Bioactive amide and α-aminophosphonate inhibitors for methicillin-resistant Staphylococcus aureus (MRSA)

Article abstract of DOI:10.1007/s00706-018-2303-y

Abstract: Scaffolds of 2-acylamino-1,3,4-oxadiazole have been recently developed as transglycosylase inhibitors against MRSA. In the present study, structure–activity relationships of new derivatives of 2-acylamino-1,3,4-oxadiazole were explored with focus on the substitution of the aromatic rings. The in vitro antibacterial activity of these compounds against MRSA strain was evaluated using agar disc diffusion method. These inhibitors have an amide linker between 1,3,4-oxadiazole ring and the aromatic ring B. The role of this linker on the bioactivity of the compounds was also studied. The results showed promising series of 2-α-aminophosphonate-1,3,4-oxadiazole as inhibitors for MRSA strain. Both series revealed two structural features which appear to be essential for anti-MRSA activities, the first one is the incorporation of two electron-withdrawing groups at meta- and para- positions within aromatic ring B which contributed to a higher activity against MRSA strain. The second is the new α-aminophosphonate linker serving as bio-isosteric analogue of the corresponding amide linker and giving comparable results with the amide derivatives. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-018-2303-y

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-018-2303-y
ORIGINAL PAPER
Bioactive amide and α‑aminophosphonate inhibitors
for methicillin‑resistant Staphylococcus aureus (MRSA)
Nader M. Boshta1,2 · Enas A. Elgamal1 · Ibrahim E. T. El-Sayed1
Received: 26 June 2018 / Accepted: 25 September 2018
© Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
Scafolds of 2-acylamino-1,3,4-oxadiazole have been recently developed as transglycosylase inhibitors against MRSA. In
the present study, structure–activity relationships of new derivatives of 2-acylamino-1,3,4-oxadiazole were explored with
focus on the substitution of the aromatic rings. The in vitro antibacterial activity of these compounds against MRSA strain
was evaluated using agar disc difusion method. These inhibitors have an amide linker between 1,3,4-oxadiazole ring and the
aromatic ring B. The role of this linker on the bioactivity of the compounds was also studied. The results showed promising
series of 2-α-aminophosphonate-1,3,4-oxadiazole as inhibitors for MRSA strain. Both series revealed two structural features
which appear to be essential for anti-MRSA activities, the frst one is the incorporation of two electron-withdrawing groups
at meta- and para- positions within aromatic ring B which contributed to a higher activity against MRSA strain. The sec-
ond is the new α-aminophosphonate linker serving as bio-isosteric analogue of the corresponding amide linker and giving
comparable results with the amide derivatives.
Graphical abstract
Keywords Phosphorus compounds · Drug research · Antibiotics · 1,3,4-oxadiazole · Amide coupling · Staphylococcus
aureus
Introduction
Prevention of fatalities from antimicrobial resistance bacte-
rial infections is one of current challenges in global health. It
has been reported that methicillin-resistant Staphylococcus
Electronic supplementary material The online version of this
aureus (MRSA) is responsible for almost 50% of the 23,000
article (https://doi.org/10.1007/s00706-018-2303-y) contains
documented fatalities due to antibiotic-resistant infections
supplementary material, which is available to authorized users.
in the United States [1]. The US Centers of Disease Control
* Nader M. Boshta
and Prevention (CDC) has identifed the S. aureus strain as
serious healthcare threat.
nboshta@uni-bonn.de
The β-lactamase-resistant antibiotic methicillin was dis-
covered in 1959 and is still used as frst-line treatment for S.
aureus infections that show no response to classical penicil-
lins. Two years later, the frst case of MRSA was reported
1
Chemistry Department, Faculty of Science, Menoufa
University, Shibin El-Koam, Egypt
2
Pharmaceutical Institute, Pharmaceutical Chemistry I,
University of Bonn, An der Immenburg 4, 53121 Bonn,
Germany
Vol.:(0123456789)
1 3

N. M. Boshta, E. A. Elgamal
in England [2]. The S. aureus strain is resistant to many
antibacterial drugs including macrolides [3], glycopeptides
[4], oxazolidinones [5] and fuoroquinolones [4, 6–8]. There
is currently a need to develop inhibitors to prevent the fatal
infections from MRSA.
properties such as pKA values and aqueous solubility as well
as the biological properties [24, 25].
The biological activities of α-aminophosphonate com-
pound 2 bearing the 1,3,4-oxadiazole moiety have not been
reported. Further evaluations of their biological activities on
diferent strains of bacteria are currently needed. We report
in the current study, α-aminophosphonate compounds with
the 1,3,4-oxadiazole moiety that show bioactivity as anti-
microbial agents.
A high-throughput screening (HTS) study at The Genom-
ics Research Center of Taiwan on a library of 2 million com-
pounds was performed to evaluate the antimicrobial activity
against MRSA including the inhibition of the transglycosy-
lase enzyme. The results from this study showed the anti-
MRSA activity of several compounds with minimal inhibi-
tory concentration (MIC) values as low as 0.1 µg/cm3 [9].
In this study, the oxadiazole derivatives (scafold A, Fig. 1)
have emerged as one of the top nine active scafolds. We
therefore selected these oxadiazole derivatives to study the
substituent efects on the aromatic rings on the biological
activity. To study the efect of the substitution on the aro-
matic rings on the biological activity, the 1,3,4-oxadiazoles
and their derivatives have been shown to possess diverse
and benefcial biological activities such as anti-infammatory
[10], antimicrobial [11–13], anticonvulsant [14], antiviral
[15] and antimalarial efects [16].
This study aims at the optimization of the amide moiety
of scafold A to improve the anti-MRSA activity. This is
accomplished by replacing the amide moiety of scafold A
with the tetrahedral α-aminophosphonate group, as well as
varying the substitution at the B ring. This led to the synthe-
sis of new target of inhibitor 2. In addition, the phenyl ring
of compound 1 (ring A) was replaced with the correspond-
ing heterocyclic pyridine ring that has predictable efects
on lipophilicity, polar surface area and hydrogen bonding
capacity required to improve the water solubility [26].
Results and discussion
Next, we considered incorporating α-aminophosphonate
moiety in the oxadiazole derivatives. The
α-aminophosphonate moiety was selected because com-
pounds with α-aminophosphonate moiety have been shown
to have intriguing biological activities. For example, com-
pounds with α-aminophosphonate moiety are biologically
active as antimicrobial [17, 18], antitumoral [19, 20] and
antiviral agents [21] as possessing the ability to inhibit
enzymes representing potential therapeutical targets [22,
23]. Another advantage for the α-aminophosphonate deriva-
tives is their ability to serve as isosteric or bio-isosteric ana-
logues of the corresponding amide and peptide counterparts
(Fig. 1). The planar amide moiety can be replaced by the
bulkier tetrahedral α-aminophosphonate group, obtaining a
versatile and novel fragment that leads to unique physical
Chemistry
Diferent substitution patterns at the phenyl rings A and B
of compound 1 have already been investigated within HTS
study to identify the preliminary SAR. Based on these fnd-
ings, our frst endeavours were devoted at synthesizing novel
derivatives of compound 1 bearing electron-withdrawing
groups at the para and/or meta positions of the B ring. This
strategy was pursued both for improving the antibacterial
activity and for collecting additional information concerning
the SAR of this scafold.
For the synthesis of the amide and α-aminophosphonate
derivatives 9 and 10, respectively, the corresponding
5-(3-bromophenyl)-1,3,4-oxadiazol-2-amine (8a) and
Fig. 1 Design of novel 2-acylamino-1,3,4-oxadiazoles and 2-α-aminophosphonate-1,3,4-oxadiazoles
1 3

Bioactive amide and α-aminophosphonate inhibitors for methicillin-resistant Staphylococcu…
5-(6-bromopyridin-2-yl)-1,3,4-oxadiazol-2-amine (8b) were
selected as suitable starting materials. These intermediates
were synthesized from the commercially available esters 3.
The frst attempt, employing hydrazine hydrate in ethanol
at refux temperature, aforded the undesired dihydrazide
5b, as a result of the simultaneous nucleophilic aromatic
substitution on the heterocyclic ring. Treatment of this inter-
mediate with cyanogen bromide gave the corresponding oxa-
diazolyl hydrazinylpyridinium bromide 6b in high purity,
as confrmed by liquid chromatography–mass spectrometry
(LC–MS) analysis. When the hydrazinolysis was performed
under mild conditions (room temperature for 1 h), aforded
the corresponding hydrazide 7 which undergoes cyclization
with cyanogen bromide to give the desired amino oxadiazole
derivatives 8 (Scheme 1).
high yields with easy reaction setup and product isolation.
Satisfying yields of the product were obtained by precipi-
tation and fltration from the reaction mixture (Scheme 2,
Table 1).
A typical synthetic method for the α-aminophosphonate
derivatives (Kabachnik–Fields reaction) is the one-
pot reaction of three components, aldehyde, amine and
phosphite derivatives. In the view of the increasing bio-
logical importance and the chemical applications of the
α-aminophosphonate derivatives, researchers in the last
35 years have been developing a variety of suitable syn-
thetic procedures for the synthesis of these compounds [17,
27–34]. In the present work, we further optimized the condi-
tions for the synthesis of α-aminophosphonate derivatives.
The best results were obtained when the amino oxadiazole
derivative 8b was treated with 1.2 equivalents of substituted
benzaldehyde and 1 equivalent of triphenyl phosphite in gla-
cial acetic acid at 80 °C for 4 h. The product was recrystal-
lized afording good-to-moderate yields. Detailed synthetic
procedure is described in experimental part (Scheme 3,
Table 2).
The synthetic strategy of the amide derivatives 9a–9h
is the amide coupling between the key intermediate 8a and
appropriate carboxylic acids. The amide bond was formed
between carboxylic acid chloride and the amine derivatives
in the presence of base. Thus, the reaction between 8a and
the corresponding carboxylic acid chloride in the presence
of triethylamine (TEA) was frst attempted. Control by thin
layer chromatography (TLC) and LC–MS analysis showed
that only traces of the amide product was formed after 18 h
or after heating the mixture for 5 h at 40 °C. No signifcant
change could be observed and mainly unreacted starting
material was present. These results indicated that other con-
ditions for the amide coupling might be required. To opti-
mize the amide coupling conditions, we used propanephos-
phonic acid anhydride (T3P) as an amide coupling reagent
in the presence of TEA as a base, which provides amides in
Biological evaluation
The synthesized amide and α-aminophosphonate deriva-
tives bearing 1,3,4-oxadiazole moiety were then evaluated
for their in vitro antibacterial activity against MRSA strain
by agar disc difusion method [35] as recommended by
Clinical and Laboratory Standards Institute (CLSI) [36].
The assay was carried out by impregnation of synthesized
compounds (10 μg/cm3) in dimethyl sulfoxide (DMSO) and
Scheme 1
1 3

N. M. Boshta, E. A. Elgamal
Scheme 2
Table 1 2-Acylamino-1,3,4-
oxadiazoles 9a–9h
Product
Ar
Yield / % Product
Ar
Yield / %
9a
74
83
69
9e
9f
81
CF3
Cl
Cl
F
9b
9c
58
CN
F
9g
67
Cl
F
O
Cl
F
9d
78
9h
83
F
F
F
Scheme 3
1 3

Bioactive amide and α-aminophosphonate inhibitors for methicillin-resistant Staphylococcu…
Table 2 α-Aminophosphonates
Product
Ar
Yield / % Product
Ar
Yield / %
39
10a–10j
10a
43
38
10f
Cl
F
F
10b
10c
10g
65
49
F
F
Cl
F
54
46
63
10h
10i
10j
Br
O
10d
10e
32
27
O
N
F
F
NO2
29 mm
29 mm
30
25
20
15
10
5
30
25
20
15
10
5
27 mm
26 mm
24 mm
22 mm
20 mm
19 mm
19 mm
17 mm
15 mm
15 mm
15 mm
15 mm
12 mm
11 mm
7 mm
0
0
0
0
0
Fig. 2 In vitro antibacterial activity against MRSA for amide deriva-
tives. a The IZ for each sample is measured three times using standard
micrometer of high accuracy (error= 0.005 mm) then the average
value is represented
Fig. 3 In vitro antibacterial activity against MRSA for
b
α-aminophosphonate derivatives.
The IZ for each sample is
measured three times using standard micrometer of high accuracy
(error= 0.005 mm) then the average value is represented
1 3

N. M. Boshta, E. A. Elgamal
the inhibition zone for each derivative surrounding the disc
is measured in mm scale and the results are compared with
the commercial reference drug gentamicin [37]. Figures 2
and 3 show summary of the results.
Mono-substitution with an electron-withdrawing group (F
or Br) at meta-position showed good-to-moderate activity,
compounds 10e and 10h, respectively. Comparable with
10e, adding one methoxy group or nitro group to p-position
provided compound 10c and 10j with weaker anti-MRSA
activity. The mono-substitution using electron-withdraw-
ing groups (F) at p-position provided compound 10a that
showed lower activity than 10e and adding one methyl group
to m-position aforded compound 10g, leading to a dramatic
decrease in the activity against MRSA strain. The results of
compounds 10d and 10i having dimethyl amine and methoxy
group, respectively, showed no activity against MRSA strain.
In this context, the SAR results further proves that the
presence of electron-withdrawing substituents at meta- and
para-positions of the ring B is essential for anti-MRSA
activity. In addition, this is in agreement with the previous
SAR preliminary results from the HTS study. Moreover,
the SAR results confrmed that the α-aminophosphonate
derivatives well-tolerated against the MRSA strain and
serve as bio-isosteric analogues of the corresponding amide
derivatives.
Figure 2 shows that the novel amide derivatives 9a, 9c,
9d, 9e, 9f and 9h could efectively inhibit the growth of
the tested MRSA strain with inhibition zone (IZ) values in
the range of 19–29 mm. In detail, the rank order of activity
for these derivatives was as following 9h, IZ=29 mm>9c,
IZ = 27 mm >9e, IZ = 24 mm >9d, IZ = 22 mm >9f,
IZ=20 mm >9a, IZ=19 mm. These results are consistently
higher than the results from the standard drug gentamicin
with IZ = 15 mm. Compounds 9b and 9g showed instead
a moderate-to-poor activity with IZ values 11 and 7 mm,
respectively, which is less efective than the standard drug
gentamicin.
On the other hand, the novel α-aminophosphonate deriva-
tives 10b, 10e, 10f and 10j could also efectively inhibit the
growth the tested MRSA strain with inhibition zone val-
ues in the range of 17–29 mm. The rank order of activity
was as following 10f, IZ=29 mm>10b, IZ=26 mm >10e,
IZ=19 mm >10j, IZ =17 mm, all surpassing the activity
of the standard drug gentamicin, analogously to the series
of amide derivatives. Among α-aminophosphonate deriva-
tives, compounds 10a, 10c and 10h showed moderate activ-
ity with IZ values of 12, 15 and 15 mm, respectively. The
synthesized derivatives 10d, 10g and 10i showed no activity
against the tested MRSA strain.
Conclusion
We synthesized a novel series of amide and
α-aminophosphonate derivatives bearing 1,3,4-oxadiazole
moiety as new inhibitors against MRSA strain based on the
HTS scafold A. Two series of compounds were synthe-
sized by introducing various substitutes at ring B followed
by SAR. The purity of the compounds were monitored at
254 nm and proved to be≥95%. The in vitro antibacterial
activity against MRSA strain results showed that: (1) in
both series amide and α-aminophosphonate derivatives; (a)
mono-electron withdrawing substituent at meta-position on
the ring B (compounds 9a, 10e, and 10h) shows better activ-
ity compared with the one at para-position (compounds 9b
and 10a); (b) compared with that mono-electron withdraw-
ing substitutions on the ring B, two electron withdrawing
substituents at meta- and para-positions contributed to a
higher activity against MRSA strain (compounds 9c, 9d, 9e,
10b, and 10j), and (2) α-aminophosphonate linker between
the 1,3,4-oxadiazole ring and the aromatic ring B serve as
bio-isosteric analogues of the corresponding amide linker
and gives comparable results with the amide derivatives.
Concerning the structure–activity relationship (SAR), the
results in Figs. 2 and 3 showed that the nature (electron with-
drawing or electron donating) and the substituted position
(ortho-, meta-, or para-) of the substituent groups attached to
ring B directly afected on the rank order of activity against
MRSA strain. The set of amide derivatives 9c, 9d, and 9e
containing electron withdrawing groups at meta- and para-
positions exhibited high anti-MRSA activity, following the
rank of order (3-Cl, 4-Cl >3-CF3, 4-Cl >3-F, 4-F), respec-
tively. Furthermore, adding on additional electron withdraw-
ing group (F) to ortho-position of ring B provided compound
9h with the highest anti-MRSA activity. On the other hand,
mono-substitution with an electron-withdrawing group (Cl)
at meta-position showed only a moderate activity (compound
9a). The mono-substitution afording the p-fuoro derivative
9b and m-methoxy derivative 9g, rendered the compound
having moderate-to-poor activity against MRSA strain.
One of the most important targets of this study is
to investigate the SAR and the compatibility of the
α-aminophosphonate derivatives with substitution of ring
B towards the anti-MRSA activity. In this context, the bio-
logical results suggested that di-substitution at meta- and
para-positions with electron-withdrawing groups of ring B
(3-Cl, 4-F > 3-F, 4-Cl) contributed to the highest activity
against MRSA strain, compounds 10f and 10b, respectively.
Experimental
All reagents were used in analytical grades. Solvents were
desiccated if necessary by standard methods. Reactions were
monitored by TLC (silica gel 60F254, Merck, Darmstadt,
Germany). Melting points were determined on a Melting
1 3

Bioactive amide and α-aminophosphonate inhibitors for methicillin-resistant Staphylococcu…
Point Apparatus (Stuart Scientifc, Stone, Stafordshire,
UK). NMR spectra were carried out with a 400 MHz at
Ulm University, Germany. Chemical shifts (δ) are reported
in parts per million (ppm) relative to the respective solvent
or tetramethylsilane (TMS) as internal standard and standard
abbreviations were used (a=apparent; b=broad; s=singlet;
d=doublet; t=triplet; q=quartet; m=multiplet). Elemental
analyses were determined on a Yanaca CHN Corder MT-3
elemental analyser in the microanalysis laboratory at Cairo
University. The purities of isolated products were deter-
mined by ESI-mass spectra obtained on an LC–MS instru-
ment (Applied Biosystems API 2000 LC–MS/MS, HPLC
Agilent 1100). The required starting materials, 3-bromoben-
zohydrazide (7a) [38], 6-bromopicolinyl hydrazide (7b) [39]
and 5-(3-bromophenyl)-1,3,4-oxadiazol-2-amine (8a) [40]
were synthesized according to the literature.
layer was combined and washed with water then dried over
magnesium sulphate. The solvent was evaporated and the
crude product was purifed by column chromatography using
mixture of dichloromethane and ethyl acetate (8:2) as an elu-
ent to aford the corresponding amide derivatives.
N‑[5‑(3‑Bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]‑3‑chloro‑
benzamide (9a, C15H9BrClN3O2 Yield 124 mg (74%) as a
pale yellow powder. M.p.: 190–192 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 7.56 (t, J = 7.82 Hz, 1H, Ar–H), 7.81 (d,
J=7.82 Hz, 1H, Ar–H), 7.82–7.83 (m, 3H, Ar–H),7.92 (d,
8.39 Hz, 1H, Ar–H), 8.04 (d, J=7.91 Hz, 1H, Ar–H), 8.46
(s, 1H, Ar–H), 12.82 (s, 1H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 120.30, 122.11, 122.86, 125.54, 125.84,
127.18, 127.38, 128.83, 131.54, 132.20, 134.50, 134.98,
135.56, 158.62 ppm; HPLC–UV–MS (254 nm): purity 96%;
LC–MS (ESI): m/z calcd. 376.96, found 378.0 ([M+H]+).
5‑(6‑Bromopyridin‑2‑yl)‑1,3,4‑oxadiazol‑2‑amine
(8b, C7H5BrN4O) A suspension of 0.15 g 7b (0.70 mmol)
in 0.40 cm3 MeOH and 0.20 cm3 1,4-dioxane was treated
with 0.26 cm3 BrCN (3 M solution in CH2Cl2, 0.78 mmol)
dropwise at room temperature. Stirring for 1 h, then 0.12 g
NaHCO3 (1.42 mmol) was added and the resulting suspen-
sion was continued stirring for 18 h. The resulting white
precipitate was fltered of, washed with water and dried
under high vacuum to aford 145 mg (84%) 8b as a white
solid that recrystallized from ethanol. M.p.: 119–121 °C; 1H
NMR (400 MHz, DMSO-d6): δ = 7.55 (s, 2H, NH2), 7.75
(d, J=7.88 Hz, 1H, Ar–H), 7.90 (t, J=7.80 Hz, 1H, Ar–H),
7.99 (d, J=7.70 Hz, 1H, Ar–H) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 121.32, 130.60, 140.13, 140.27, 140.79,
151.17, 161.12 ppm; HPLC–UV–MS (254 nm): purity 98%;
LC–MS (ESI): m/z calcd. 239.96, found 241.0 ([M+H]+).
N‑[5‑(3‑Bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]‑4‑fluoro‑
benzamide (9b, C15H9BrFN3O2) Yield 130 mg (83%) as a
pale yellow powder. M.p.: 182–184 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 7.58 (t, J = 7.93 Hz, 1H, Ar–H), 7.71 (d,
J = 8.97 Hz, 1H, Ar–H), 7.78 (d, J = 7.84 Hz, 1H, Ar–H),
7.84 (d, J=8.97 Hz, 1H, Ar–H), 7.94 (d, J=7.83 Hz, 1H,
Ar–H), 8.05–8.07 (m, 1H, Ar–H), 8.15 (s, 1H, Ar–H), 8.35
(d, 8.62 Hz, 1H, Ar–H), 12.56 (s, 1H, NH) ppm; 13C NMR
(100 MHz, DMSO-d6): δ=115.76, 122.21, 122.37, 123.95,
125.05, 125.49, 126.46, 127.32, 127.37, 128.34, 131.22,
131.29, 131.46, 132.97, 134.40, 158.45 ppm; HPLC–UV–
MS (254 nm): purity 97%; LC–MS (ESI): m/z calcd. 360.99,
found 361.9 ([M+H]+).
N‑[5‑(3‑Bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]‑3,4‑dichlo‑
robenzamide (9c, C15H8BrCl2N3O2) Yield 128 g (69%)
1
General procedure for preparation of amides 9a–9h
as a white solid. M.p.: 186–188 °C; H NMR (400 MHz,
DMSO-d6): δ=7.58 (t, J=7.93 Hz, 1H, Ar–H), 7.84–7.88
(m, 2H, Ar–H), 7.96 (dd, J = 1.04, 7.82 Hz, 1H, Ar–H),
8.00 (dd, J=2.08, 8.39 Hz, 1H, Ar–H), 8.05 (s, 1H, Ar–H),
8.27 (d, J=2.07 Hz, 1H, Ar–H) ppm; 13C NMR (100 MHz,
DMSO-d6): δ = 122.37, 125.04, 125.40, 128.32, 128.56,
130.28, 130.96, 131.48, 131.71, 133.28, 134.45, 135.58,
158.50 ppm; HPLC–UV–MS (254 nm): purity 96%; LC–MS
(ESI): m/z calcd. 410.92, found 411.0 ([M+H]+).
To a stirred suspension of corresponding acid (1.1 equiv.)
in 10 cm3 dichloromethane, 100 mg aminooxadiazole 8a
(0.42 mmol, 1 equiv.) and 116 mm3 Et3N (0.83 mmol, 2
equiv.) were added followed by addition of 291.6 mg T3P
(50% in dichloromethane, 0.46 mmol, 1.1 equiv.) at 0 °C
then allowed to warm to room temperature. The suspen-
sion was cleared up and the product was precipitated after
1 h. The precipitate was fltered of, washed with 100 cm3
dichloromethane, 100 cm3 sodium hydrogen carbonate, and
200 cm3 water to aford the corresponding amides 9 in a high
yield and purity after recrystallizing from methanol. In case
of amides 9c, 9f and 9g no precipitation formed after the
addition of T3P; the reaction was stirred at room tempera-
ture overnight until a complete consumption of the respec-
tive aniline was detected by TLC. The reaction mixture was
poured on a saturated sodium hydrogen carbonate solution
and extracted with ethyl acetate (3×50 cm3). The organic
N‑[5‑(3‑Bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]‑3,4‑difluoro‑
benzamide (9d, C15H8BrF2N3O2) Yield 124 mg (78%) as a
light yellow solid. M.p.: 201–203 °C; 1H NMR (400 MHz,
DMSO-d6): δ=7.46–7.66 (m, 2H, Ar–H), 7.76–7.89 (m, 1H,
Ar–H), 7.94 (d, J=7.84 Hz, 1H, Ar–H), 7.99–8.10 (m, 2H,
Ar–H), 8.25 (dd, J = 2.19, 7.11 Hz, 1H, Ar–H), 12.55 (s,
1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ=117.19,
117.34, 120.01, 122.36, 125.03, 125.40, 128.31, 129.80,
130.97, 131.70, 134.44, 158.96 ppm; HPLC–UV–MS
1 3

N. M. Boshta, E. A. Elgamal
(254 nm): purity 97%; LC–MS (ESI): m/z calcd. 378.98,
found 380.0 ([M+H]+).
General procedure for preparation
of α‑aminophosphonate derivatives 10a–10j
N‑[5‑(3‑Bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]‑4‑chloro‑3‑
(trifluoromethyl)benzamide (9e, C16H8BrClF3N3O2) Yield
151 mg (81%) as a white solid. M.p.: 179–181 °C; 1H NMR
(400 MHz, DMSO-d6): δ=7.58 (t, J=7.93 Hz, 1H, Ar–H),
7.84 (dd, J=1.51, 8.50 Hz, 1H, Ar–H), 7.95–7.98 (m, 2H,
Ar–H), 8.06 (s, 1H, Ar–H), 8.31 (dd, J=2.04, 8.36 Hz, 1H,
Ar–H), 8.48 (d, J=1.99 Hz, 1H, Ar–H), 12.83 (s, 1H, NH)
ppm; 13C NMR (100 MHz, DMSO-d6): δ=40.06, 119.81,
121.62, 122.37, 123.44, 125.06, 125.35, 126.69, 126.90,
127.69, 128.34, 131.72, 132.20, 134.01, 134.50, 135.07,
158.52 ppm; HPLC–UV–MS (254 nm): purity 95%; LC–MS
(ESI): m/z calcd. 444.94, found 446.0 ([M+H]+).
Aldehyde (1.2 eq), 100 mg 5-(6-bromopyridin-2-yl)-1,3,4-
oxadiazol-2-amine (8b, 0.41 mmol, 1 eq), and 128.74 mg
triphenylphosphite (1 eq) were dissolved in 2 cm3 glacial
acetic acid and stirred at 80 °C for 4 h (TLC analysis showed
the complete consumption of the amine). The solvent was
evaporated and the residue was dissolved in methanol and
left at −20 °C overnight afording the crystalized product.
The product was fltered of, washed with cold methanol to
aford the corresponding α-aminophosphonate derivative 10
in a good yield and purity. In case of 10b, 10f, 10i and 10j,
the fltered product showed low purity, the column chro-
matography was used for the purifcation using a mixture
of dichloromethane and ethyl acetate (8:2) as an eluent to
aford the aminophosphonate derivatives in moderate yields.
N‑[5‑(3‑Bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]‑5‑cy‑
ano‑2‑fluorobenzamide (9f, C16H8BrFN4O2) Yield 93 mg
(58%) as a pale brown powder. M.p.: 187–189 °C; 1H NMR
(400 MHz, DMSO-d6): δ=7.54-7.63 (m, 2H, Ar–H), 7.71–
7.78 (m, 2H, Ar–H), 7.83 (d, J=7.75 Hz, 1H, Ar–H), 7.95
(d, J = 7.52 Hz, 1H, Ar–H), 8.04 (s, 1H, Ar–H), 12.53 (s,
1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ=119.76,
119.93, 121.93, 122.35, 125.06, 125.41, 125.82, 127.90,
128.32, 131.76, 134.42, 157.72, 158.42, 160.12 ppm;
HPLC–UV–MS (254 nm): purity 98%; LC–MS (ESI): m/z
calcd. 385.98, found 387.0 ([M+H]+).
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadia‑
zol‑2‑yl]amino](4 fluorophenyl)methylphosphonate
(10a, C26H19BrFN4O4P) Yield 140 mg (43%) as a pale brown
solid. M.p.: 260–263 °C; 1H NMR (400 MHz, DMSO-d6):
δ = 5.79 (dd, J = 9.91, 22.01 Hz, 1H, N–CH–P), 7.00 (d,
J = 8.25 Hz, 2H, Ar–H), 7.10 (d, J = 8.17 Hz, 2H, Ar–H),
7.19 (t, J= 7.94 Hz, 2H, Ar–H), 7.27 (d, J= 8.74 Hz, 2H,
Ar–H), 7.34–7.37 (m, 4H, Ar–H), 7.74–7.80 (m, 3H, Ar–H),
7.92 (t, J= 7.82 Hz, 1H, Ar–H), 8.03 (d, J= 7.71 Hz, 1H,
Ar–H), 9.68 (d, J = 11.62 Hz, 1H, NH) ppm; 13C NMR
(100 MHz, DMSO-d6): δ = 53.57, 54.83, 115.31, 115.48,
120.17, 120.78, 125.35, 129.51, 129.84, 130.06, 130.54,
140.77, 141.27, 143.67, 149.75, 149.94, 157.17, 161.10,
163.45 ppm; HPLC–UV–MS (254 nm): purity 96%; LC–MS
(ESI): m/z calcd. 580.03, found 581.0 ([M+H]+).
N‑[5‑(3‑Bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]‑3‑methoxy‑
benzamide (9g, C16H12BrN3O3) Yield 104 mg (67%) as a
light yellow solid. M.p.: 168–170 °C; 1H NMR (400 MHz,
DMSO-d6): δ=3.77 (s, 1H, OCH3), 7.59 (d, J=7.79 Hz, 1H,
Ar–H), 7.63 (d, J=7.72 Hz, 1H, Ar–H), 7.70–7.74 (m, 2H,
Ar–H), 7.78 (d, J=7.83 Hz, 1H, Ar–H), 7.82–7.86 (m, 1H,
Ar–H), 7.97 (d, J=7.84 Hz, 1H, Ar–H), 8.07 (s, 1H, Ar–H),
12.53 (s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ=55.42, 119.02, 122.20, 122.37, 123.95, 125.05, 125.52,
126.46, 127.31, 128.34, 131.46, 131.69, 132.96, 134.38,
158.40 ppm; HPLC–UV–MS (254 nm): purity 95%; LC–MS
(ESI): m/z calcd. 373.01, found 373.9 ([M+H]+).
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadiazol‑2‑yl]‑
amino](4‑chloro‑3‑fluorophenyl)methylphosphonate
(10b, C26H18BrClFN4O4P) Yield 135 mg (38%) as a light
1
brown solid. M.p.: 270–272 °C; H NMR (400 MHz,
DMSO-d6): δ=5.90 (dd, J=10.00, 22.71 Hz, 1H, N–CH–P),
7.05 (d, J = 8.67 Hz, 2H, Ar–H), 7.11 (d, J = 8.68 Hz,
2H, Ar–H), 7.20 (t, J = 7.41 Hz, 2H, Ar–H), 7.31–7.39
(m, 4H, Ar–H), 7.61 (d, J = 8.48 Hz, 1H, Ar–H), 7.68 (d,
J=16.14 Hz, 1H, Ar–H), 7.79 (d, J=14.16 Hz, 2H, Ar–H),
7.93 (t, J= 7.83 Hz, 1H, Ar–H), 8.03 (d, J= 7.72 Hz, 1H,
Ar–H), 9.69 (d, J = 11.25 Hz, 1H, NH) ppm; 13C NMR
(100 MHz, DMSO-d6): δ = 53.34, 54.60, 115.17, 116.79,
120.09, 120.82, 125.43, 125.68, 129.56, 129.88, 130.75,
135.61, 140.78, 141.27, 143.64, 149.62, 149.87, 157.28,
163.27 ppm; HPLC–UV–MS (254 nm): purity 98%; LC–MS
(ESI): m/z calcd. 613.99, found 615.0 ([M+H]+).
N‑[5‑(3‑Bromophenyl)‑1,3,4‑oxadiazol‑2‑yl]‑2,4,5‑tri‑
fuorobenzamide (9h, C15H7BrF3N3O2) Yield 137 mg (83%) as
a pale brown solid. M.p.: 181–183 °C; 1H NMR (400 MHz,
DMSO-d6): δ=7.58 (t, J=7.94 Hz, 1H, Ar–H), 7.85–7.87
(m, 2H, Ar–H), 7.97 (d, J=8.86 Hz, 1H, Ar–H), 8.02 (dd,
J=2.23, 7.67 Hz, 1H, Ar–H), 8.08 (s, 1H, Ar–H), 12.58 (s,
1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ=119.24,
122.20, 122.36, 123.94, 125.08, 125.32, 126.46, 127.31,
128.35, 131.46, 132.96, 134.49, 157.54 ppm; HPLC–UV–
MS (254 nm): purity 96%; LC–MS (ESI): m/z calcd. 396.97,
found 397.8 ([M+H]+).
1 3

Bioactive amide and α-aminophosphonate inhibitors for methicillin-resistant Staphylococcu…
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadiazol‑2‑yl]‑
amino](3‑fluoro‑4‑methoxyphenyl)methylphosphonate
(10c, C27H21BrFN4O5P) Yield 136 mg (54%) as a white solid.
M.p.: 272–274 °C; 1H NMR (400 MHz, DMSO-d6): δ=3.84
(s, 3H, OCH3), 5.76 (dd, J=10.27, 21.84 Hz, 1H, N–CH–P),
6.63–6.70 (m, 1H, Ar–H), 6.75–6.81 (m, 2H, Ar–H), 6.85
(s, 1H, Ar–H), 7.01 (d, J= 8.48 Hz, 2H, Ar–H), 7.10 (d,
J = 7.59 Hz, 1H, Ar–H), 7.16–7.24 (m, 2H, Ar–H), 7.32–
7.40 (m, 4H, Ar–H), 7.50 (d, J=8.00 Hz, 1H, Ar–H), 7.92
(t, J=7.83 Hz, 1H, Ar–H), 8.03 (d, J=7.69 Hz, 1H, Ar–H),
9.65 (d, J=10.11 Hz, 1H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): δ=53.46, 54.52, 55.90, 113.85, 115.02, 120.17,
120.31, 120.83, 125.39, 125.43, 129.57, 129.72, 129.77,
129.90, 140.83, 141.32, 143.70, 157.21, 163.43 ppm;
HPLC–UV–MS (254 nm): purity 95%; LC–MS (ESI): m/z
calcd. 610.04, found 611.0 ([M+H]+).
(10f, C26H18BrClFN4O4P) Yield 100 mg (39%) as a pale brown
solid. M.p.: 263–265 °C; 1H NMR (400 MHz, DMSO-d6):
δ = 5.87 (dd, J = 10.13, 22.85 Hz, 1H, N–CH–P), 7.07 (d,
J = 8.56 Hz, 2H, Ar–H), 7.14 (d, J = 8.61 Hz, 2H, Ar–H),
7.25–7.27 (m, 2H, Ar–H), 7.33–7.38 (m, 4H, Ar–H), 7.63 (d,
J=8.37 Hz, 1H, Ar–H), 7.70 (d, J=15.80 Hz, 1H, Ar–H),
7.83 (d, J = 14.76 Hz, 2H, Ar–H), 7.97 (t, J = 7.76 Hz,
1H, Ar–H), 8.10 (d, J = 7.77 Hz, 1H, Ar–H), 9.71 (d,
J=11.27 Hz, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-
d6): δ = 53.51, 54.68, 115.21, 117.01, 120.11, 120.87,
125.51, 125.69, 129.61, 129.90, 130.71, 135.62, 140.81,
141.31, 143.66, 149.69, 149.90, 157.25, 163.31 ppm;
HPLC–UV–MS (254 nm): purity 96%; LC–MS (ESI): m/z
calcd. 613.99, found 615.0 ([M+H]+).
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadiazol‑2‑yl]‑
amino](4‑fluoro‑3‑methylphenyl)methylphosphonate
(10 g, C27H21BrFN4O4P) Yield 152 mg (65%) as a white solid.
M.p.: 255–258 °C; 1H NMR (400 MHz, DMSO-d6): δ=2.38
(s, 3H, CH3), 5.78 (dd, J=9.96, 21.91 Hz, 1H, N–CH–P),
7.02 (d, J=8.19 Hz, 2H, Ar–H), 7.11 (d, J=8.10 Hz, 2H,
Ar–H), 7.23 (t, J=7.99 Hz, 2H, Ar–H), 7.31 (d, J=8.82 Hz,
2H, Ar–H), 7.35-7.48 (m, 3H, Ar–H), 7.76–7.82 (m, 4H,
Ar–H), 7.90 (t, J = 7.88 Hz, 1H, V), 8.05–8.07 (m, 1H,
Ar–H), 9.71 (d, J = 11.90 Hz, 1H, NH) ppm; 13C NMR
(100 MHz, DMSO-d6): δ = 20.53, 53.72, 54.89, 120.35,
122.25, 122.43, 129.07, 129.20, 130.84, 131.44, 132.69,
136.44, 136.75, 140.73, 141.06, 143.47, 147.98, 150.42,
156.02, 164.69 ppm; HPLC–UV–MS (254 nm): purity 95%;
LC–MS (ESI): m/z calcd. 594.05, found 595.0 ([M+H]+).
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadiazol‑2‑yl]‑
amino][4‑(dimethylamino)phenyl]methylphosphonate
(10d, C28H25BrN5O4P) Yield 116 mg (46%) as a pale yel-
low solid. M.p.: 266–268 °C; 1H NMR (400 MHz, DMSO-
d6): δ=2.90 (s, 6H, –NCH3), 5.54 (dd, J=10.17, 21.14 Hz,
1H, N–CH–P), 6.74 (d, J = 8.85 Hz, 2H, Ar–H), 6.98 (d,
J = 8.63 Hz, 2H, Ar–H), 7.10 (d, J = 8.64 Hz, 2H, Ar–H),
7.15–7.20 (m, 2H, Ar–H), 7.33–7.36 (m, 4H, Ar–H),
7.46–7.52 (m, 2H, Ar–H), 7.74–7.80 (m, 1H, Ar–H), 7.88–
7.93 (m, 1H, Ar–H), 7.98–8.04 (m, 1H, Ar–H), 9.52 (d,
J=11.98 Hz, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-
d6): δ=40.02, 53.87, 55.15, 112.03, 115.18, 120.26, 120.72,
125.21, 128.93, 129.51, 129.62, 129.78, 140.72, 141.23,
143.74, 144.12, 149.97, 150.42, 155.99, 157.00, 163.64,
164.66 ppm; HPLC–UV–MS (254 nm): purity 98%; LC–MS
(ESI): m/z calcd. 605.08, found 605.9 ([M+H]+).
Diphenyl (3‑bromophenyl)[[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxa‑
d i a z o l ‑ 2 ‑ y l ] a m i n o ] m e t h y l p h o s p h o n a t e
(10 h, C26H19Br2N4O4P) Yield 130 mg (49%) as a pale brown
solid. M.p.: 264–266 °C; 1H NMR (400 MHz, DMSO-d6):
δ=5.82 (dd, J=10.19, 22.48 Hz, 1H, N–CH–P), 7.02 (d,
J=8.73 Hz, 2H, Ar–H), 7.10 (d, J=8.58 Hz, 2H, Ar–H),
7.16–7.23 (m, 3H, Ar–H), 7.34–7.37 (m, 3H, Ar–H), 7.46–
7.53 (m, 2H, Ar–H), 7.57 (t, J=7.71 Hz, 2H, Ar–H), 7.79
(d, J=7.78 Hz, 1H, Ar–H), 7.91 (t, J=7.79 Hz, 1H, Ar–H),
8.04 (d, J=7.12 Hz, 1H, Ar–H), 9.71 (d, J=10.25 Hz, 1H,
NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ=53.28, 56.16,
115.26, 115.90, 116.59, 120.36, 122.43, 125.48, 129.08,
130.85, 131.44, 136.76, 140.74, 141.26, 141.72, 143.48,
144.15, 149.62, 150.06, 156.03, 157.73, 161.30, 163.49 ppm;
HPLC–UV–MS (254 nm): purity 96%; LC–MS (ESI): m/z
calcd. 639.95, found 640.0 ([M+H]+).
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadia‑
zol‑2‑yl]amino](3‑fluorophenyl)methylphosphonate
(10e, C26H19BrFN4O4P) Yield 152 mg (63%) as a white solid.
M.p.: 243–246 °C; 1H NMR (400 MHz, DMSO-d6): δ=5.85
(dd, J=10.16, 22.50 Hz, 1H, N–CH–P), 7.01 (d, J=8.69 Hz,
2H, Ar–H), 7.10 (d, J=8.69 Hz, 2H, Ar–H), 7.16–7.25 (m,
3H, Ar–H), 7.35–7.39 (m, 3H, Ar–H), 7.45–7.52 (m, 2H,
Ar–H), 7.58 (t, J=7.60 Hz, 2H, Ar–H), 7.79 (d, J=7.93 Hz,
1H, Ar–H), 7.92 (t, J = 7.83 Hz, 1H, Ar–H), 8.03 (d,
J = 6.88 Hz, 1H, Ar–H), 9.69 (d, J = 10.25 Hz, 1H, NH)
ppm; 13C NMR (100 MHz, DMSO-d6): δ = 53.81, 55.06,
115.10, 115.28, 115.45, 120.10, 120.80, 124.57, 125.38,
129.53, 129.86, 130.45, 136.51, 140.77, 141.27, 143.66,
149.65, 149.92, 157.22, 160.97, 162.93, 163.46 ppm;
HPLC–UV–MS (254 nm): purity 98%; LC–MS (ESI): m/z
calcd. 580.03, found 580.9 ([M+H]+).
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadia‑
zol‑2‑yl]amino](3‑methoxyphenyl)methylphosphonate
(10i, C27H22BrN4O5P) Yield 79 mg (32%) as a pale yellow
solid. M.p.: 261–263 °C; 1H NMR (400 MHz, DMSO-d6):
δ = 3.75 (s, 3H, –OCH3), 5.72 (dd, J = 10.22, 21.98 Hz,
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadiazol‑2‑yl]‑
amino](3‑chloro‑4‑fluorophenyl)methylphosphonate
1 3

N. M. Boshta, E. A. Elgamal
12. El-Boraey HAL, El-Gokha AAA, El-Sayed IET, Azzam MA
(2015) Med Chem Res 24:2142
1H, N–CH–P), 6.97 (dd, J = 8.38, 29.15 Hz, 3H, Ar–H),
7.06–7.22 (m, 3H, Ar–H), 7.24–7.38 (m, 4H, Ar–H), 7.51
(s, 1H, Ar–H), 7.77–7.80 (m, 2H, Ar–H), 7.87–8.07 (m, 3H,
Ar–H), 9.65 (s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-
d6): δ=40.06, 54.43, 55.20, 114.14, 120.28, 120.82, 125.41,
129.07, 129.56, 129.89, 135.18, 140.73, 141.32, 143.72,
144.14, 149.84, 150.04, 156.03, 157.17, 159.30, 163.53,
164.70 ppm.
13. Jin L, Song B, Zhang G, Xu R, Zhang S, Gao X, Hu D, Yang S
(2006) Bioorg Med Chem Lett 16:1537
14. Kukhar VPHH (2000) Aminophosphonic and aminophosphinic
acids: chemistry and biological activity. Wiley, Chichester, p 468
15. Du S, Faiger H, Belakhov V, Baasov T (1999) Bioorg Med Chem
7:2671
16. Joossens J, Ali OM, El-Sayed I, Surpateanu G, Van der Veken P,
Lambeir A-M, Setyono-Han B, Foekens JA, Schneider A, Schma-
lix W, Haemers A, Augustyns K (2007) J Med Chem 50:6638
17. Ma J-A (2006) Chem Soc Rev 35:630
Diphenyl [[5‑(6‑bromopyridin‑2‑yl)‑1,3,4‑oxadiazol‑2‑yl]‑
amino](3‑fluoro‑4‑nitrophenyl)methylphosphonate
(10j, C26H18BrFN5O6P) Yield 70 mg (27%) as a white solid.
M.p.: 275–277 °C; 1H NMR (400 MHz, DMSO-d6): δ=5.88
(dd, J=10.10, 22.79 Hz, 1H, N–CH–P), 7.03 (d, J=8.76 Hz,
2H, Ar–H), 7.12 (d, J = 8.69 Hz, 2H, Ar–H), 7.23 (t,
J=7.51 Hz, 2H, Ar–H), 7.35–7.39 (m, 4H, Ar–H), 7.60 (d,
J=8.39 Hz, 1H, Ar–H), 7.73 (d, J=16.10 Hz, 1H, Ar–H),
7.80 (d, J=14.56 Hz, 2H, Ar–H), 7.91 (t, J=7.79 Hz, 1H,
Ar–H), 8.01–8.03 (m, 1H, Ar–H), 9.73 (d, J = 11.29 Hz,
1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ=53.50,
54.71, 114.97, 119.79, 119.95, 120.49, 124.26, 125.11,
129.22, 129.55, 130.21, 136.26, 140.96, 141.89, 143.36,
149.61, 156.91, 163.15 ppm; HPLC–UV–MS (254 nm):
purity 95%; LC–MS (ESI): m/z calcd. 625.02, found 626.0
([M+H]+).
18. Smith AB, Yager KM, Taylor CM (1995) J Am Chem Soc
117:10879
19. Amir M, Shahani S (1998) Indian J Heterocycl Chem 8:107
20. Ashour FAAM, Sara A (1990) Alexandria J Pharm Sci 4:29
21. El-Essawy FA, Boshta NM, Alotaibi MA, Elsayed MS, Tarabees
R, Saleh EA (2016) Res Chem Intermed 42:8157
22. El-Essawy FA, Boshta NM, El-Sawaf AK, Nassar AA, Khalafal-
lah MS (2016) Chem Res Chin Univ 32:967
23. Nassar OM (1997) Indian J Heterocycl Chem 7:105
24. Akhter M, Husain A, Azad B, Ajmal M (2009) Eur J Med Chem
44:2372
25. Küçükgüzel G, Kocatepe A, De Clercq E, Sahin F, Güllüce M
(2006) Eur J Med Chem 41:353
26. Lewis D, Pennington DTM (2017) J Med Chem 60:3552
27. Ambica KS, Taneja SC, Hundal MS, Kapoor KK (2008) Tetrahe-
dron Lett 49:2208
28. Azizi N, Saidi MR (2003) Tetrahedron 59:5329
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31. Ghosh R, Maiti S, Chakraborty A, Maiti DK (2004) J Mol Catal
A Chem 210:53
32. Heydari A, Hamadi H, Pourayoubi M (2007) Catal Commun
8:1224
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1 3