Nano silver particles catalyzed synthesis, molecular docking and bioactivity of α-thiazolyl aminomethylene bisphosphonates

Article abstract of DOI:10.1080/10426507.2019.1700413

A new series of α-thiazolyl aminomethylene bisphosphonates were synthesized by a three component reaction of 4-aryl substituted thiazol-2-amine with different dialkyl/aryl phosphites and triethyl orthoformate in the presence of Ag NPs (nano particles) as a catalyst under solvent free conditions. All the synthesized target compounds were characterized by ¹H, ¹³C, ³¹P, mass and elemental analysis. The target compounds were screened for their in?vitro antioxidant, antibacterial and antifungal activity. Molecular docking studies were also performed. The results revealed that among the synthesized compounds tetramethyl(((4-(4-methoxyphenyl)thiazol-2-yl)amino) methylene)bis(phosphonate) (5d), tetramethyl(((4-(4-fluorophenyl)thiazol-2-yl)amino) methylene) bis(phosphonate) (5h), and tetramethyl(((4-(4-bromophenyl)thiazol-2-yl)amino)methylene) bis (phosphonate) (5j) showed remarkably higher antioxidant activity by DPPH and H₂O₂ than the standard ascorbic acid. Compounds tetramethyl(((4-phenyl thiazol-2-yl)amino) methylene) bis(phosphonate) (5a), 5d, 5h and tetraethyl(((4-(4-bromophenyl)thiazol-2-yl) amino)methylene)bis (phosphonate) (5k) showed good antibacterial activity. 5a, 5d, and 5h also showed rather higher antifungal activity than the standard flucanozole. Computational docking methods have been used to predict how several aminomethylene bisphosphonate derivatives compete against the inhibitor BPH-1330 at the crystal enzyme structure of the 4H3A protein active site and how R and R₁ influence their binding ability.

Full text of DOI:10.1080/10426507.2019.1700413

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Nano silver particles catalyzed synthesis,
molecular docking and bioactivity of α-thiazolyl
aminomethylene bisphosphonates
Sreelakshmi Poola, Mohan Gundluru, Maheshwara Reddy Nadiveedhi,
Madhu Sudhana Saddala, Prasada Rao P. T. S. R. K. & Suresh Reddy Cirandur
To cite this article: Sreelakshmi Poola, Mohan Gundluru, Maheshwara Reddy Nadiveedhi, Madhu
Sudhana Saddala, Prasada Rao P. T. S. R. K. & Suresh Reddy Cirandur (2019): Nano silver
particles catalyzed synthesis, molecular docking and bioactivity of α-thiazolyl aminomethylene
bisphosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1700413
Nano silver particles catalyzed synthesis, molecular docking and bioactivity
of a-thiazolyl aminomethylene bisphosphonates
a
a,b
a
c
Sreelakshmi Poola , Mohan Gundluru , Maheshwara Reddy Nadiveedhi , Madhu Sudhana Saddala ,
d
a,e
Prasada Rao P. T. S. R. K. , and Suresh Reddy Cirandur
a
b
Department of Chemistry, Sri Venkateswara University, Tirupati, India; DST-PURSE Centre, Sri Venkateswara University, Tirupati, India;
c
d
Department of Ophthalmology, University of Missouri, Columbia, MO, USA; Department of Chemistry, P.B. Siddhartha College of Arts and
e
Science, Vijayawada, India; Institute of Food Security and Sustainable Agriculture, Universiti Malaysia Kelantan Kampus Jeli, Jeli,
Kelantan, Malaysia
ABSTRACT
ARTICLE HISTORY
A new series of a-thiazolyl aminomethylene bisphosphonates were synthesized by a three compo-
nent reaction of 4-aryl substituted thiazol-2-amine with different dialkyl/aryl phosphites and tri-
ethyl orthoformate in the presence of Ag NPs (nano particles) as a catalyst under solvent free
conditions. All the synthesized target compounds were characterized by H, C, P, mass and
elemental analysis. The target compounds were screened for their in vitro antioxidant, antibacterial
and antifungal activity. Molecular docking studies were also performed. The results revealed that
among the synthesized compounds tetramethyl(((4-(4-methoxyphenyl)thiazol-2-yl)amino)
methylene)bis(phosphonate) (5d), tetramethyl(((4-(4-fluorophenyl)thiazol-2-yl)amino) methylene)
bis(phosphonate) (5h), and tetramethyl(((4-(4-bromophenyl)thiazol-2-yl)amino)methylene) bis
Received 29 June 2019
Accepted 30 November 2019
1
13
31
KEYWORDS
a-Thiazolyl aminomethyle-
nebisphosphonates; nano
Ag particles; antioxidant;
antibacterial; antifungal;
docking studies
2 2
(phosphonate) (5j) showed remarkably higher antioxidant activity by DPPH and H O than the
standard ascorbic acid. Compounds tetramethyl(((4-phenyl thiazol-2-yl)amino) methylene)
bis(phosphonate) (5a), 5d, 5h and tetraethyl(((4-(4-bromophenyl)thiazol-2-yl) amino)methylene)bis
(
phosphonate) (5k) showed good antibacterial activity. 5a, 5d, and 5h also showed rather higher
antifungal activity than the standard flucanozole. Computational docking methods have been
used to predict how several aminomethylene bisphosphonate derivatives compete against the
inhibitor BPH-1330 at the crystal enzyme structure of the 4H3A protein active site and how R and
R1 influence their binding ability.
GRAPHICAL ABSTRACT
Introduction
two decades, on the mechanism of action of BPs, revealed
that they can shorten the life span of osteoclasts by induc-
Bisphosphonates (BPs) are metabolically stable analogs of
the naturally occurring inorganic pyrophosphates in which
the oxygen atom bridge is isosterically replaced with substi-
tuted methylene group. Geminal bisphosphonates and their
related acids constitute an important class of pharmacologic-
[
5–7]
tion of programed cell death (apoptosis).
Recently they
have been proved to prevent lucocorticoid-induced osteo-
[
8–10]
porosis in rheumatoid arthritis.
BPs have also been
used as drugs for use in various other diseases, such as
Paget’s disease of the bone, bone metastasis resulting from
multiple myeloma or certain forms of cancer, rheumatoid
[
1]
ally active molecules
which were used as chelating
[
2]
agents. Nitrogen-containing bisphosphonates (N-BPS), a
[
11,12]
arthritis, periodontal disease and inflammation.
Besides
class of geminal bisphosphonates (BPS) are important drugs
for wide variety of diseases. The early uses of BPs were their well-known anti-bone resorption properties,
industrial, as complexing agents, corrosion inhibitors, fertil- tumor properties,
izers and additives in oil industries. Studies over the last derivatives
[
3]
[13]
anti-
[
14]
[15]
antimicrobial activity,
some of their
[
4]
inhibit
cancer
manifestations
through
CONTACT Suresh Reddy Cirandur
csrsvu@gmail.com
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1700413.
ß 2019 Taylor & Francis Group, LLC

2
S. POOLA ET AL.
Figure 1. Nitrogen containing biologically active bisphosphonates.
antiangiogenic, anti-invasive and immuno modulatory substrates has been used for the preparation of the hetero-
[
16–18]
actions.
ties in in vitro studies. Moreover, some recent clinical stud- yields.
involved reductive amination of carbonyl derivatives with
They also possess selective antioxidant proper- cyclic [ substituted-1,1-bisphosphonates
in
different
28–31]
Aminomethylene bisphosphonates synthesis
ies in the animals indicated anti-inflammatory effects for
them in rheumatoid arthritis.
agents for “bone scanning” for which they were useful for
detecting the bone metastases and other bone lesions.
recent years gem-bisphosphonates have become the subject
of renewed attention, since it was discovered that some of
them are potent growth inhibitors of protozoa responsible
[
32]
[
19]
aminomethyl diphosphonate.
nitriles with phosphorous acid or phosphites,
from carboxylic acids, amides with phosphorous acid or
Acid catalyzed reactions of
Bisphosphonates were
[
33,34]
synthesis
[
20]
In
[
35]
phosphites
and condensation of amines with triethyl
orthoformate and phosphites are the other reported
[
36–39]
methods.
Heterocycles form a major classical division of organic
chemistry and are of enormous use in biologically and
industrially. It is well known that the heterocycles are pre-
sent in all kinds of organic compounds of interest in elec-
tronics, biology, pharmacology, material science, optics and
so on. They play an important role in medicinal chemistry
and serve as a key template for the development of various
[
21]
for tropical diseases.
These include Trypanosoma cruzi,
the pathogen that causes Chagas’ disease, T. brucei, which
causes sleeping sickness, and Plasmodium falciparum,
responsible for malaria. Some of the nitrogen containing
bisphosphonates
vent osteoporosis, and treat Paget’s disease of bone.
[
22]
shown in Figure 1 used to treat or pre-
Nitrogenous bisphosphonates act on bone metabolism by therapeutic agents.[40] Molecules that possess sulfur atoms
[
41]
binding and blocking the enzyme farnesyl diphosphate syn- are present and very important in living organisms.
In
this context, one important class of heterocycle compound
The synthesis of some bisphosphonates involves Beckman that contains one sulfur atom is known as thiazole. This
[
23]
thase (FPPS) in the HMG-CoA reductase pathway.
[
24]
rearrangement of oximes in the presence of phosphites,
class is present in many natural and synthetic products with
Wittig-Horner reagents, such as tetraalkyl methane-1,1- a wide range of pharmacological activities, such as antiviral,
bisphosphonate, with halo-substrates to synthesize the anticancer, antibacterial, antifungal, antiparkinsonian, anti-
[
25–27]
required bisphosphonates.
Michael addition reaction of convulsant and anti-inflammatory activities that can be well
methylene-1,1-bisphosphonate to diene of alkyl or aryl illustrated by the large number of drugs in the market

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Figure 2. Thiazole derivatives with biological activity.
42]
[
containing this function group.
As examples, the anticon- Initially under refluxion of 4-substituted acetophenones with
vulsivant, the antihelmintic, the antiparkinsonian, the anti- thiourea in presence of aq. NaICl and obtained correspond-
2
[
43]
schistosomal, [ vitamin B ,
as insecticidal, anti- ing substituted 4-thiazol-2-amines (3a–l). Reaction of 3a–l
1
44,45]
[46]
inflammatory,
antineoplastic, antibiotic, anti-gout,
antiviral, antimicrobial, antifungal
with dialkyl/arylphosphite in presence of triethyl orthofor-
agents are shown in mate with Ag NPs as catalyst under solvent free conditions
[
47]
Figure 2. The exploration for new biologically active hetero- afford the title compounds 5a–l was shown in Scheme 1.
cyclic analogs continues to be an intensive research area in
The reaction conditions were optimized with respect to a
medicinal chemistry.
model reaction of 4-(4-methoxyphenyl)thiazol-2-amine (3a),
We now report a relatively simple synthesis of tetra alkyl/ dimethyl phosphite (4a), and triethyl orthoformate. It was
aryl(((4-(4-phenyl substituted) thiazol-2-yl)amino)methyle- carried out without using any catalyst under solvent free
ne)bisphosphonates in good yields using Ag NPs as a catalyst. conditions and the yields obtained were very low. In order
Nano Ag particles is having its physical and chemical stability, to make the reaction efficient it was run in the presence of
ease of handling, selectivity in reactions, air and water com- different Lewis acid catalysts such as CuCl , BF ꢀEt O,
2
3
2
patibility, recyclability, remarkable ability to suppress side ZnCl2 BiCl AlCl , FeCl , and SiO the product yields
,
3,
3
3
2
reactions in acid-sensitive substrates. Thus Ag NPs which is increased from 40% to 50–60% only. Further we checked
[
48–50]
used for the synthesis of various organic compounds
the reaction in the presence of Ag NPs catalyst and obtained
found to be an efficient catalyst for the synthesis of the title higher product yields (94%) than in the presence of the
compounds. There are no reports so far on the synthesis of remaining catalysts in the model reaction and obtained 5a
tetra alkyl/aryl(((4-(4-phenyl substituted) thiazol-2-yl)amino)
methylene) bisphosphonates using Ag NPs as catalyst.
in high product yield (Table 1, Entry 11). In this reaction
triethyl orthoformate acts as both substrate and solvent. The
model reaction was run with or without Lewis acid catalysts
CuCl , BF .Et O, ZnCl BiCl3, AlCl3, FeCl and SiO and
2
3
2
2,
3
2
Results and discussion
also in presence of Ag NPs under solvent free conditions.
The synthesis of bisphosphonates bearing thiazol-2-yl moiety The yields obtained were high with Ag NPs as catalyst under
derivatives has been accomplished by a two-step process. conventional method.
5

4
S. POOLA ET AL.
Scheme 1. Synthesis of thiazolyl aminomethylene bisphosphonates (5a–l).
Table 1. Screening of different catalysts in the synthesis of a-thiazolyl amino- mixture to separate the insoluble Ag NPs. It was collected
a
methylene bisphosphonates (5a–l).
by filtration and washed with DCM and finally dried under
b
Entry
Catalyst
Time (h)
Yield (%)
vacuum and reused for the subsequent five runs. The yields
obtained were 94, 90, 88, 85 and 82. Thus results showed
that the efficiency of the recovered catalyst gradually
decreases with the number of subsequent runs (Figures S1
and S2, Supplemental Materials).
1
2
3
4
5
6
7
8
9
1
1
1
1
a
.
.
.
.
.
.
.
.
–
6
4
3
4.5
5
4.5
5
3
60 min
45 min
40 min
25 min
25 min
40
58
54
63
62
65
54
68
70
82
80
94
94
CuCl
BF
ZnCl
2
(5 mol%)
O (5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
3
ꢀEt
2
2
BiCl
AlCl
FeCl
3
3
3
SiO
2
.
Ag NPs (1 mol%)
Ag NPs (2.5 mol%)
Ag NPs (5 mol%)
Ag NPs (7.5 mol%)
Ag NPs (10 mol%)
Mechanism
0.
1
2.
3.
The mechanism of the reaction involves initial interaction of
triethyl orthoformate with the Ag NPs catalyst surface and
Reaction of 4-phenyl thiazol-2-amine (0.002 mol), dimethyl phosphite (0.0045 mol) enhances the electrophilicity of the active carbon atom of
and triethyl orthoformate (0.0025mol) using various catalysts along with Ag NPs
orthoformate. Subsequent nucleophilic attack by thiazol
ꢁ
(
7.5mol%) under neat conditions at 60 C for about 20–30min.
[
35]
b
Isolated yield.
amine
on the electrophilically activated carbon atom of
the orthoformate forms an intermediate. The formed inter-
mediate by the addition of phosphite molecule leads to ami-
nomethylene bisphosphonates.
a
Table 2. Synthesis of a-thiazolyl aminomethylene bisphosphonates (5a–l).
b
Compound
R
1
R
2
Time (min)
Yield (%)
5
5
5
5
5
5
5
5
5
5
5
5
a
a
b
c
d
e
f
g
h
i
H
H
H
OCH
OCH
OCH
OCH
F
F
Br
Br
Br
Me
Et
Ph
Me
Et
Bu
Ph
Me
Et
Me
Et
25
20
30
25
20
20
25
25
20
25
20
25
94
90
87
88
90
85
87
92
94
88
92
88
Biology
3
3
3
3
In vitro antioxidant activity
All the synthesized compounds were screened for their free
radical scavenging activity by 2,2-diphenyl-1-picrylhydrazyl
j
k
l
(DPPH) and Hydrogen peroxide (H O ) methods (Figures
2 2
S3 and S4, Supplemental Materials).
Ph
All reactions were carried out with 4-aryl substituted thiazol amines (1)
0.002 mol), with different dialkyl phosphites (2) (0.0045 mol) and triethylor-
(
thoformate (3) (0.0025 mol) Conventionally with Ag NPs catalyst (7.5 mol%), 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical
ꢁ
at 60 C, nearly 20–30 min and under solvent free conditions.
b
scavenging assay
Isolated Yields.
Among the synthesized compounds from 5a–l were eval-
To evaluate the required catalyst concentration, the reac-
[
51]
uated for their antioxidant activity by DPPH assay,
the
tion was carried out at different concentrations 1, 2.5, 5, 7.5,
and 10 mol%. It was observed that 7.5 mol% of Ag NPs gives
maximum yield (94%). So 7.5 mol% of Ag NPs was deter-
mined as the optimum catalyst quantity required for this
reaction. Compounds 5a–l were synthesized and the results
are presented in Table 2.
compounds 5d with IC50 as 29.45 ± 1.14 mg/mL 5h with
IC50 as 31.08 ± 1.38 mg/mL and 5j with IC50 as
3
3.12 ± 1.35 mg/mL showed remarkably higher antioxidant
activity than the standard ascorbic acid with IC50 as
3
4.54 ± 1.42 mg/mL. 5a with IC50 35.23± mg/mL exhibited
DPPH radical scavenging activity nearer to standard. The
remaining compounds exhibited DPPH radical scavenging
activity in the following order: 5b (IC50 43.67± mg/mL), 5c
Reusability of catalyst
After completion of the reaction, the catalyst Ag NPs was (IC50 54.24 ± 1.23 mg/mL), 5e (IC50 36.53 ± 1.56 mg/mL), 5f
recovered by adding dichloromethane to the reaction (IC50 38.32 ± 1.32 mg/mL), 5g (IC50 65.87 ± 1.52 mg/mL), 5i

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
Table 3. Docking results of predicted active synthesis compounds docked on 4H3A.
Compound name
Binding energies, DG (kcal/mol)
No. of H-bonds
H-bond residues
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
g
h
i
ꢂ168.4
ꢂ194.8
ꢂ171.0
ꢂ205.3
ꢂ161.8
ꢂ179.7
ꢂ150.4
ꢂ195.6
ꢂ189.0
ꢂ198.6
ꢂ176.6
ꢂ160.7
ꢂ191.5
0
2
3
0
1
1
0
0
2
2
5
1
3
Asn-28, His-43, Arg-51, Tyr-68, Phe-89, Glu-96, Ser-99, Asn-144, and Tyr-145
Asn-28 and His-43
Arg-51, Glu-96, and Ser-99
Asn-28, His-43, Arg-51, Tyr-68, Phe-89, Glu-96, Ser-99, Asn-144, and Tyr-145
Phe-89
Phe-89
Arg B817, Lys B721, and Asp B831
Asn-28, His-43, Arg-51, Tyr-68, Phe-89, Glu-96, Ser-99, Asn-144, and Tyr-145
Phe-89
His-43 and Phe-89
Tyr-68, Asn-144, and Tyr-145
Phe-89
j
k
l
Streptomycin
His-43, Leu-67, and Ala-142
(
(
IC50 64.32 ± 1.42 mg/mL), 5k (IC50 52.12 ± 1.32 mg/mL), 5l values showed rather higher antifungal activity than the
IC50 58.25 ± 1.58 mg/mL).
standard flucanozole. 5f and 5e showed antifungal activity
nearer to standard flucanozole. Remaining 5b, 5c, 5f, 5g, 5i,
5
k, and 5l showed poor antifungal activity against three
Hydrogen peroxide (H O ) radical scavenging assay
2
2
fungi (Figure S6, Supplemental Materials).
Compounds 5a–l synthesized were screened for their antioxi-
[
52]
dant activity by H O method.
Compounds 5d with IC50
2
2
Docking studies
as 24.32 ± 1.25 mg/mL, 5h with IC50 as 25.43 ± 1.83 mg/mL, and
5
j with IC50 as 27.98 ± 1.45 mg/mL showed remarkably higher The structure of E. coli undecaprenyl diphosphate synthase
antioxidant activity than the standard Ascorbic acid with IC50 in complex with BPH-1330 (PDB: 4H3A) was obtained from
[
55,56]
the Protein Data Bank (http://www.rcsb.org/pdb).
as 28.32 ± 1.48 mg/mL. 5a with IC50 28.63 ± 1.43 mg/mL and 5f
with IC50 28.97 ± 1.51 mg/mL exhibited H O radical scaveng-
Docking experiments were performed using the MOE soft-
2
2
[
57]
ware
in order to find the preferred binding conforma-
tions of the test compounds in the receptor. The analysis of
the binding conformation using a scoring function is based
ing activity nearer to standard. The remaining compounds
exhibited H O radical scavenging activity in the following
2
2
order: 5b (IC50 43.54 ± 1.54 mg/mL), 5c (IC50 38.78 ± 1.72 mg/
mL), 5e (IC50 46.43 ± 1.65 mg/mL), 5g (IC50 32.54 ± 1.49 mg/
mL), 5i (IC50 36.84 ± 1.23 mg/mL), 5k (IC50 43.32 ± 1.65 mg/
mL), 5l (IC50 45.67 ± 1.50 mg/mL).
[
58]
on the free energy of binding.
pounds were docked against the competitive inhibitor BPH-
330 at the crystal enzyme structure of the 4H3A protein.
All the synthesized com-
1
Molecular docking studies were performed in an attempt to
gain insights on how the synthesized compounds 5a–l, inter-
act on E. coli undecaprenyl diphosphate synthase active
Antibacterial activity
[
59]
site
which was docked on to standard streptomycin and
Compounds synthesized from 5a–l were screened for antibac-
terial activity against gram positive (Bacillus subtilis) and gram
negative (Escherichia coli, Pseudomonas aeruginosa) bacteria
the compounds (5a–l). The molecular docking study is to
evaluate their recognition of the 4H3A binding pocket.
The molecular docking study revealed that the compound
a bound with the key residues Asn-28, His-43, Arg-51, Tyr-
8, Phe-89, Glu-96, Ser-99, Asn-144, and Tyr-145 with
[
53]
by disc diffusion method. Among all these synthesized com-
5
6
pounds showed the results on three bacteria as follows. 5a with
1
5.6 ± 0.25, 13.4 ± 0.43, 15.7 ± 0.32 zone of inhibition (ZOI) val-
ꢂ168.4 kcal/mol binding free energy within the active site of
ues, 5d with 12.7 ± 0.16, 11.5 ± 0.68, 14.6 ± 0.62 ZOI values, 5h
with 11.8 ± 0.56, 10.8 ± 0.29, 13.4 ± 0.87 (ZOI) values, and 5k
4
H3A. The compound 5b formed two hydrogen bonds with
the key residues Asn-28 and His-43 with ꢂ178.8 kcal/mol
binding free energy within the active site of 4H3A. The com-
pound 5c formed three hydrogen bonds with the key residues
Arg-51, Glu-96, and Ser-99 with ꢂ171.0 kcal/mol binding free
energy within the active site of 4H3A. The compound 5d
bound with the key residues Asn-28, His-43, Arg-51, Tyr-68,
Phe-89, Glu-96, Ser-99, Asn-144, and Tyr-145 with
ꢂ280.3 kcal/mol binding free energy within the active site of
1
6.9 ± 0.16, 17.2 ± 0.28 and 18.3 ± 0.28 with activity compared
to standard drug Streptomycin 11.3 ± 0.23, 10.1 ± 0.27,
2.3 ± 0.35. 5b, 5c, and 5e showed antibacterial activity nearer
1
to standard streptomycin. Remaining 5f, 5g, 5i, 5k, and 5l
showed poor antibacterial activity against three bacteria
(Figure S5, Supplemental Materials).
4
H3A. The compound 5e formed one hydrogen bond with the
Antifungal activity
key residue Phe-89 with ꢂ161.8 kcal/mol binding free energy
Compounds synthesized from 5a–l were evaluated against within the active site of 4H3A. The compound 5f formed one
Aspergillus niger, Candida albicans, and Candida tropicalis hydrogen bond with the key residue Phe-89 with ꢂ179.7 kcal/
[
54]
by employing disc diffusion method.
Among those 5a mol binding free energy within the active site of 4H3A. The
with 16.0 ± 0.45, 15.8 ± 0.34, 16.1 ± 0.49 Zone of Inhibition compound 5g bound with the key residues Arg B817, Lys B721
ZOI) values, 5d with 14.1 ± 0.21, 12.4 ± 0.14, 14.6 ± 0.28 ZOI and Asp B831 with ꢂ150.4 kcal/mol binding free energy within
values, and 5h with 15.3 ± 0.13, 12.6 ± 0.26, 14.9 ± 0.18 ZOI the active site of 4H3A. The compound 5h bound with the key
(

6
S. POOLA ET AL.
residues Asn-28, His-43, Arg-51, Tyr-68, Phe-89, Glu-96, Ser- compounds 5d, 5h, and 5j when compared to their other
9
9, Asn-144, and Tyr-145 with ꢂ276.6 kcal/mol binding free counterparts also concurs with their high bioactivity. Thus
energy within the active site of 4H3A. The compound 5i 5d, 5h, and 5j serve as lead molecules for further develop-
formed two hydrogen bonds with the key residue Phe-89 with ment of more bioactive molecules from this group by fine-
ꢂ189.0 kcal/mol binding free energy within the active site of tuning their structure with respect to activity.
4
H3A. The compound 5j formed two hydrogen bonds with the
key residues His-43 and Phe-89 with ꢂ156.6 kcal/mol binding
free energy within the active site of 4H3A. The compound 5k
formed four hydrogen bonds with the key residues Tyr-68,
Asn-144 and Tyr-145 with ꢂ176.6 kcal/mol binding free
energy within the active site of 4H3A. The compound 5l
formed one hydrogen bond with the key residues Phe-89 with
ꢂ160.7 kcal/mol binding free energy within the active site of
Experimental
All the chemicals acetophenone, P-methoxy acetophenone,
P-bromo acetophenone, P-fluoro acetophenone, and iodine
were procured from Sd. Fine Chem. Ltd., Boisar, India and
Qualigens, Mumbai, India. Dimethyl phosphite, diethyl
phosphite, dibutyl phosphite, and diphenyl phosphite were
procured from Sigma Aldrich Chemical Company, Inc.,
USA and were used without further purification.
Triethylorthoformate was procured from Alfa aesar. All the
solvents and reagents were dried and purified before use by
adopting the standard laboratory procedures and techniques.
Progress of the reactions and purity of the compounds were
monitored by thin layer chromatography (TLC) on alumi-
num sheet of silica gel 60 F254, E-Merck, Germany using
iodine as visualizing agent. The conventional reaction was
carried out using IKA C-MAG HS7 heater. Melting points
were determined in open capillary tube on EZ-Melt
Automated Melting point Apparatus and are uncorrected.
IR spectra were recorded as neat samples on Bruker
Alpha-Eco ATR-FTIR [Attenuated Total Reflection - Fourier
Transform Infrared] interferometer with single-reflection
sampling module equipped with Zn-Se crystal, the data is
4H3A. The active site residues such as Asn-28, His-43, Arg-51,
Tyr-68, Phe-89, Glu-96, Ser-99, Asn-144, and Tyr-145 are
involving in the anti-bacterial property of 4H3A protein shown
in Table 3. The molecular docking studies revealed that synthe-
sized compounds are competitors against the bacterial infec-
tion compared to the standard streptomycin (Figures S7–S9,
Supplemental Materials).
Structure activity relationship (SAR) studies
Analysis of structure-bioactivity relationship of the com-
pounds 5a–l shows that the compounds 5d, 5h, and 5j with
sterically less crowded methyl group at the phosphite moiety
and 4-(4-methoxyphenyl), 4-(4-fluorophenyl) and 4-(4-bro-
mophenyl) thiazole-2-amino moieties at the a-carbon of the
bisphosphonate skeleton exhibited high antioxidant activity.
ꢂ1
5a even though it contains sterically methyl group at the
expressed in reciprocal centimeters (cm ). NMR spectra
phosphite moiety, it was moderately active which is slightly
nearer to standard. 5e and 5f though contains ethyl and
butyl groups on phosphite moiety exhibited moderately
active but less than the standard. 5b, 5c, 5g, 5i, 5k, and 5l
containing ethyl and phenyl groups on phosphite moiety
due to their bulky nature exhibited poor antioxidant activity
than that of standard. So the order of the antioxidant activ-
ity with respect to atoms/groups substituted on 4-phenyl
group is 4-methoxy > 4-fluoro > 4-bromo > 4-H. 5a, 5d,
and 5h with sterically less crowded methyl group at the
phosphite moiety and 4-bromo phenyl, 4-(4-methoxyphenyl)
and 4-(4-fluorophenyl) thiazole-2-amino moieties at the
a-carbon of the bisphosphonate skeleton exhibited potent
antibacterial and antifungal activity when compared to
others. 5k with 4-(4-bromophenyl) thiazole-2-amino moiety
though it contains ethyl group on phosphorous moiety
exhibited good antibacterial activity. 5c, 5e, 5f exhibited
moderate antibacterial activity and 5k exhibited moderate
antifungal activity. 5b, 5g, 5i, 5j, and 5l exhibited poor anti-
bacterial activity. 5b, 5c, 5e, 5g, 5i, 5j, and 5l exhibited poor
antifungal activity. With respect to the nature of groups on
the 4-pheny irrespectively 5a with H exhibited good antibac-
terial and antifungal activity than that of other groups. So
were recorded on Jeol Resonance 400 MHz NMR spectrom-
1
13
eter operating at 400 MHz for H, 100 MHz for C and
3
1
1
61.8 MHz for P NMR. NMR in CDCl and referenced to
3
1
13
31
TMS ( H and C) and 85% H PO ( P). Mass spectra were
3
4
recorded on ESI-MS model instrument in positive mode and
elemental analysis was carried out in FLASH EA Thermo
Finnigan 1112 instrument.
The UV–visible spectra of synthesized nanoparticles were
analyzed using Nanodrop 8000 ND (UV–visible spectropho-
tometer, Thermo Scientific). The particle size analysis and
Zeta potential measurement were carried out by Horiba SZ-
1
00 nanoparticle analyzer. The particle size was performed by
dynamic light scattering (DLS) of nanoparticles present in the
solution At DST-PURSE center S.V. University Tirupati.
Scanning electron microscopy (SEM) and EDX was per-
formed by Oxford Inca Penta FeTX3 EDS instrument attached
to Carl Zeiss EVO MA 15 Scanning Electron Microscope
(200 kV) machine with a line resolution 2.32 (in Å) in
Department of physics, S. V. University, Tirupati. Then
1
13
31
Supplemental Materials contains sample H, C, and
P
NMR and IR spectra of the products 5 (Figures S10–S35).
the order with respect to atoms or groups on 4-phenyl is 4- Synthesis of Ag nanoparticles (Ag NPs)
H > 4-bromo > 4-fluoro > 4-methoxy. Scrutiny of the struc-
tures of compounds 5 a–l reveals that even though the basic
Preparation of fruit extract
a-(4-phenyl)thiazolamino methylene bisphosphonate struc- Ripened fruits of anjura were used for the preparation of
ture remains the same in all compounds, among all of the aqueous extract. This ripened fruit (30 g) were thoroughly

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Figure 3. UV–vis spectrum of synthesized Ag NPs.
NPs. The reduction of silver ion and stability of silver nano-
particle was determined in a range of 200–700 nm using
Nanodrop 8000 ND UV–vis spectrophotometer which was
shown in Figure 3.
Particle size determination of the synthesized Ag NPs
were determined under by Laser diffraction studies and
shown in Figure 4. Laser diffraction revealed that the aver-
age diameter of the particles was found to be 1.9 nm. EDS
analysis was performed and shown in Figure 5. SEM images
of Ag NPs were shown in Figure 6 within 2–1 mm.
Figure 4. EDX spectrum of the Ag NPs.
General procedure for the synthesis of 3a
To a stirred solution of thiourea (0.002 mol, 0.15 g), and
ketone (0.001 mol, 0.12 g) in THF (10 mL) at room tempera-
washed in Mili-Q water and dried. The fruit extract was pre-
pared by taking of finely cut fruits (30 g) in a 250 mL
Erlenmeyer flask with Mili-Q water (100 mL) and then
boiled for about 5 min. The obtained extract was filtered by
using Whatman filter paper No-1, then the filtrate was col-
lected. The pure form of aqueous filtrate was collected as
sample and stored at 4 C.
To the aqueous filtrate extract (anjura fruit extract which
acts as reducing agent, 10 mL) was added silver nitrate for
ture was slowly added aq. NaICl (0.0005 mol, 0.11 ml, 30%
2
[
61]
w/w aqueous NaICl2).
The resultant reaction mixture was
refluxed for 12H. After completion of reaction (TLC), the
solvent was evaporated under the vacuum. Then the resulted
residue was diluted with water and extracted with ethyl acet-
ate. The organic layer was separated and washed successively
with of 10% sodium bisulfate solution (5 mL), 10% sodium
ꢁ
the reduction of silver ions and the resultant mixture was bicarbonate (3 mL) of water. The organic layer was dried
stirred at room temperature for about 15 min. A well- over anhydrous sodium sulfate and concentrated under the
defined absorption peak at 425 nm exhibited by the nanome- reduced pressure to give the crude product. Pure product
[
60]
tallic Ag NPs
and consequent color change from colorless was obtained after silica gel column chromatography with
to reddish yellow confirm the successful synthesis of Ag 30% EtOAc-Hexane.

8
S. POOLA ET AL.
(
1H, s, Ar-H), 4.32 (1H, s, Ar NH), 3.45 (6H, d, J ¼ 9.6 Hz,
P-OCH ), 3.23 (6H, d, J ¼ 9.4 Hz, P-OCH ), 2.14 (1H, d,
3
3
13
J ¼ 26 Hz, P-C-H); C(CDCl3 100 MHz) d: 167.32 (C10),
,
1
52.45 (C7), 134.36 (C5), 129.45 (C1), 129.42 (C3), 128.75
(
(
1
C2), 127.64 (C4), 127.61 (C6), 104.3(C8), 69.54 (C13), 53.18
31
C14 & C16), 53.12 (C18 & C19); P NMR (CDCl
3
,
þ
61.7 MHz) d: 20.45; ESI-MS m/z: 407 [M þ H] ; Anal.
calcd for C H N O P S C, 40.32; H, 4.92; N, 6.89; Found:
C,40.28; H, 4.86; N, 6.83.
14
20 2 6 2
[
62]
Tetraethyl(((4-phenyl thiazol-2-yl)amino)methylene)bi-
s(phosphonate) (5b)
Figure 5. Particle size of the synthesized Ag NPs.
ꢁ
White solid; Yield: 90%; Mp: 135–137 C; IR (KBr) (ꢀmax,
ꢂ1
1
cm ): 3237(NH), 1248(P ¼ O), 804 (P-C
); HNMR
Aliphatic
(
CDCl , 400 MHz) d: 7.83–7.81 (2H, m, Ar-H), 7.42–7.29
3
(3H, m, Ar-H), 6.77 (1H, s, Ar-H), 5.21 (1H, s Ar -NH),
4
.30–4.21 (8H, m, P-OCH CH ), 2.01 (1H, d, J ¼ 28 Hz, P-
2
3
C-H), 1.32 (6H, t, J ¼ 9.5 Hz, P-OCH CH ), 1.29 (6H, t,
2
3
13
J ¼ 9.2 Hz, P-OCH CH ); C(CDCl 100 MHz) d: 165.32
2
3
3,
(
1
(
C5), 150.04 (C2), 131.44 (C1), 128.57 (C17), 128.02 (C19),
27.18 (C18), 125.90 (C16), 125.34 (C20), 101.60 (C8), 63.76
C22 & C24), 63.21 (C26 & C28), 16.38 (C23 & C25),
31
1
5.83,15.74(C27 & C29); PNMR (CDCl3 161.7 MHz) d:
,
þ
2
1.06; ESI-MS m/z: 463 [M þ H] ; Anal. calcd for
C H N O P S C, 46.45; H, 6.32; N, 6.06; Found: C, 46.39;
18
28
2
6 2
H, 6.28; N, 6.01.
Figure 6. SEM images of Ag NPs.
Tetraphenyl(((4-phenyl thiazol-2-yl)amino)methylene)bi-
s(phosphonate) (5c)
Conventional heating method for the synthesis of
aminomethylene bisphosphonates from (5 a–l)
ꢂ1
Yellow liquid; Yield: 87%; IR (KBr) (ꢀmax, cm ): 3365(NH),
1
1
243(P ¼ O), 824 (P-C
); HNMR (CDCl 400 MHz)
Aliphatic
3,
Ag NPs (7.5 mol%, 0.80 g) was added to a mixture of 4- d: 8.21–7.14 (25H, m, Ar-H), 7.12 (1H, s, Ar-H), 5.12 (1H,
13
methoxy phenyl thiazol amine (0.002 mol, 0.35 g) (3a), s, Ar-NH), 2.73 (1H, d, J ¼ 22 Hz, P-C-H); C(CDCl3,
dimethyl phosphite (0.0045 mol, 0.41 mL) (4a), and triethyl 100 MHz) d: 163.12 (C10), 150.34 (C7), 150.23(C22), 150.16
orthoformate (0.0025 mol, 0.38 mL) taken in a 50 mL round (C23), 150.12 (2C4), 150.06 (C25), 134.52 (C5), 132.15
bottomed flask. The mixture was stirred for about (C27), 131.47 (C29), 131.28 (C32, C34), 131.21 (C37),
ꢁ
2
0–30 min at 60 C. After completion of the reaction which 131.18 (C39), 131.16 (42), 131.02 (C44), 129.82 (C1), 129.76
was monitored by TLC, the reaction mixture was cooled (C3), 128.54 (C2), 127.65 (C4), 127.54 (C6), 121.65 (C28,
C33), 121.54 (C38, C43), 120.48 (2C6), 120.43 (C30), 120.38
and extracted with dichloromethane to separate the catalyst
(
C31), 120.32 (C35), 120.28 (C36), 120.24 (C40), 120.12
for reuse. The catalyst residue was dried under vacuum at
31
ꢁ
(C41), 120.09 (C45), 105.43 (C8), 69.32 (C13); P NMR
(
Anal. calcd for C H N O P S C, 63.41; H, 4.32; N, 4.28;
1
00 C and reused. Then the organic extract was washed
þ
CDCl3, 161.7 MHz) d: 23.16; ESI-MS m/z: 655 [M þ H] ;
with water, dried over anhydrous Na SO , and concentrated
2
4
under reduced pressure to obtain the crude product which
was purified by column chromatography using silica gel
34 28 2 6 2
Found: C, 63.36; H, 4.27; N, 4.23.
(100–200 mesh) as the adsorbent and ethyl acetate-hexane
in 7:3 ratio as the eluent and obtained pure a-amino
bisphosphonate 5a in 94% yield. The same procedure was
adopted for the preparation of other compounds from 5b–l.
Tetramethyl(((4-(4-methoxyphenyl)thiazol-2-yl)amino)me-
thylene)bis(phosphonate) (5d)
ꢁ
Yellow solid; Yield: 88%; Mp: 130–132 C; IR (KBr) (ꢀmax,
ꢂ1
1
cm ): 3288 (NH), 1238 (P ¼ O), 817 (P- C
); HNMR
Aliphatic
(
CDCl , 400 MHz) d: 7.76–7.72 (2H, m, Ar-H), 7.22 (1H, s,
3
Spectral characterization of the title compounds 5a–l
Ar-H), 6.94–6.92 (2H, m, Ar-H), 5.68 (1H, s, -NH), 3.84
(3H, s, OCH ), 3.46 (6H, d, J ¼ 10.9 Hz, P-OCH ), 3.39 (6H,
Tetramethyl(((4-phenyl thiazol-2-yl)amino)methylene)bi-
s(phosphonate) (5a)
3
3
d, J ¼ 10.7 Hz, P-OCH ), 2.42 (1H, d, J ¼ 24 Hz, P-C-H);
3
ꢁ
13
Pale Yellow solid; Yield: 94%; Mp: 127–130 C; IR (KBr)
C(CDCl , 100 MHz) d: 165.36 (C11), 160.30 (C2), 150.40
3
ꢂ1
(
ꢀmax, cm ): 3342 (NH), 1228(P ¼ O), 838 (P-CAliphatic); (C7), 127.94 (C4), 127.70 (C5), 114.52 (C1), 114.34 (C3),
1
HNMR (CDCl 400 MHz) d: 7.79–7.43 (5H, m, Ar-H), 7.23 66.36 (C14), 55.36 (C8), 54.01, 53.75 (C17 & C22), 53.46,
3
,

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
9
3
1
5
3.31 (C20 & C21); P NMR (CDCl , 161.7 MHz) d: 22.06; Tetramethyl(((4-(4-fluorophenyl)thiazol-2-yl)amino)methy-
3
þ
ESI-MS m/z: 437 [M þ H] ; Anal. calcd for C H N O P S lene)bis(phosphonate) (5h)
15
22 2 7 2
ꢁ
C, 41.32; H, 5.12; N, 6.82; Found: C, 41.24; H, 5.09; N, 6.76. White solid; Yield: 92%; Mp: 126–129 C; IR (KBr) (ꢀmax,
ꢂ1
1
cm ): 3352(NH), 1213(P ¼ O), 818 (P-C
); HNMR
Aliphatic
(
CDCl , 400 MHz) d: 7.92–7.43 (4H, m, Ar-H), 7.32 (1H, s,
3
Tetraethyl(((4-(4-methoxyphenyl)thiazol-2-yl)amino)methy- Ar-H), 5.18 (1H, s, -NH), 3.64 (6H, d, J ¼ 10.6 Hz, P-
lene)bis(phosphonate) (5e)
OCH ), 3.51 (6H, d, J ¼ 10.4 Hz, P-OCH ), 2.54 (1H, d,
3
3
ꢁ
13
Pale Yellow solid; Yield: 90%; Mp: 123–125 C, IR (KBr) J ¼ 22 Hz, P-C-H); C(CDCl3 100 MHz) d: 164.45 (C11),
,
ꢂ1
(
ꢀmax, cm ): 3213 (NH), 1244 (P ¼ O), 830(P-CAliphatic); 162.91 (C2), 152.45 (C7), 131.43 (C6), 131.32 (C4), 130.26
1
HNMR (CDCl , 400 MHz) d: 7.74–7.72 (2H, m, Ar-H), (C5), 116.45 (C1), 116.32(C3), 105.21 (C9), 69.34 (C14),
3
31
6
.92–6.90 (1H, s, Ar-H), 6.60–6.54 (2H, m, Ar-H), 5.60 (1H, 53.34 (C17 & C22), 53.12 (C20 & C21); P NMR (CDCl3,
þ
s, -NH), 4.40–4.01 (H, m, -POCH CH ), 3.65 (3H, s, 161.7 MHz) d: 20.32; ESI-MS m/z: 425 [M þ H] ; Anal.
2
3
-
-
(
OCH ), 2.42 (1H, d, J ¼ 22 Hz, P-C-H), 1.46–0.88 (12H, t, calcd for C14
H19FN
2
O
6
P
2
S C, 39.62; H, 4.53; N, 6.60; Found:
3
1
3
POCH CH ); C(CDCl , 100 MHz) d: 166.35 (C11), 159.32 C, 39.58; H, 4.42; N, 6.56.
2
3
3
C2), 150.44 (C7), 127.69 (C4), 127.50 (C6), 113.92 (C1),
1
6
13.54 (C3), 100.24 (C9), 64.01 (C14), 63.75 (C23 & C25)
3.46, 63.31 (C27 & C29), 55.35 (C8), 16.57, 16.39 (C24 &
Tetraethyl(((4-(4-fluorophenyl)thiazol-2-yl)amino)methyle-
ne)bis(phosphonate) (5i)
31
C26), 16.30, 16.01 (C28 & C30);
P NMR (CDCl ,
ꢁ
3
Yellow solid; Yield: 94%; Mp: 125–128 C; IR (KBr) (ꢀmax,
þ
1
61.7 MHz) d: 23.06; ESI-MS m/z: 493 [M þ H] ; Anal.
ꢂ1
1
cm ): 3346 (NH), 1242(P ¼ O), 832 (P-C
); HNMR
Aliphatic
calcd for C H N O P S C, 46.35; H, 6.15; N, 5.69; Found:
1
9
30 2 7 2
(
CDCl , 400 MHz) d: 7.65–7.48 (4H, s, Ar-H), 7.32 (1H, s,
3
C, 45.23; H, 6.03; N, 5.62.
Ar-H), 5.42 (1H, s, -NH), 4.65–4.61 (8H, m, POCH CH ),
2
3
3
.42 (12H, t, P-OCH CH ), 2.1 (1H, d, J ¼ 28 Hz, P-C-H),
2
3
1
3
C(CDCl , 100 MHz) d: 163.43 (C11), 151.06 (C7), 131.45
3
Tetrabutyl(((4-(4-methoxyphenyl)thiazol-2-yl)amino)methy-
lene)bis(phosphonate) (5f)
(
1
6
C5), 130.34 (C1), 130.23 (C3), 127.45 (C4), 126.42 (C6),
21.32 (C2), 105.42 (C9), 69.84 (C14), 66.85 (C23 & C25),
2.81 (C27 & C29), 16.45 (C24 & C26), 16.34 (C28 & C30);
ꢁ
Pale Yellow solid; Yield: 85%; Mp: 140–144 C; IR (KBr) (ꢀmax,
ꢂ1
1
cm ): 3246 (NH), 1246 (P ¼ O), 838 (P-C
); HNMR 31
Aliphatic
PNMR (CDCl3 161.7 MHz) d: 21.65; ESI-MS m/z: 481
,
(
CDCl , 400 MHz) d: 7.79–7.76 (2H, m, Ar-H), 7.24 (1H, s, Ar-
þ
3
[
5
M þ H] ; Anal. calcd for C H FN O P S C, 45.32; H,
18
27
2 6 2
H), 6.94–6.69 (2H, m, Ar-H), 5.67 (1H, s, -NH), 4.48–4.20 (8H,
.64; N, 5.83; Found: C, 45.28; H, 5.62; N, 5.78.
m, -POCH CH CH CH ), 3.86 (3H, s, -OCH ), 2.42 (1H, d,
2
2
2
3
3
J ¼ 28 Hz, P-C-H), 1.89–1.72 (8H, m, -POCH CH CH CH ),
2
2
2
3
Tetramethyl(((4-(4-bromophenyl)thiazol-2-yl)amino)methy-
lene)bis(phosphonate) (5j)
1
.46–1.35 (8H, m, -POCH CH CH CH ), 0.88–0.70 (12H, m,
2 2 2 3
13
-
POCH CH CH CH ); C(CDCl , 100 MHz) d: 165.36 (C11),
2 2 2 3 3
ꢁ
Yellow solid; Yield: 88%; Mp: 136–139 C; IR (KBr) (ꢀmax,
1
1
60.30 (C2), 150.40 (C7), 127.94 (C6), 127.40 (4), 125.63 (C5),
14.52(C1), 114.34 (C3), 103.24 (C9), 72.52 (C14), 66.52 (C21,
ꢂ1
1
cm ): 3295 (NH), 1256 (P ¼ O), 817 (P-C
); HNMR
Aliphatic
(
CDCl , 400 MHz) d: 7.83–7.54 (4H, m, Ar-H), 7.27 (1H, s,
C25, C29 & C35), 57.36 (C8), 31.73 (C22, C26, C30 & C36),
3
31
Ar-H), 5.25 (1H, s, -NH), 3.56 (6H, d, J ¼ 9.8 Hz, P-OCH ),
3
1
8.46 (C23, C27, C31 & C37), 13.17 (C24, C28, C32 & C33); P
3
.43 (6H, d, J ¼ 9.6 Hz P-OCH ), 2.73 (1H, d, J ¼ 22 Hz, P-
13
3
NMR (CDCl , 161.7 MHz) d: 24.32; ESI-MS m/z: 605
3
þ
C-H); C(CDCl3 100 MHz) d: 165.32 (C11), 151.23 (C7),
,
[
4
M þ H] ; Anal. calcd for C H N O P S C, 53.23; H, 7.12; N,
2
7
46 2 7 2
1
32.32 (C1), 132.29 (C3), 132.26 (C5), 129.45 (C4), 124.54
.63; Found: C, 53.18; H, 7.06; N, 4.58.
(
C2), 69.45 (C14), 53.45 (C17 & C22), 53.29 (C20 & C21);
31
P NMR (CDCl3 161.7 MHz) d: 20.45; ESI-MS m/z: 486
,
þ
[
M þ H] ; Anal. calcd for C H BrN O P S C, 34.45; H,
Tetraphenyl(((4-(4-methoxyphenyl)thiazol-2-yl)amino)me-
14 19
2
6 2
3
.98; N, 5.77; Found: C, 34.37; H, 3.86; N, 5.73.
thylene)bis(phosphonate) (5g)
White liquid; Yield: 87%; IR (KBr) (ꢀ , cm ): 3324
ꢂ1
max
1
(
NH), 1216 (P ¼ O), 812 (P-CAliphatic
)
HNMR (CDCl3,
Tetraethyl(((4-(4-bromophenyl) thiazol-2-yl)amino)methy-
lene)bis(phosphonate) (5k)
4
00 MHz) d: 7.84–6.74 (25H, m, Ar-H), 5.40 (1H, s, -NH),
3
.82 (3H, s, P-OCH ) 2.41 (1H, d, J ¼ 24 Hz, P-C-H);
ꢁ
3
Yellow solid; Yield: 92%; Mp: 145–148 C; IR (KBr) (ꢀmax,
1
3
ꢂ1
1
C(CDCl 100 MHz) d: 164.32 (C11), 160.40 (C2), 150.40
3
,
cm ): 3325(NH), 1252(P ¼ O), 848 (P-C
); HNMR
Aliphatic
(C23, C24, C25 & C26), 150.05 (C7), 132.51 (C28, C33),
(
CDCl , 400 MHz) d: 7.80–7.52 (4H, s, Ar-H), 7.24 (1H, s,
3
1
1
31.93(C38 & C43), 131.87 (C30, C35), 131.81(C40, C45)
28.32 (C4 & C6), 125.21 (C5), 121.58 (C29, C34), 121.32
Ar-H), 5.32 (1H, s, -NH), 4.75–4.62 (8H, m, POCH CH ),
2
3
3
.45 (12H, m, P-OCH CH ), 2.19 (1H, d, J ¼ 32 Hz, P-C-H);
2
3
13
(C39 & C44), 121.24 (C27& C31), 120.56 (42 & 46), 120.16
C(CDCl , 100 MHz) d: 165.23 (C11), 150.06 (C7), 132.45
3
(
5
C32 & C36), 120.10 (C37 & C41), 107.94 (C9), 69.56 (14), (C5), 132.34 (C1), 132.23 (C3), 128.45 (C4), 128.42 (C6),
3
1
5.28 (C8); P NMR (CDCl3, 161.7 MHz) d: 26.01; ESI-MS 123.32 (C2), 107.45 (C9), 71.84 (C14), 61.85 (C23 & C25),
þ
m/z: 685 [M þ H] ; Anal. calcd for C H N O P S C, 61.81 (C27 & C29), 16.32 (C24 & C26), 16.28 (C28 & C30);
35
30 2 7 2
31
6
1.38; H, 4.48; N, 4.09; Found: C, 60.26; H, 4.32; N, 4.02.
PNMR (CDCl3, 161.7 MHz) d: 21.86; ESI-MS m/z: 542

1
0
S. POOLA ET AL.
þ
[
5
M þ H] ; Anal. calcd for C H BrFN O P S C, 39.82; H, Funding
18
27
2
6 2
.05; N, 5.17; Found: C, 39.74; H, 5.02; N, 5.12.
One of our authors Mr. Mohan Gundluru expresses sincere thanks to
the funding DST-PURSE 2nd Phase Program in S.V. University,
Tirupati funded by DST-New Delhi, India for providing instrumenta-
tion facility through SRF (File No: 17118-UGC-III(3)/DST-PURSE 2nd
Phase/2017, Dt: 23-08-2018).
Tetraphenyl(((4-(4-bromophenyl)thiazol-2-yl)amino)methy-
lene)bis(phosphonate) (5l)
ꢁ
White solid; Yield: 88%; Mp: 154–158 C; IR (KBr) (ꢀmax,
ꢂ1
1
cm ): 3326 (NH), 1248 (P ¼ O), 814 (P-C
); HNMR
Aliphatic
(
CDCl , 400 MHz) d: 8.21–7.12 (25H, m, Ar-H), 5.34 (1H, s,
3
NH), 2.73 (1H, d, J ¼ 28 Hz, P-C-H); C(CDCl , 100 MHz)
13
ORCID
-
3
d: 165.32 (C11), 153.34 (C7), 153.28 (C23, C24, C25 & C26), Suresh Reddy Cirandur
http://orcid.org/0000-0002-9804-9683
1
1
32.45 (C5), 132.42 (C3), 132.38 (C1), 130.35 (C28, C30),
30.23 (C38, C40), 130.12 (C34 & C36), 130.10 (C43 &
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C45), 128.42 (C4 & C6), 122.43 (C2), 121.94 (C29, C34, C39
C44) 120.95 (C27 & C31), 120.93 (C32 & C36), 120.86
&
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Disclosure statement
No potential conflict of interest was reported by the authors.

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