Gram-negative bacteria and five Gram-positive bacteria and Candida albicans strains. The results showed that all the synthesized compounds exhibited moderate antibacterial activities against both references and multidrug-resistant and antifungal strains. The compound?(IV)e?showed the highest activities against all pathogens of the tested microbial strains with?MIC of 0.125?μg/mL.?The compounds (IV)h, (IV)f, (IV)b, and (IV)d exhibited moderate and promising activities with MIC of 0.125?μg/mL. Structure–activity relationship revealed that inhibitory activity of the synthesized compounds is related to the type of the substituted group on phenyl rings, and these results showed that the electron-donating groups at?ortho?and?para?positions have a high relationship increasing antimicrobial activities than the electron‐withdrawing groups. These results confirm that coumarylthiazole α-aminophosphonates compounds can be potential antimicrobial drugs candidate. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11030-021-10242-2

Molecular Diversity
https://doi.org/10.1007/s11030-021-10242-2
ORIGINAL ARTICLE
Synthesis and potent antimicrobial activity of novel coumarylthiazole
α‑aminophosphonates derivatives
Bilal Litim1 · Zinelaabidine Cheraiet2 · Saida Meliani3 · Abdelghani Djahoudi4 · Abbes Boukhari1
Received: 24 March 2021 / Accepted: 28 May 2021
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021
Abstract
Herein, we reported a novel series of α-aminophosphonates derivatives (IV)a–m bearing an important pharmacophore
coumarylthiazole moiety. All the new compounds have been synthesized via Kabachnik–Fields reaction under ultrasonic
irradiation. The products were obtained in good yield with a simple workup and were confrmed using various spectroscopic
methods. All these compounds (IV)a–m were screened for their in vitro for antimicrobial activity against thirteen Gram-
negative bacteria and fve Gram-positive bacteria and Candida albicans strains. The results showed that all the synthesized
compounds exhibited moderate antibacterial activities against both references and multidrug-resistant and antifungal strains.
The compound (IV)e showed the highest activities against all pathogens of the tested microbial strains with MIC of 0.125 μg/
mL. The compounds (IV)h, (IV)f, (IV)b, and (IV)d exhibited moderate and promising activities with MIC of 0.125 μg/mL.
Structure–activity relationship revealed that inhibitory activity of the synthesized compounds is related to the type of the
substituted group on phenyl rings, and these results showed that the electron-donating groups at ortho and para positions
have a high relationship increasing antimicrobial activities than the electron‐withdrawing groups. These results confrm that
coumarylthiazole α-aminophosphonates compounds can be potential antimicrobial drugs candidate.
Graphic abstract
Keywords Coumarylthiazole · α-aminophosphonates · Antimicrobial · Multidrug-resistant · Kabachnik–Fields reaction
* Bilal Litim
billellitim23@gmail.com
Extended author information available on the last page of the article
Vol.:(0123456789)
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Molecular Diversity
antihyperglycemic, inhibition of diverse enzymes, and anti-
cancer [15, 16]. Moreover, the biological activities of the
diferent analogs of the synthesized coumarins are infu-
enced by their substitution in diferent positions, among
these derivatives the coumarins having various substituted
thiazole rings show promising biological activities [17].
Recently, many scientifc studies on analogs of the coumar-
ylthiazole motif having potential biological activities such
as anti-acetylcholinesterase [18] 1, anti-infammatory [19],
antibacterial and anti-tuberculosis agents [20] 2, as well as
inhibition of carbonic anhydrase and antioxidant have been
carried out [21, 22] 3.4 (Fig. 1).
Introduction
According to a report by World Health Organization (WHO),
multidrug-resistant pathogen strains are among the biggest
challenges in treating bacterial infections diseases world-
wide, urgent strategy is required to fght antimicrobial resist-
ance expected to cause more fnancial crisis by forcing 24
million people into extreme poverty by 2030 and causing 10
million deaths annually by 2050 [1]. Based on these facts
and due to the high degree of antimicrobial resistance, the
discovery of new and efective antibacterial drugs must be
discovered to overcome bacterial resistance and develop
efective treatments [2].
Recently, the synthesis of α-aminophosphonates has
attracted the attention of many scientific researchers in
organic and medicinal chemistry [23], due to structural
analogies to amino acids and their various pharmacologi-
cal properties [24], such as anti-Alzheimer [25], antimi-
crobial [26], antiviral [27], and antioxidant [28]. Access
to α-aminophosphonates moiety has been achieved by
various methods [29]. The Kabachnik–Fields reaction is
one and the simplest of the most practical approaches for
α-aminophosphonate syntheses described in the literature.
The reaction generally requires various catalysts, such
as ethyl lactate [30], phenyl phosphonic acid [31], xan-
than sulfuric acid [32], SnCl2 [33], TiO2 [34], FeCl3 [35],
Amberlite-IR 120 [36], Yb(PFO)3 [37], SbCl3/Al2O3 [38],
and CF3CO2H [39]. However, many of these catalysts suf-
fer from at least one of the following drawbacks such as low
yields, long reaction times, high reaction temperature, tedi-
ous workup, use unrecyclable catalysts, so an inexpensive
Current strategies in the pharmacological research of new
lead compounds mostly refer to a large collection of mol-
ecules proven to be broadly and useful as therapeutic agents
such as pyrazolone and its derivatives [3, 4], benzoxazole
[5], indole [6], pyrimidine analogs [7]. Therefore, com-
pounds that contain thiazole heterocycles are well known in
a variety of natural products [8], thiazole derivatives exhibit
a broad spectrum in various synthetic pharmaceuticals and
medicinal chemistry [9] such as antimicrobial and antima-
larial agents [10], Alzheimer [11], antiproliferative agents
[12], anti-cancer agents [13], and anti-infammatory [14]. In
addition, Coumarin and its derivatives constitute an impor-
tant class of heterocyclic compounds that hold an impera-
tive place in medicinal chemistry. They are distributed in
nature and possess a large array of pharmacological activi-
ties like antibacterial, anticoagulant, anti-HIV, antioxidant,
antitubercular, antihypertensive, anticonvulsant, antifungal,
Fig. 1 Biological profle of
coumarylthiazole derivatives
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Molecular Diversity
Scheme 1 Synthesis of new
α-aminophosphonates substi-
tuted coumarylthiazole (IV)a–m
derivatives
Table 1 Optimization of reaction conditions
A new series of α-aminophosphonates derivatives (IV)
a–m containing an important pharmacophore (coumarylthi-
azole heterocycle) were synthesized, and using Kabach-
nik–Fields reaction conditions, the reaction to give the target
compounds (IV)a–m it was started from 3-(2-aminothiazol-
5-yl)-2H-chromen-2-one (III), aldehyde, and triethyl phos-
phite under ultrasound irradiation using a green ionic liquid
[TEAA] as a catalyst at ambient temperature (Scheme 1).
The reaction conditions, yields, and reaction times are sum-
marized in Table 1.
Entry
Solvent
Temp. (°C)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
CH3CN
PhCH3
THF
110
120
90
80
80
rt
120
120
120
120
120
10
nr
nr
10
30
52
92
20
EtOH
EtOH/TEAA
TEAA/US
TEAB/US
rt
60
The frst step of the synthesis involved the formation of
3-acetylcoumarin (I) obtained by the condensation between
salicylaldehyde and ethyl acetoacetate in ethanol at 0–5 °C
in the presence of a catalytic amount of piperidine. The sec-
ond precursor, 3-(2-bromoacetyl)-2H-chromen-2-one (II),
was synthesized by brominating 3-acetyl coumarin in chlo-
roform. 3-(2-aminothiazol-5-yl)-2H-chromen-2-one (III)
was obtained by reaction of compound (II) with thiourea in
ethanol and neutralized with ammonia. Finally, compounds
(IV) a-m were obtained when reacted 3-(2-aminothiazol-
5-yl)-2H-chromen-2-one (III), aldehyde, and triethyl phos-
phite via Kabachnik–Fields reaction under ultrasonic irra-
diation in the presence of ionic liquid [TEAA] as a catalyst.
This procedure ofers several advantages such as giving pure
product without chromatography purifcation and high yield
in a short time reaction (Scheme 1).
Conditions: 1 mL TEAA (triethylammonium acetate), 1 mmol sub-
strate, US (ultrasounds) 40 kHz
nr no reaction
aYield (%): a yield of isolated product
alternative to α-aminophosphonates can be used, namely sol-
vent-free and using green catalyst conditions is our aim [40].
In this work, we have synthesized and characterized
novel α-aminophosphonates derivatives substituted with
coumarylthiazole rings using Kabachnik–Fields reaction
under ultrasonic irradiation and solvent-free conditions, the
antimicrobial activities of the synthesized compound were
evaluated against references and multidrug-resistant bacteria
and Candida albicans strain.
Firstly, we have reported Kabachnik–Fields reaction
between 3-(2-aminothiazol-5-yl)-2H-chromen-2-one (III),
benzaldehydes, and triethyl phosphite in diferent solvents
such as toluene, THF, acetonitrile, and ethanol. After the
reaction mixture was stirred at refux for 120 min, no desired
product was detected (Table 1, entries 1, 2, 3, and 4). The
solvent has been found to have a remarkable efect on the
evaluation of the reaction and the yields found vary around
0–30%. Then, we have wanted to improve these results by
using an ionic liquid with an acid–base character of Brönsted
[TEAA] as a solvent and catalyst. The reaction is carried out
under refux in ethanol and without solvent under ultrasonic
irradiations. It was found that the reaction without solvent
Results and discussion
Chemistry
Coumarylthiazole derivatives are known for their potential
antibacterial activity [20]. Our design strategy was based on
the synthesis of new α-aminophosphonates containing cou-
marylthiazole scafold. On the other hand, we thought that
the presence of α-aminophosphonates moiety contributes
to improving the biological activity against references and
multidrug-resistant bacteria.
1 3

Molecular Diversity
Table 2 Ultrasound irradiations
assisted synthesis of
α-aminophosphonates in ionic
liquid TEAA
Compound
R
Time (min)
30
Yield (%)
83
M.p. (°C)
a
204.0–205.7
b
20
75
221.3–222.4
c
d
e
f
15
10
82
87
65
73
243.4–244.2
184.0–188.0
262.1–263.4
212.6–213.1
30
150
g
30
90
215.4–216.6
h
i
30
60
75
69
193.5–194.4
228.9–229.7
j
120
180
76
65
236.8–237.5
207.1–208.3
k
l
25
30
92
91
210.5–211.4
213.1–214.2
m
Conditions: aldehyde (1 mmol), amine (1 mmol), triethylphosphite (1 mmol), TEAA
(1 mL), 40 kHz
1 3

Molecular Diversity
in ionic liquid [TEEA] and under ultrasonic irradiation was
given the best yield (92%) after 10 min (Table 1, entries 5
and 6).
And the HMBC spectra indicate and confrm the correla-
tion between proton–carbon (1–3 and 1–4). The elemental
analysis furthermore confrmed the assigned structures of
all synthesized compounds.
To present the efectiveness of TEAA as a catalyst in the
synthesis of α-aminophosphonates, we have used another
ionic liquid TEAB which has the same character as TEAA,
the results showed that TEAA is more efcient than another
ionic liquid (Table 1, entry 7).
Biological results
All the new compounds (IV)a–m were characterized
by spectroscopic techniques IR, 1H-NMR, 13C-NMR, 31P-
NMR, and 2D NMR heteronuclear single‐quantum coher-
ence [HSQC], heteronuclear multiple bond correlation
[HMBC], and elemental analysis. This confrmed the exact
structure of the compounds (Table 2).
Recently, it is known that many synthetic coumarylthi-
azole derivatives have various pharmacological proper-
ties. Among these properties, they have interesting antimi-
crobial activity [41]. The literature reports reveal that the
α-aminophosphonates derivatives displayed good antibacte-
rial activity against both Gram‐negative and Gram‐positive
bacterial strains [42].
The infrared spectroscopic indicated the absorptions
at 3418 cm−1 and 1233 cm−1 corresponded to (N–H) and
(P=O) stretching, respectively, of α-aminophosphonates
groups. Absorptions at 1540 cm−1 corresponded to imine
group (C=N) stretching for thiazole ring, and absorptions
at 1716 cm−1 corresponded to lactone group (O–C=O)
We have considered that the synthesized compounds
might possess certain antimicrobial activities due to a com-
bination of coumarylthiazole and α-aminophosphonates
moiety in the same scafold.
All the newly synthesized compounds (IV)a–m have been
evaluated in vitro for their antibacterial activity against the
selected strains of Gram-negative and Gram-positive bac-
teria and one fungal strain, using the broth micro-dilution
method. Dimethyl sulfoxide (DMSO) was used as a negative
control. For the control test, we have used Imipenem, Cipro-
foxacin, Amikacinekacine as a positive control to compare
the minimal inhibitory concentration (MIC), the MIC values
are reported in Tables 3 and 4.
1
stretching from coumarin rings. From the H-NMR spec-
troscopic, it was possible to observe the presence of sig-
nals at δ = 1.2 ppm and δ = 4.1 ppm corresponded to
methyl (CH3–CH2–O–P) and methylene (CH3–CH2–O–P),
respectively, of phosphonates groups; the proton (N–H) of
α-aminophosphonates groups was detected at δ=8.9 ppm,
the signal between δ=5.6—6.5 ppm corresponded the pro-
ton from asymmetric Carbone (*C), the signals of protons
corresponded the thiazole and coumarin rings were detected
at δ=7.5 ppm and δ=8.4 ppm, respectively, and the signals
corresponded to aromatic hydrogens were observed between
δ=7.46—8.96 ppm. The 13C-NMR spectroscopic analysis
also confrmed the structural identity by observing the new
characteristic type of doublets signals at δ = 16 ppm and
δ=63 ppm corresponded for methylene (CH3–CH2–O–P)
and ethylene (CH3–CH2–O–P), respectively, due to the
coupling of the carbon atoms with the phosphorus atoms
(JC–P), and the signals at δ= 16 ppm and δ = 63 ppm cor-
responded to methyl and methylene, respectively, of
α-aminophosphonates groups, the signal corresponded the
asymmetric Carbone (*C) was observed at δ=53, 7 ppm, the
signals at δ=159 ppm and δ=166, 63 ppm relating to cou-
marin carbonyl and thiazole ring, respectively. The 31P-NMR
spectroscopic analysis was found to give a signal ranging
between δ=19.7—20.2 ppm confrming the presence of the
atom of phosphors for the phosphonates groups.
The results clearly showed that all the tested compounds
had excellent antimicrobial efects against the diferent bac-
teria strains ranging between 0.125—128 μg/mL compared
with standard drugs (positive control). The highest activity
was observed with the compound (IV)e with MIC values
of 0.125 μg/mL against both Gram-negative and Gram-
positive bacteria strains. In addition, four compounds (IV)
h, (IV)f, (IV)b, and (IV)d also showed excellent activity
with MIC values ranging between 0.125—64 μg/ML and
0.125—4 μg/mL against both Gram-negative and Gram-
positive bacteria strain, respectively.
The compound (IV)e exhibited the strongest inhibition
against Escherichia coli ATCC 25922, Escherichia coli
ESBL, (Kpc +),(Kpc_), Klebsiella pneumonia Sey Mar-
seille, Serratia marcescens, Salmonella sp, Pseudomonas
aeruginosa ATCC 27853, Pseudomonas aeruginosa imi-
penem-resistant (VIM-2.1), and Acinetobacter baumanni.
OXA-23 with MIC values 0.125 μg/mL for Gram-negative
bacteria strain, and high inhibition against Bacillus cereus,
Staphylococcus aureus ATCC25900, Staphylococcus aureus
ATCC25923, and Staphylococcus aureus ATCC 29213 with
MIC values 0.125 μg/mL for Gram-positive bacteria strain
The structure attribution of proton–carbon of the repre-
sentative compounds was further confrmed by 2D NMR
(HSQC, HMBC) experiments (400 MHz). The HSQC spec-
tra confrm all the vicinal correlation proton–carbon (1–2).
1 3

Molecular Diversity
Table 3 Values of MIC (µg/mL) of the synthesized α-aminophosphonates derivatives against the tested Gram-positive bacteria
Bacillus cereus
Staph.aureus
ATCC25900
Staph.aureus
ATCC25923
Staph.aureus
ATCC 29213
Enterococcus faecalis Condida albicans
VANCO R
(IV)a
4
0.5
4
++
4
++
0.125
1
0.125
0.125
1
4
++
16
++
++
1
4
0.125
2
1
1/64
0.125
0.125/16
0.5
0.125
128
–
–
–
2
(IV)b
(IV)c
0.5/4
0.125
0.125
++
++
++
8
2/128
4
++
++
–
(IV)d
4
0.125
0.125
0.125
++
++
0.125
0.125
0.5
16
0.5
–
–
0.125
0.125
0.125
0.5
0.25
++
++
128
++
8
–
–
–
–
++
++
0.125
0.125
0.125
0.125
0.125
0.25
0.125
1
–
–
–
–
(IV)e
0.125
2
32
0.5/64
0.125
0.125
0.125
0.125
2/128
–
(IV)f
(IV)g
(IV)h
(IV)i
(IV)j
(IV)k
(IV)l
(IV)m
Imipenema
Ciprofoxacina
Amikacinea
Fluconazolea
–
–
–
–
–
–
–
–
++: no inhibition (or concentration>512 μg/mL), –: not applicable
R resistant, MIC minimum inhibitory concentration
aPositive reference
was comparable and even more efcient than the stand-
ard drugs, Imipenem, Ciprofoxacin, and Amikacine. Fur-
thermore, the following compounds (IV)h, (IV)f, (IV)b,
and (IV)d have exceptional and strong inhibition activity
against Escherichia coli ATCC 25922, Escherichia coli
ESBL, Salmonella, Pseudomonas aeruginosa ATCC 27853,
and Pseudomonas aeruginosa imipenem-resistant (VIM-
2.1) with MIC values 0.125 μg/mL Gram-negative bacte-
ria strain and against Staphylococcus aureus ATCC25923,
Staphylococcus aureus ATCC 29213 with MIC values
0.125 μg/mL Gram-positive bacteria strain. So all of these
compounds can be considered as broad-spectrum potential
antibacterial agents.
compounds was found in the range of 1-128 μg/mL less than
the drug fuconazole 2 μg/mL, and most of these compounds
can be therefore considered as potential antifungal agents.
Based on the results of Tables 3 and 4, we were found that
the synthesized compounds substituted with heterocyclic
rings (IV)l and (IV)m have excellent and remarkable activ-
ity, the compound (IV)l exhibited a high inhibition against
Bacillus cereus, Enterococcus faecalis resistant for vanco-
mycin, and Candida albicans with MIC value 0.125 μg/mL.
On the other hand, the compound (IV)m showed moderate
and high inhibition against Gram-negative bacteria strain
Klebsiella pneumoniae Carbapenem-sensible (Kpc-), Ser-
ratia marcescens, and Salmonella sp with MIC value ranging
between 0.125–0.50 μg/mL.
On the other hand, we were observed that the follow-
ing multidrug-resistant bacteria strain Pseudomonas aer-
uginosa imipenem-resistant (VIM-2.2), Acinetobacter bau-
manni (NDM-1), and Acinetobacter baumanni OXA-23 were
exhibited less resistance against the synthesized compounds
with MIC ranging between 0.125 and 128 μg/mL. These
results can confrm efectively the potential inhibition of the
synthesized compounds against multidrug resistance strains.
The in vitro antifungal activity of all the synthesized
compounds (IV)a–m was screened against Candida albicans
strain using the drug Fluconazole as a reference standard,
four compounds (IV)e, (IV)i, (IV)j, and (IV)l were found
having good and moderate promising activity with MIC
values 0.125 μg/mL, the antifungal activity of the other
In this study, we have found that the novel coumarylthi-
azole α-aminophosphonates synthesized compounds have
moderate activity for antimicrobial pathogen with interesting
MIC values. A modal MIC around 0.125 μg / mL relatively
low and much lower than the MIC of antibiotics used in
medicine: Imipenem, Ciprofoxacin, Amikacine, and Flu-
conazole (Fig. 2) which demonstrated an appreciable utility
and leave the possibility of increasing the doses in the event
of resistance provided.
1 3

Molecular Diversity
1 3

Molecular Diversity
Fig. 2 Comparison of MIC
values of compounds (IV)a-m
with Imipenem, Ciprofoxacin,
Amikacine, and Fluconazole as
references.
200
0
Compounds
E.coli ESBL
E.coli cipro R
Pseudomenas aeruginosa (VIM-2 .1)
Acinetobacter baumanni (NDM-1)
Condida albicans
Pseudomenas aeruginosa (VIM-2 .2)
Acinetobacter baumanni. OXA-23
Structure‒activity relationship analysis
Conclusion
The structure–activity relationship (SAR) of the coumar-
ylthiazole α-aminophosphonates derivatives presented
from data of Tables 3 and 4: the best activity among all
the newly synthesized compounds was exhibited with the
bromine substituent derivative at the ortho position of the
phenyl ring (IV)e against both antibacterial and antifun-
gal with MIC values 0.125 μg/mL, the diferent substitu-
tions at the phenyl ring were showed a high relationship
increasing antibacterial activity, the electron-donating
groups at ortho and para positions: 4-hydroxy-3-meth-
oxy > 2-hydroxy > 4-methoxy increase inhibitory activi-
ties with MIC values ranging between 0.125–128 μg/mL
against microbial strains. Moreover, several compounds
with electron‐withdrawing groups at ortho and para posi-
tions: 2-Bromo>4-Chloro were showed strong antimicrobial
activity with MIC modal of 0.125 μg/mL, the presence of
nitro group (electron‐withdrawing group) at meta position
(IV)b showed high inhibitory activity against Gram-negative
bacteria with MIC values ranging between 0.125–32 μg/mL.
The heterocyclic substitutions (IV)l and (IV)m (pyrrole and
chromene, respectively) showed interesting antibacterial and
antifungal activities, in particular, the pyrrole derivative
(IV)l resulted more active on some Gram-positive bacteria
and Candida albicans, while the chromene derivative (IV)m
showed better activity against some Gram-negative bacteria.
According to the SAR study, it is clear that the inhibitory
efect is directly related to the type of the substituted group
on the phenyl ring. Increasing antimicrobial activity depends
on the presence of the α-aminophosphonates moiety and is
required for a scafold to be efective against both references
and MDR strains.
We reported herein an efcient synthesis of thirteen coumar-
ylthiazole α-aminophosphonates under ultrasound irradiation.
All these compounds have been characterized by spectral anal-
yses and tested for their potential antibacterial activity against
Gram-positive and Gram-negative bacteria and antifungal
activity against Candida Albicans by comparison with standard
drugs, Imipenem, Ciprofoxacin, Amikacine, and fuconazole.
We have found that the highest activity was observed by com-
pounds (IV)e with MIC values of 0.125 μg/mL followed by
compounds (IV)h, (IV)f, (IV)b, and (IV)d, respectively, against
antimicrobial strain; thees results revealed that the inhibitory
activity of the synthesized compounds could also be afected
by the type of substituent on the phenyl ring. Electron-donat-
ing substituents groups especially in ortho and para positions
showed quite better activities than the electron‐withdrawing
groups. All the synthesized compounds showed moderate and
interesting antimicrobial activities and can use as new potent
antimicrobial drugs for therapeutic use.
Experimental section
General
Melting points (m.p) of all the synthesized compounds were
determined by the Buchi Melting Point B-545 apparatus and
the values are uncorrected. Sonication was performed in a
FUNGILAB ultrasonic bath with a frequency of 40 kHz and
output power of 250 W. IR spectra were recorded on a Perki-
nElmer FT-600 spectrometer. 1H, 13C, 31 P spectra were
recorded on a Bruker spectrometer 400 MHz, 101 MHz, and
162 MHz, respectively, in δ ppm using TMS as the stand-
ard. Elemental analysis (C, H, and N) was performed on a
1 3

Molecular Diversity
PerkinElmer 2400 CHN elemental analyzer model 1106.
Coupling constants J are in Hertz, Multiplicity is indicated
by one of the following: s (singlet), d (doublet), t (triplet), q
(quartet), dd (doublet of doublet), ddd (doublet of a doublet
of doublet),m (multiplet), and chemical shifts are given in
ppm and calibrated with DMSO‐d6. All reactions were moni-
tored by thin‐layer chromatography with silica gel Merck 60
F254-percolated aluminum plates (0.25 mm). The visualiza-
tion was performed with a UV light at 254 nm and ninhydrin
solution as developing agents. The synthetic starting material,
reagents, and solvents were purchased from Merck, Sigma-
Aldrich, and Fluka.
(d, J=8.3 Hz, 1H), 7.37 (td, J =7.5, 1.1 Hz, 1H), 7.19 (s,
2H). 13C NMR (101 MHz, DMSO-d6) δ 167.93, 159.21,
152.66, 138.60, 131.94, 131.47, 129.14, 125.14, 120.87,
119.75, 116.71, 116.28, 109.18.
Synthesis of triethyl ammonium acetate
(TEAA)
Triethylammonium acetate (TEAA) has been easily prepared
from the reaction of triethylamine and acetic acid according to
the reported method [47]. The synthesis of TEAA was carried
out in a 250-mL round-bottomed fask, which was immersed
in a water-bath and ftted with a refux condenser. (10 mmol)
of Acetic acid (10 mmol) was added dropwise with constant
stirring at 70 °C for 1 h. The mixture was heated at 80 °C with
stirring for 2 h to ensure that the reaction had proceeded to
completion. The TEAA was found in 98% yield.
Synthesis of 3‑acetyl‑2H‑chromen‑2‑one (I)
A mixture of salicylaldehyde (1 mmol) and ethyl acetoac-
etate (1.2 mmol) was cooled and maintained at 0–5 °C; few
drops of piperidine were added dropwise with continuous
stirring. The reaction mixture was left overnight, resulting
in the formation of a yellow-colored solid which was washed
by ether and purifcation by recrystallization (EtOH/CHCl3)
1:3 mixture, gave 3-acetylcoumarin (I) as fne yellow nee-
dles in good yields. Isolation and spectral data of this com-
pound were reported in the literature [43, 44].
General procedure for the synthesis
of α‑aminophosphonate‑substituted
coumarylthiazole (IV)a–m
In a 10-mL round-bottom fask taken a mixture of aldehyde
(1 mmol) and 3-(2-amino-1,3-thiazol-4-yl)coumarin (III)
(1 mmol) and TEAA (1 mL) as a catalyst at room tempera-
ture and then triethyl phosphite (1 mmol) was added. Then
reaction mixture was exposed to ultrasound irradiation (US)
for the appropriate time. After completion of the reaction,
as indicated by TLC silica gel; dichloromethane: methanol
(9.5:0.5). 5 mL of water was added to the mixture. The ionic
liquid was dissolved in water and fltered for separation of
the product. The separated product was washed with water.
The solid product was purifed by recrystallization in etha-
nol. Compounds (IV)a–m were obtained with 65–92% yield.
Synthesis of 3‑(2‑bromoacetyl)‑2H‑chromen‑2‑one
(II)
3-Acetylcoumarin (I) (10 mmol) was dissolved in alco-
hol-free chloroform (20 mL) and a solution of bromine
(10 mmol) in chloroform (5 mL) was added dropwise from a
dropping funnel with constant stirring at 15 min, the mixture
was heated for 20 min on a water-bath to expel most of the
hydrogen bromide, the solid obtained was washed by ether,
purifcation by recrystallization from glacial acetic acid
gave 3-(bromoacetyl)-coumarin (II) as white shiny needles
in good yields. Isolation and spectral data of this compound
were reported in the literature [45]
Diethyl((4‑nitrophenyl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)thia‑
zol‑2‑yl)amino)methyl)phosphonate (IV)a Orange powder.
Recrystallized from EtOH. Yield: 83%; mp: 204–205.7 °C;
1
Synthesis of 3‑(2‑amino‑1,3‑thiazol‑4‑yl)coumarin
(III)
IR (KBr,cm−1): 3383.31, 1739.41, 1520.65, 1236.76; H-
NMR (400 MHz, DMSO-d6) δ 8.96 (dd, J=9.4, 4.4 Hz, 1H),
8.66 (s, 1H), 8.29 (d, J=8.5 Hz, 2H), 7.88 (ddd, J=7.8, 4.5,
1.8 Hz, 3H), 7.67 – 7.60 (m, 1H), 7.60 (s, 1H), 7.46 – 7.36
(m, 2H), 5.91 (dd, J = 22.7, 9.4 Hz, 1H), 4.20 – 3.86 (m,
3-(2-amino-1,3-thiazol-4-yl)coumarin (III) was pre-
pared by a mixture of Thiourea (5 mmol) and a solution of
3-(bromoacetyl)-coumarin (II) (5 mmol) in boiling ethanol
(20 mL). The mixture was refuxed for 1 h, then cooled and
neutralized with aqueous ammonia. The solid obtained was
fltered of, washed with ethanol without recrystallization or
other purifcation. The product was obtained in 90% yield [46].
3-(2-amino-1,3-thiazol-4-yl)coumarin: C12H8N2O2S;
4H), 1.21 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.0 Hz, 3H). 13
C
NMR (101 MHz, DMSO-d6) δ=166.38 (d, JC–P =11.4 Hz),
159.17, 152.70, 147.47 (d, JC–P =3.2 Hz), 144.85, 143.09,
139.14, 131.99, 129.92 (d, JC–P =5.4 Hz), 129.16, 125.14,
123.81 (d, JC–P =2.0 Hz), 120.72, 119.81, 116.31, 110.39,
63.48 (d, JC–P = 6.9 Hz), 63.23 (d, JC–P = 6.7 Hz), 55.79,
54.28, 16.72 (d, JC–P = 5.3 Hz), 16.53 (d, JC–P = 5.5 Hz).
31P NMR (162 MHz, DMSO-d6) δ 20.05. Anal. Calcd. for
1
MW = 244.03; Yellow powder. Yield: 90%; H NMR
(400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.82 (d, J =7.7 Hz,
1H), 7.61 (ddd, J=8.9, 7.3, 1.7 Hz, 1H), 7.51 (s, 1H), 7.43
1 3

Molecular Diversity
C23H22N3O7PS (%): C, 53.59; H, 4.30; N, 8.15. Found: C,
54.09; H, 4.12; N, 8.36.
1H), 6.90 – 6.72 (m, 2H), 6.06 (dd, J=21.1, 9.6 Hz, 1H),
4.08 (dqd, J=17.1, 7.1, 3.4 Hz, 2H), 3.99 – 3.70 (m, 2H),
1.21 (t, J=7.0 Hz, 3H), 1.06 (t, J=7.1 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) δ=159.17, 155.57 (d, JC–P =6.6 Hz),
152.68, 143.14, 138.68, 131.96, 129.45 (d, JC–P =4.0 Hz),
129.08, 125.16, 123.25, 121.02, 119.73, 119.32, 116.36,
115.45, 109.97, 62.85 (d, JC–P = 4.9 Hz), 62.78 (d,
JC–P =5.1 Hz), 49.32, 47.75, 46.15, 16.76 (d, JC–P =5.4 Hz),
16.50 (d, JC–P =5.5 Hz). 31P NMR (162 MHz, DMSO-d6)
δ 22.21. Anal. Calcd. for C23H23N2O6PS (%): C, 56.79; H,
4.77; N, 5.76 Found: C, 56.68; H, 4.69; N, 5.65.
Diethyl((3‑nitrophenyl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)thia‑
zol‑2‑yl)amino)methyl)phosphonate (IV)b Yellow powder.
Recrystallized from EtOH. Yield: 75%; mp: 221.3–222 °C;
1
IR (KBr,cm−1): 3430.00, 1723.05, 1530.30, 1220.00; H-
NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 9.5, 4.2 Hz,
1H), 8.71 (s, 1H), 8.58 – 8.52 (m, 1H), 8.19 (d, J=8.2 Hz,
1H), 8.08 (d, J = 7.7 Hz, 1H), 7.89 – 7.82 (m, 1H), 7.73
(t, J = 8.0 Hz, 1H), 7.63 (d, J= 7.2 Hz, 1H), 7.60 (s, 1H),
7.46 – 7.37 (m, 2H), 5.94 (dd, J =22.1, 9.4 Hz, 1H), 4.13
(ddd, J=13.5, 9.5, 7.2 Hz, 2H), 4.07 – 3.88 (m, 2H), 1.21
(t, J = 7.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) δ = 166.35 (d, JC–P = 11.3 Hz),
159.17, 152.72, 148.18 (d, JC–P =2.3 Hz), 143.13, 139.31 (d,
JC–P =24.2 Hz), 135.45 (d, JC–P =5.5 Hz), 131.98, 130.19,
129.07, 125.15, 123.39 (d, JC–P =5.5 Hz), 123.16, 120.74,
119.85, 116.33, 110.39, 63.44 (d, JC–P =6.8 Hz), 63.19 (d,
JC–P =6.7 Hz), 55.40, 53.87, 16.69 (d, JC–P =5.4 Hz), 16.51
(d, JC–P =5.6 Hz). 31P NMR (162 MHz, DMSO-d6) δ 20.33.
Anal. Calcd. for C23H22N3O7PS (%): C, 53.59; H, 4.30; N,
8.15. Found: C, 53.10; H, 4.54; N, 7.87.
Diethyl((2‑bromophenyl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)thia‑
zol‑2‑yl)amino)methyl)phosphonate (IV)e Yellow powder.
Recrystallized from EtOH. Yield: 65%; mp: 262–263 °C;
1
IR (KBr,cm−1): 3429.48, 1722.41, 1543.33, 1233.39 H
NMR (400 MHz, DMSO-d6) δ=8.96 (dd, J=9.1, 5.1, 1H),
8.68 (s, 1H), 7.77 (d, J = 7.7, 1H), 7.70 – 7.57 (m, 3H),
7.58 (d, J=11.2, 1H), 7.47 – 7.35 (m, 3H), 7.23 (t, J=7.7,
1H), 6.07 (dd, J=22.3, 9.1, 1H), 4.20 – 4.08 (m, 2H), 3.91
(dp, J=10.1, 7.2, 1H), 3.82 – 3.69 (m, 1H), 1.25 (t, J=7.0,
3H), 1.05 (t, J = 7.0, 3H). 13C NMR (101 MHz, DMSO-
d6) δ=166.40 (d, JC–P =14.0 Hz), 159.10, 152.71, 143.01,
138.91, 136.84, 132.91, 132.05, 130.12 (t, JC–P = 3.5 Hz),
128.94, 128.31 (d, JC–P 2.9 Hz), 125.19 (d, JC–P =12.5 Hz),
120.86, 119.71, 116.37, 110.64, 63.33 (d, JC–P = 6.8 Hz),
63.15 (d, JC–P = 6.8 Hz), 55.43, 53.87, 16.78 (d,
JC–P =5.4 Hz), 16.45 (d, JC–P =5.4 Hz). 31P NMR (162 MHz,
DMSO) δ 20.55. Anal. Calcd. for C23H22BrN2O5PS (%): C,
50.28; H, 4.04; N, 5.10 Found: C, 50.37; H, 4.11; N, 5.17.
Diethyl((2‑nitrophenyl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)thia‑
zol‑2‑yl)amino)methyl)phosphonate (IV)c Brown powder.
Recrystallized from EtOH. Yield: 82%; mp: 243.4–244.2 °C;
1
IR (KBr,cm−1): 3434.02, 1723.51, 1536.00, 1218.00; H-
NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J=9.1, 5.4 Hz, 1H),
8.36 (s, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.89 (d, J=8.0 Hz,
1H), 7.79 (t, J=7.6 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.58
(d, J=7.2 Hz, 3H), 7.39 (dt, J=7.5, 3.3 Hz, 2H), 6.51 (dd,
J=23.6, 9.0 Hz, 1H), 4.14 (p, J=7.4 Hz, 2H), 4.06 – 3.83
D i e t h y l ( ( 4 ‑ h y d r o x y ‑ 3 ‑ m e t h o x y p h e n y l )
((5‑(2‑oxo‑2H‑chromen‑3‑yl)thiazol‑2‑yl)amino)methyl)phos‑
phonate (IV)f Yellow powder. Recrystallized from EtOH.
Yield: 73%; mp: 212–213 °C; IR (KBr,cm−1): 3493.25,
3237.42, 1691.05, 1542.19, 1215.78; 1H-NMR (400 MHz,
DMSO-d6) δ 8.98 (s, 1H), 8.71 (s, 1H), 8.64 (dd, J= 9.7,
3.2 Hz, 1H), 7.90 (dd, J = 7.9, 1.5 Hz, 1H), 7.61 (ddd,
J=8.7, 7.3, 1.6 Hz, 1H), 7.57 (s, 1H), 7.46 – 7.35 (m, 2H),
7.22 (t, J=1.9 Hz, 1H), 6.99 (dt, J=8.2, 2.1 Hz, 1H), 6.77
(d, J = 8.1 Hz, 1H), 5.58 (dd, J = 21.0, 9.7 Hz, 1H), 4.17
– 3.99 (m, 2H), 3.98 – 3.73 (m, 5H), 1.19 (t, J = 7.0 Hz,
3H), 1.08 (t, J=7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-
d6) δ=166.67 (d, JC–P =11.4 Hz), 159.23, 152.70, 147.71,
146.67, 143.18, 138.96, 131.92, 129.14, 127.28, 125.15,
121.54 (d, JC–P =6.2 Hz), 120.85, 119.89, 116.30, 115.57,
113.49 (d, JC–P =5.5 Hz), 109.89, 62.90 (d, JC–P =4.5 Hz),
62.83 (d, JC–P = 3.9 Hz), 56.21, 55.76, 54.21, 16.77
(d, JC–P = 5.4 Hz), 16.58 (d, JC–P = 5.7 Hz). 31P NMR
(162 MHz, DMSO-d6) δ 21.88 (d, J=2.9 Hz). Anal. Calcd.
for C24H25N2O7PS (%): C, 55.81; H, 4.88; N, 5.42 Found:
C, 55.74; H, 4.72; N, 5.34.
(m, 2H), 1.25 (t, J=7.0 Hz, 3H), 1.09 (t, J=7.0 Hz, 3H). 13
C
NMR (101 MHz, DMSO-d6) δ=166.53 (d, JC–P =13.7 Hz),
159.04, 152.69, 149.70 (d, JC–P =7.0 Hz), 142.95, 138.57,
134.10 (d, JC–P = 2.4 Hz), 132.14 (d, JC–P = 22.5 Hz),
130.03 (d, JC–P =4.0 Hz), 129.59 (d, JC–P =2.5 Hz), 128.67,
125.20 (d, JC–P =16.2 Hz), 120.69, 119.60, 116.38, 110.94,
63.63 (d, JC–P = 6.9 Hz), 63.29 (d, JC–P = 6.9 Hz), 50.65,
49.09, 16.71 (d, JC–P = 5.1 Hz), 16.40 (d, JC–P = 5.3 Hz).
31P NMR (162 MHz, DMSO-d6) δ 19.79. Anal. Calcd. for
C23H22N3O7PS (%): C, 53.59; H, 4.30; N, 8.15. Found: C,
53.27; H, 4.46; N, 7.92.
Diethyl((2‑hydroxyphenyl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)
thiazol‑2‑yl)amino)methyl)phosphonate (IV)d Yel-
low powder. Recrystallized from EtOH. Yield: 87%; mp:
184–188 °C; IR (KBr,cm−1): 3480.00, 3246.02, 1705.08,
1543.04, 1236.04; 1H-NMR (400 MHz, DMSO-d6) δ 9.86
(s, 1H), 8.62 (dd, J = 9.6, 3.5 Hz, 1H), 8.55 (s, 1H), 7.84
(dd, J = 7.7, 1.5 Hz, 1H), 7.62 (ddd, J = 8.6, 7.2, 1.6 Hz,
1H), 7.55 (s, 1H), 7.51 – 7.33 (m, 3H), 7.16 – 7.05 (m,
1 3

Molecular Diversity
Diethyl((3‑bromophenyl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)thi‑
azol‑2‑yl)amino)methyl)phosphonate (IV)g White solid.
Recrystallized from EtOH. Yield: 90%; mp: 215.4–216.6 °C;
21.39. Anal. Calcd. for C24H25N2O6PS (%): C, 57.59; H,
5.03; N, 5.60 Found: C, 57.48; H, 5.04; N, 5.52.
1
IR (KBr,cm−1): 3427.75, 1723.27, 1540.45, 1222.12; H
Diethyl((4‑methoxyphenyl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)thi‑
azol‑2‑yl)amino)methyl)phosphonate (IV)j Yellow powder.
Recrystallized from EtOH. Yield: 76%; mp: 236.8–237 °C;
NMR (400 MHz, DMSO-d6) δ=8.80 (dd, J=9.6, 4.0, 1H),
8.68 (s, 1H), 7.98 – 7.73 (m, 2H), 7.69 – 7.56 (m, 3H),
7.51 (d, J=8.1, 1H), 7.39 (dt, J=21.8, 7.8, 3H), 5.75 (dd,
J=21.9, 9.6, 1H), 4.19 – 3.82 (m, 5H), 1.15 (dt, J =38.5,
7.1, 6H). 13C NMR (101 MHz, DMSO-d6) δ = 166.43 (d,
JC–P = 11.3 Hz), 159.19, 152.72, 143.14, 139.61, 139.13,
131.97, 131.50 (d, JC–P =5.5 Hz), 130.99 (d, JC–P =2.7 Hz),
130.77, 129.13, 127.89 (d, JC–P =5.7 Hz), 125.15, 121.91
(d, JC–P =2.4 Hz), 120.78, 119.86, 116.32, 110.22, 63.27 (d,
JC–P =7.0 Hz), 63.07 (d, JC–P =6.8 Hz), 55.47, 53.95, 16.60
(dd, JC–P =20.9 Hz, 5.4 Hz). 31P NMR (162 MHz, DMSO)
δ 20.76. Anal. Calcd. for C23H22BrN2O5PS (%): C, 50.28; H,
4.04; N, 5.10 Found: C, 50.17; H, 3.91; N, 5.03.
1
IR (KBr,cm−1): 3418.48, 1716.49, 1543.33, 1233.39; H-
NMR (400 MHz, DMSO-d6) δ 8.72 (dd, J = 9.8, 3.4 Hz,
1H), 8.69 (s, 1H), 7.95 – 7.88 (m, 1H), 7.61 (ddd, J=8.6,
7.3, 1.6 Hz, 1H), 7.57 (s, 1H), 7.55 – 7.50 (m, 2H), 7.46 –
7.35 (m, 2H), 6.95 (d, J= 8.4 Hz, 2H), 5.65 (dd, J= 21.3,
9.7 Hz, 1H), 4.16 – 3.99 (m, 2H), 3.95 (ddt, J = 17.4,
14.3, 6.7 Hz, 1H), 3.89 – 3.76 (m, 1H), 3.74 (s, 3H), 1.19
(t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H). 13C NMR
(101 MHz, DMSO-d6) δ = 166.63 (d, JC–P = 11.4 Hz),
159.27, 159.24, 159.22, 152.69, 143.15, 138.97, 131.93,
130.06 (d, JC–P =5.9 Hz), 129.23, 125.12, 120.81, 119.86,
116.29, 114.06, 109.96, 62.96 (d, JC–P =6.9 Hz), 62.83 (d,
JC–P =6.8 Hz), 55.54, 55.31, 53.77, 16.76 (d, JC–P =5.2 Hz),
16.56 (d, JC–P =5.5 Hz). 31P NMR (162 MHz, DMSO-d6)
δ 21.78. Anal. Calcd. for C24H25N2O6PS (%): C, 57.59; H,
5.03; N, 5.60 Found: C, 57.65; H, 5.13; N, 5.67.
Diethyl((4‑chlorophenyl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)thia‑
zol‑2‑yl)amino)methyl)phosphonate (IV)h White powder.
Recrystallized from EtOH. Yield: 75%; mp: 193.5–194.4 °C;
1
IR (KBr,cm−1): 3491.91, 1720.44, 1539.00, 1234.45; H-
NMR (400 MHz, DMSO-d6) δ 8.79 (dd, J = 9.6, 3.9 Hz,
1H), 8.66 (s, 1H), 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.66 –
7.57 (m, 3H), 7.58 (s, 1H), 7.51 – 7.36 (m, 3H), 5.73 (dd,
J=22.0, 9.6 Hz, 1H), 4.15 – 4.00 (m, 2H), 4.00 – 3.82 (m,
D i e t h y l ( ( 4 ‑ ( d i m e t h y l a m i n o ) p h e n y l )
((5‑(2‑oxo‑2H‑chromen‑3‑yl)thiazol‑2‑yl)amino)methyl)
phosphonate (IV)k Brown powder. Recrystallized from
EtOH. Yield: 65%; mp: 207.1–208.3 °C; IR (KBr,cm−1):
2H), 1.19 (t, J=7.0 Hz, 3H), 1.10 (t, J=7.0 Hz, 3H). 13
C
1
NMR (101 MHz, DMSO-d6) δ=166.51 (d, JC–P =11.5 Hz),
164.76, 159.20, 152.70, 143.13, 139.06, 135.94, 132.85 (d,
JC–P = 3.2 Hz), 131.96, 131.82, 130.60 (d, JC–P = 5.8 Hz),
129.80, 129.19, 128.65 (d, JC–P = 2.1 Hz), 125.22 (d,
JC–P = 19.3 Hz), 120.78, 119.84, 116.30, 110.16, 63.22
(d, JC–P = 6.9 Hz), 63.02 (d, JC–P = 6.8 Hz), 55.42, 53.89,
16.73 (d, JC–P = 5.4 Hz), 16.53 (d, JC–P = 5.5 Hz).31P
NMR (162 MHz, DMSO-d6) δ 20.92. Anal. Calcd. for
C23H22ClN2O5PS (%): C, 54.71; H, 4.39; N, 5.55 Found: C,
54.79; H, 4.48; N, 5.61.
3422.00, 1723.21, 1541.27, 1216.59; H NMR (400 MHz,
DMSO-d6) δ=8.67 (s, 1H), 8.60 (dd, J=9.8, 3.2, 1H), 7.96
– 7.89 (m, 1H), 7.66 – 7.53 (m, 2H), 7.46 – 7.35 (m, 4H),
6.71 (d, J=8.4, 2H), 5.55 (dd, J=21.1, 9.7, 1H), 4.06 (ddd,
J = 16.6, 9.7, 6.9, 2H), 3.93 (dt, J = 10.2, 7.1, 1H), 3.87 –
3.72 (m, 1H), 3.33 (s, 1H), 2.87 (s, 6H), 1.18 (t, J = 7.0,
3H), 1.08 (t, J = 7.0, 3H). 13C NMR (101 MHz, DMSO-
d6) δ=166.74 (d, JC–P =11.5 Hz), 159.23, 152.68, 150.39,
143.15, 138.88, 131.92, 129.58 (d, JC–P =6.0 Hz), 129.26,
125.12, 123.64, 120.86, 119.87, 116.28, 112.37, 109.82,
62.77 (dd, JC–P = 9.7 Hz, 6.8 Hz), 55.44, 53.88, 16.78 (d,
JC–P =5.3 Hz), 16.60 (d, JC–P =5.5 Hz). 31P NMR (162 MHz,
DMSO) δ 22.12. Anal. Calcd. for C25H28N3O5PS (%): C,
58.47; H, 5.50; N, 8.18 Found: 58.54; H, 5.59; N, 8.25.
Diethyl(((5‑(2‑oxo‑2H‑chromen‑3‑yl)thiazol‑2‑yl)amino)
(3‑methoxyphenyl)methyl)phosphonate (IV)i Yellow powder.
Recrystallized from EtOH. Yield: 69%; mp: 228.9–229 °C;
1
IR (KBr,cm−1): 3419.59, 1719.13, 1539.12, 1247.39; H
NMR (400 MHz, DMSO-d6) δ = 8.75 (s, 1H), 8.70 (dd,
J = 9.8, 3.3, 1H), 7.83 – 7.91 (m, 1H), 7.56 – 7.66 (m,
2H), 7.35 – 7.46 (m, 2H), 6.97 (d, J= 1.9, 2H), 5.64 (dd,
J=21.2, 9.7, 1H), 3.81 – 4.18 (m, 4H), 3.31 (s, 3H), 1.21
(t, J=7.0, 3H), 1.10 (t, J=7.0, 3H). 13C NMR (101 MHz,
DMSO-d6) δ=166.61 (d, JC–P =11.3 Hz), 159.21, 153.04
(d, JC–P = 2.0 Hz), 152.72, 143.18, 139.06, 132.07 (d,
JC–P = 25.4 Hz), 129.04, 125.18, 120.83, 119.91, 116.33,
110.03, 106.65 (d, JC–P =5.9 Hz), 62.98 (t, JC–P =6.5 Hz),
60.46 (d, JC–P = 1.6 Hz), 56.48, 16.78 (d, JC–P = 5.3 Hz),
16.56 (d, JC–P = 5.6 Hz). 31P NMR (162 MHz, DMSO) δ
Diethyl(((5‑(2‑oxo‑2H‑chromen‑3‑yl)thiazol‑2‑yl)amino)
(1H‑pyrrol‑2‑yl)methyl)phosphonate (IV)l Red solid. Recrys-
tallized from EtOH. Yield: 91%; mp: 210.5–211.4 °C;
IR (KBr,cm−1): 3432.87, 1723.99, 1537.69, 1231.70;
1H NMR (400 MHz, DMSO-d6) δ = 10.75 (s, 1H), 8.71
(s, 1H), 8.40 (dd, J = 9.5, 2.0, 1H), 7.85 (dd, J = 7.7, 1.6,
1H), 7.62 (ddd, J = 8.7, 7.3, 1.6, 1H), 7.58 (s, 1H), 7.47
– 7.34 (m, 2H), 6.72 (dq, J = 2.6, 1.3, 1H), 6.21 (dq,
J = 4.0, 2.1, 1H), 6.01 (q, J = 2.8, 1H), 5.72 (dd, J = 20.5,
9.5, 1H), 4.16 – 3.75 (m, 3H), 1.18 (t, J= 7.0, 3H), 1.08
(t, J=7.1, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.72
1 3

Molecular Diversity
(d, JC–P =9.4 Hz), 159.23, 152.70, 143.15, 138.89, 131.94,
129.02, 125.80 (d, JC–P =2.5 Hz), 125.20, 120.88, 119.85,
118.10 (d, JC–P =2.1 Hz), 116.35, 109.92, 108.17, 107.78 (d,
JC–P =4.9 Hz), 62.95 (d, JC–P =6.8 Hz), 50.19, 48.59, 16.74
(d, JC–P =5.3 Hz), 16.57 (d, J=5.5 Hz). 31P NMR (162 MHz,
DMSO-d6) δ 20.65. Anal. Calcd. for C21H22N3O5PS (%): C,
54.90; H, 4.83; N, 9.15 Found: C, 54.79; H, 4.75; N, 9.09.
was determined by broth micro-dilution method used DMSO
in μg/mL [50]. And the microbial suspensions were prepared
in Muller-Hinton broth from test organisms sub-cultured on
nutrient agar and incubated at 37 °C for24 h.
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s11030-021-10242-2.
Acknowledgements This study is supported by the General Directorate
for Scientifc Research and Technological Development (DG‐RSDT),
Algerian Ministry of Scientifc Research, Algeria. We are grateful to
CRAPC SPA Expertise for recording elemental analyses and NMR
spectra.
Diethyl((4H‑chromen‑3‑yl)((5‑(2‑oxo‑2H‑chromen‑3‑yl)thia‑
zol‑2‑yl)amino)methyl)phosphonate (IV)m Dark brown solid.
Recrystallized from EtOH. Yield: 92%; mp: 213.1–214.2 °C;
1
IR (KBr,cm−1): 3450.00, 1722.74, 1539.01, 1218.00; H
NMR (400 MHz, DMSO-d6) δ=8.57 – 8.49 (m, 3H), 8.19
(dd, J=8.0, 1.7, 1H), 7.82 (tdd, J=8.6, 7.3, 1.7, 2H), 7.67
(dd, J=8.6, 1.0, 1H), 7.65 – 7.57 (m, 2H), 7.54 (ddd, J=8.1,
7.1, 1.1, 1H), 7.46 – 7.35 (m, 2H), 5.91 (dd, J =20.5, 9.2,
1H), 4.26 – 3.96 (m, 4H), 1.24 (t, J = 7.0, 3H), 1.15 (t,
J = 7.0, 3H). 13C NMR (101 MHz, DMSO-d6) δ = 175.00
(d, JC–P =4.5 Hz), 166.45 (d, JC–P =10.6 Hz), 159.13, 156.09
(d, JC–P =7.1 Hz), 152.69, 143.22, 138.73, 135.01, 132.02,
128.95, 126.40, 125.27, 123.36, 120.97 (d, JC–P =8.1 Hz),
119.70, 119.02, 116.37, 63.44 (d, JC–P =6.8 Hz), 63.10 (d,
JC–P =6.9 Hz), 46.78, 45.19, 16.73 (d, JC–P =5.4 Hz), 16.61
(d, JC–P = 5.5 Hz). 31P NMR (162 MHz, DMSO) δ 21.00.
Anal. Calcd. for C26H25N2O6PS (%): C, 59.54; H, 4.80; N,
5.34 Found: C, 59.62; H, 4.87; N, 5.41.
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Authors and Afliations
Bilal Litim1 · Zinelaabidine Cheraiet2 · Saida Meliani3 · Abdelghani Djahoudi4 · Abbes Boukhari1
1
3
Laboratory of Organic Synthesis, Modeling
Laboratory of Microbiology, Department of Biochemistry,
Faculty of Sciences, Badji Mokhtar-Annaba University, BP
205, Annaba, Algeria
and Optimization of Chemical Processes, Department
of Chemistry, Faculty of Sciences, Badji Mokhtar-Annaba
University, BP 12, 23000 Annaba, Algeria
4
Laboratory of Microbiology, Department of Pharmacy,
Faculty of Medicine, Badji Mokhtar-Annaba University, BP
205, Annaba, Algeria
2
Laboratory of Organic Synthesis, Modeling and Optimization
of Chemical Processes, Faculty of Exact Sciences
and Natural and Life Sciences, Larbi Tebeessi-Tebessa
University, 12002 Tebessa , Algeria
1 3