(S)-4-(4-aminobenzyl)-2-oxazolidinone based 2-azetidinones for antimicrobial application and luminescent sensing of divalent metal cations

Article abstract of DOI:10.1002/jhet.3965

The impact of linezolid as an antibiotic against gram-positive bacteria has inspired synthetic chemists to use oxazolidinones as substrate molecule in the synthesis of newer scaffolds with important pharmacological implication. The oxazolidin-2-ones are key intermediates in the synthesis of many interesting biologically active compounds. Design and synthesis of a new series of (S)-4-(4-aminobenzyl)-2-oxazolidinone based multifunctional azetidinones were accomplished. Synthesis of the scaffolds was performed through a multi-step reaction process involving protection of amine functional group, conversion of protected (S)-4-(4-aminobenzyl)-2-oxazolidinone to its acetic acid derivative and then to acid chloride, and finally coupled with different substituted aromatic imines under mild reaction conditions in presence of an appropriate base. Structural characterization was carried out using conventional spectroscopic techniques. The compounds were screened for their antimicrobial activity against gram-positive and gram-negative bacteria and were found to possess better and promising antimicrobial property than some of the reported antimicrobial drugs like disulfonamide and tetracycline. Additionally, the scaffolds also exhibit prominent sensing property for divalent metal cations like Cu²⁺, Zn²⁺, and Ni²⁺, through fluorescence quenching effect.

Full text of DOI:10.1002/jhet.3965

Received: 26 November 2019
DOI: 10.1002/jhet.3965
Revised: 9 January 2020
Accepted: 27 February 2020
A R T I C L E
(
S)-4-(4-aminobenzyl)-2-oxazolidinone based 2-azetidinones
for antimicrobial application and luminescent sensing of
divalent metal cations
Shyamal Baruah | Merangmenla Aier | Amrit Puzari
Department of Chemistry, National
Abstract
Institute of Technology Nagaland,
Dimapur-797103, Nagaland, India
The impact of linezolid as an antibiotic against gram-positive bacteria has
inspired synthetic chemists to use oxazolidinones as substrate molecule in the
synthesis of newer scaffolds with important pharmacological implication. The
oxazolidin-2-ones are key intermediates in the synthesis of many interesting
biologically active compounds. Design and synthesis of a new series of (S)-
Correspondence
Amrit Puzari, Department of Chemistry,
National Institute of Technology
Nagaland, Chumukedima, Dimapur
-797103, Nagaland, India.
4-(4-aminobenzyl)-2-oxazolidinone based multifunctional azetidinones were
Email: amrit09us@yahoo.com
accomplished. Synthesis of the scaffolds was performed through a multi-step
reaction process involving protection of amine functional group, conversion of
protected (S)-4-(4-aminobenzyl)-2-oxazolidinone to its acetic acid derivative
and then to acid chloride, and finally coupled with different substituted aro-
matic imines under mild reaction conditions in presence of an appropriate
base. Structural characterization was carried out using conventional spectro-
scopic techniques. The compounds were screened for their antimicrobial activ-
ity against gram-positive and gram-negative bacteria and were found to
possess better and promising antimicrobial property than some of the reported
antimicrobial drugs like disulfonamide and tetracycline. Additionally, the scaf-
folds also exhibit prominent sensing property for divalent metal cations like
Funding information
DST-RFBR, Grant/Award Number: INT/
RUS/RFBR/P-221
2+
2+
2+
Cu , Zn , and Ni , through fluorescence quenching effect.
1
| INTRODUCTION
stimulated because of the increasing development of drug
resistant strains in bacteria to widely used antibiotics of this
type. Therefore, there is a need for functionalized β-lactams
or for new active principles in β-lactam series. Number of
broad-spectrum chemotherapeutic agents used to treat bac-
terial infection and microbial diseases, including
Multi-drug resistant bacteria strains are attracting signifi-
cant scientific interest because most of the conventional
antibiotics are becoming dysfunctional.
opment of new series of antibiotics has become an impor-
tant research objective. Initially, antimicrobial peptides
were considered for development of such drugs.
[1,2]
Therefore, devel-
[
7]
[8]
[9]
penicillin, cephalosporin, carbapenem, and mono-
[3–5]
[10]
But cer-
bactams contain 2-azetidinone (β-lactams) ring as a com-
tain limitations such as proteolytic degradation by microbial
enzymes together with toxicity factor and higher production
cost have restricted the use of such products. The chemis-
try of β-lactams has taken an important place in organic
chemistry after the discovery of penicillin by Sir Alexander
Fleming in 1928. Even now, research in this area is
mon structural feature. Nitrogen and oxygen containing
[11]
heterocycles such as 2-oxazolidinones,
1, 3-oxazinan-
are important
[6]
[12]
[13]
[14]
2-ones,
2 oxazolines,
and oxazines
building blocks for synthesis of biologically active com-
pounds. Synthetic chemists usually employ molecular build-
ing blocks for design and synthesis of new scaffolds for
J Heterocyclic Chem. 2020;1–14.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
BARUAH ET AL.
important biological applications. Oxazolidin-2-ones are
appearing as a key intermediate in many organic syntheses
leading to novel biologically active compounds that possess
potential antimicrobial activity. For example, (S)-
many of these technologies have shortcomings such as
poor solubility, low cross sensitivity, and low matrix
[
31]
interference.
Work presented here is embodiment of
such efforts to find out efficient molecular framework for
using as potent antimicrobial agent. Additionally, the
scope of using such molecular entities for detection of
heavy metals such as copper (Cu), Nickel (Ni), and zinc
(Zn) has also been investigated, keeping in mind that
development of efficient organic molecular scaffolds for
rapid and easy detection of heavy metals often attracts
significant scientific interests.
5
-aminomethyl 2-oxazolidinone is the core structure in the
[15,16]
antibacterial agent linezolid,
thetic oxazolidinone antibiotic effective against resistant
gram-positive bacteria.
the first member of syn-
[17,18]
Several of these products have
been commercialized while few others were discontinued
due to inadequate pharmacokinetics, safety risks, and other
factors. Oxazolidinone based compounds like torezolid
phosphate is being tested clinically for acute bacterial skin
[19]
infections.
Therefore, although oxazolidinone-based
azetidinones sometimes might have some limitations for
therapeutic use, there is still enough scope of invention of
new scaffolds based on oxazolidin-2-ones for important
therapeutic applications. Gram-positive resistance has grad-
ually become a serious therapeutic problem, which have
generated more interest in antibiotic research and develop-
ment. These organism exhibit resistances to most of the
2 | RESULTS AND DISCUSSION
Oxazolidinone analogues have been established as a poten-
tial inhibitor for the growth of pathogenic bacteria. They
are effective against a wide spectrum of gram-positive,
gram-negative, and anaerobic bacteria. Biological activity of
such molecules has been tested and documented in litera-
ture. In evaluating their biological activity, apart from
structure-activity relations, other factors have also been
taken into account. For example, consideration of structure
space evolves and chirality is very much important. Because
binding affinity can be different for different enantiomers.
Choosing the right chiral structure creates the opportunity
for the design of appropriate drug molecule for diverse
application. Thus, key chiral structures are an important
building block for generation of new libraries of chiral mol-
ecules with biological significance. In contrary, use of a mix-
ture of enantiomers may lead to inimical effects.
[20]
available agents.
The gram-positive bacteria, such as
staphylococci and enterococci are posing as a serious threat
with existing antimicrobial agents due to the development
of resistance. These bacteria sometimes show multidrug
[21]
resistance, even to the well-known vancomycin drug.
Usually vancomycin always works against multidrug resis-
tant staphylococci. This happens because of improper and
indiscriminate use of antibiotics. For example, streptococcus
pneumonia, which was earlier easily treated with inexpen-
sive antibiotics, nowadays its treatment is becoming a major
[22]
problem for the physicians.
Failure to combat such
multi-drug resistant organism may lead to patient mortality.
Oxazolidinones has been gaining consideration as a potent
molecule for development of antimicrobial agents
A good inhibitor is expected to have better inhibitory
power than the standard ones. Most studies have shown
that the incorporation of chiral auxiliary into oxazolidinone
[23]
[32]
because several characteristics possessed by this class of
molecule are suitable for treatment of gram-positive bacteria
and can be specifically employed for treatment of multi-
moiety dramatically improves inhibitory power.
Usually
at a molecular level, biological systems, particularly for
mammals, composed of macromolecular units like proteins,
glycolipids, and polynucleotides, which in turn formed from
chiral building blocks of L-amino acids and D-carbohydrates.
The process of drug action or disposition involves interac-
tion between the optical isomer of a drug molecule and chi-
[24]
drug resistant gram-positive bacteria.
Oxazolidines are
also suitable for development of cost economic antimicro-
[25]
bial agents. Therefore, there is a need to look for newer
scaffolds based on oxazolidinones and study their
antibacterial activity and pharmacological significance
[33]
ral biological macromolecule.
Therefore, these
(
Data S1).
interactions in biological system might even involve stereo
selectivity. Normally bonding interaction results between
the functional site of a drug molecule and complementary
site in the receptor surface or enzyme active site. Steric fac-
tors and hence the conformation, might play significant role
in case of such interactions and for stereoisomers three-
dimensional spacing of the groups need to be taken into
account. Based on these facts, we have designed a series of
azetidinones based on (S)-4-(4-aminobenzyl)-oxazolidin-
2-one. Structure of the synthesized compound is depicted in
Figure 1.
On the other hand, such type of molecules also shows
potential applicability for detection and removal of heavy
metals from biological and aquatic systems, even at low
concentration.
metals, they are generally considered as potential envi-
ronmental pollutants even at low concentrations.
Although several modern technologies have been intro-
duced for this purpose including atomic absorption
spectroscopy,
[
26]
Because of deleterious effects of heavy
[
27]
[
28]
[29]
X-ray fluorescence spectroscopy,
elec-
[30]
trochemical methods,
yet the growing popularity of

BARUAH ET AL.
3
O
The sequence of synthetic steps adopted for the
synthesis of 2-((S)-4-((E)-4-(benzylideneamino)phenyl)-
-oxazolidin-3-yl) acetic acid from the (S)-4-(4-ami-
O
HN
N
H N
O
2
H
C
H
ClCH COOH
2
2
C H ONa
2
5
N
Ethanol
Room Temperature
N
OH
nobenzyl) oxazolidin-2-one is depicted in Scheme 1.
A series of molecules were synthesized by in situ con-
version of 2-oxazolidinone acetic acid derivatives into
corresponding acid chloride and then coupling with a set
of aromatic imines. As a representative case, we have
used propyl amine and butyl amine as aliphatic amine,
and aniline as aromatic amine for imine synthesis. The
purpose of using propyl and butyl amine for the synthesis
NH
O
C
H
Methanol
O
O
O
O
0
40 , 24 Hrs
(a)
(b)
SCHEME 1 Synthesis of (A) Imines and (B) 2-((S)-4-((E)-
-(benzylideneamino) phenyl)-2-oxazolidin-3-yl) acetic acid
4
OCH3
Cl
Cl
H CO
3
N
C
H
N
C
H
(E)-N-(2,4'-dichlorobenzylidene)propan-1-amine
(E)-N-(3,4'-dimethoxybenzylidene)propan-1-amine
1
2
Cl
Cl
N
C
N
C
H
H
(E)-N-(3,4'-dichlorobenzylidene)propan-1-amine
(E)-N-benzylidenebenzenamine
3
4
N
C
N
C
H
H
O
OH
NH
N
O
O
O
O
(S)-4-((E)-4-(benzylideneamino)benzyl)oxazolidin-2-one
2-((S)-4-((E)-4-(benzylideneamino)benzyl)
-2-oxooxazolidin-3-yl)acetic acid
5
6
Cl
H CO
3
OCH3
N
C
N
C
H
H
Cl
N
N
N
N
O
O
O
O
O
O
(
S)-4-((E)-4-(benzylideneamino)benzyl)-
(S)-4-((E)-4-(benzylideneamino)benzyl)-
3
-(2-(2,4'-dichlorophenyl)-4-oxo-1-propylazetidin-3-yl) 3-(2-(3,4'-dimethoxyphenyl)-4-oxo-1-propylazetidin-3-yl)
oxazolidin-2-one
oxazolidin-2-one
7
8
Cl
Cl
N
N
C
H
C
H
N
O
N
O
N
N
O
O
O
O
(
S)-4-((E)-4-(benzylideneamino)benzyl)-3-
(S)-4-((E)-4-(benzylideneamino)benzyl)-3
-(2-oxo-1,4'-diphenylazetidin-3-yl)oxazolidin-2-one
FIGURE 1 Chemical structures of
the imines (1-5) and acetic acid product
(
2-(3,4'-dichlorophenyl)-4-oxo-1-propylazetidin-3-yl)
oxazolidin-2-one
9
10
(
6) and azetidinones (7-10)

4
BARUAH ET AL.
is to investigate the effect of increasing length of side
chain on the inhibitory activity of the products. The fol-
lowing synthetic scheme (Scheme 2) was applied for syn-
thesis of the azetidinones.
Mechanistic route for the formation of the
azetidinones of (S)-4-Aminobenzyl-oxazolidinone-2-one
can be depicted as shown in Scheme 3.
Similarly, for E. coli, compound 7 showed the highest
antimicrobial activity as it was showing the highest inhi-
bition zone of 24 mm at 100 μg/mL. Compound 7 showed
antimicrobial response even at 30 μg/mL (11 mm). Com-
pound 8 and 10 also showed antimicrobial activity at the
lowest concentration, that is, 30 μg/mL. Therefore, over-
all conclusion arrived from the results is that the mole-
cules are equally responsive against E. coli. We have also
observed that with increase in the length of the alkyl
chain of the imine unit, the antimicrobial activity of the
compound decreases. Among all the azetidinones
reported here, compound 7 has higher potential as anti-
microbial agent. However, all the other molecules exhibit
good antimicrobial activity.
For more clear understanding of the efficacy of the
reported azetidinones as antimicrobial agent, we have
also calculated the zone of inhibition of standard antimi-
crobial drug chloramphenicol (one of the well-known
broad spectrum antibiotics) against B. subtilis and E. coli,
under identical condition. Results of the analysis are
shown in Table 1 along with the respective values for the
reported compounds. Values indicate maximum inhibi-
tion of 37 mm against B. subtilis and inhibition zone of
38 mm against E. coli at 100 μL. These data revealed the
fact that although the azetidinones reported in this work
have lesser activity than the standard chloramphenicol,
still respective values for the molecules are significant
enough for using as antimicrobial agent and even few of
them can be advocated as a substitute for the standard
drug chloramphenicol.
Research interests of many scientists are focusing on the
search for new antimicrobial molecules because of the fact
that many organisms are developing resistant to the avail-
able antimicrobials. This happens due to frequent use of
antibiotics. A series of small molecules were synthesized
and tested for their potential utility as antimicrobial agent.
For that purpose, the zone of inhibition test, which is also
known as, Kirby-Bauer Test, was carried out over an agar
plate using a sterile swab and then incubating in the pres-
[34]
ence of the antimicrobial agent.
The bacterial samples
used for the purpose were Escherichia coli and B. subtilis.
Usually, if the bacteria are susceptible to the antimicrobial
agent then a zone of inhibition appears on the agar plate
but if they are resistant to the antimicrobial agent then no
inhibition zone appears on the plate. Therefore, greater the
inhibition zone, the more antimicrobial potential the com-
pound has. Zone of inhibition calculated for the series of
products against Bacillus subtilis (MTCC 441) and E. coli
(MTCC 739) is represented in Table 1, along with the values
calculated for the standard drug Chloramphenicol.
The values presented in the table strongly indicates that
the compounds exhibit good to excellent antimicrobial
activity and even in few cases the values are closer to the
values of chloramphenicol. It has been observed that in case
of compound 7, 8, and 10, even with 30 μg/mL concentra-
tion, the compounds exhibit some sort of antimicrobial
activity. Further, as indicated in the table, antimicrobial
activity of the azetidinones are far better compared to the
antimicrobial activity of the parent acetic acid derivative of
Cl
O
O
N
N
C
OH
H
SOCl2
O
O
O
N
N
O
C
2-(4-((E)-3-(benzylideneamino)benzyl)-
-oxooxazolidin-3-yl)acetyl chloride
H
2
(
S)-4-aminobenzyl-2 oxazolidinone(6). For Bacillus subtilis,
compound 7 showed excellent activity at 30 μg/mL while 7,
, 9, and 10 did not. However, the overall comparison
2-(4-((E)-3-(benzylideneamino)benzyl)-2-
(
C2H5)3N
oxooxazolidin-3-yl)acetic acid
R1
8
Cl
N
O
R
O
O
O
shows that 8 had the highest activity for Bacillus subtilis as
it was showing the highest inhibition zone (23 mm) at
1
N
N
O
N
C
O
H
N
00 μg/mL. General observation is that all the products
C
H
have good to excellent antimicrobial activity against Bacillus
subtilis.
(
S)- 4-Aminobenzyl-2 oxazolidinone based
Azetidinone
O
C
O
R1
N
O
N
O
C
R
N
O
O
N
N
C
N
N
C
H
C
H
R
H
(
i)SOCl
2
C
Ketene
R1
N
O
H
R1
N
RC
(
ii) Imine, triethylamine,
40 C, 4hr
N
0
N
OH
H
Imine
O
O
O
O
O
[2+2] Ketene-imine Cycloaddtion reaction
SCHEME 2 Synthetic scheme of the azetidinones of (S)-
-Aminobenzyl-oxazolidinone-2-one
SCHEME 3 Mechanistic route for formation of (S)-4-
aminobenzyl-2 oxazolidinone based azetidiones
4

BARUAH ET AL.
5
The zone of inhibition of azetidinone and standard
chloram-phenicol are depicted in Figure 2.
performed to improve some properties while maintaining
others.
In this work, four types of bioisoteric replacements
(
modifications of substituents in the aromatic unit)
were performed in the parent compound (S)-4-((E)-
-(benzylidene-amino)benzyl)oxazolidin-2-one, with the
4
objective of manipulating the biological properties of the
compounds. For the two different cases, that is, with
B. subtilis and E. coli, the zone of inhibition for different
concentration of the azetidinones have been plotted in the
form of a histogram, as shown in Figure 3. The histogram
clearly displays several interesting facts about the biological
activities of the compounds. For B. Subtilis, substantial
increase in antimicrobial activity was noted for the methoxy
(
─OCH ) substituted azetidinone (8) and hence it can be
3
concluded that the methoxy group positively influences the
inhibitory effect of the azetidinones. Compared to gram-
negative bacteria, E. coli, the inhibitory effect of 8 is more
prominent in case of gram-positive bacteria B. Subtilis.
Similarly, the histogram also clearly indicates that
compared to other substituted products, chlo-
rosubstituted products 7 and 10 possess remarkably high
antimicrobial activity for gram-positive bacteria as well
as for gram-negative bacteria. In this case, the
2, 4-dichloro substituted compound 7 possess relatively
higher zone of inhibition than 3, 4-substituted ones. As
expected with substituted aromatic compounds, we have
noted that substitution at ortho and para position exerts
more electronic influence than in meta position. The
same is reflected in case of these two compounds and the
3
| STRUCTURE ACTIVITY
RELATIONSHIP
FIGURE 2 Zone of inhibition of the 2-azetidinones and
standard chloramphenicol against B. subtilis and E.coli (disk
diffusion method)
Bioisosterism is an important aspect related to drug dis-
covery, where modifications to parts of a molecule are
TABLE 1 Zone of inhibition of
samples
Zone of inhibition in diameter (mm)
Bacillus subtilis (MTCC 441)
Escherichia coli (MTCC 739)
Compound
30 μL
—
50 μL
07
100 μL
11
30 μL
—
50 μL
14
100 μL
16
6
7
8
9
12
18
22
11
17
24
—
16
23
09
13
18
—
12
13
—
09
12
10
—
14
21
16
20
18
Chloramphenicol
30
34
37
31
36
38

6
BARUAH ET AL.
FIGURE 3 Histogram plotted
for zone of inhibition of compound
6, 7, 8, 9, and 10 against B. Subtilis
(
a) and E. coli (b), for three different
concentrations of the azetidinones
they can selectively bind to the 30S subunit of the ribo-
some, whereas chloramphenicol binds to the 50S
subunit.
TABLE 2 Log P values of synthesized compounds
Compound
Log P value
[36]
6
7
8
9
2.98
6.37
5
4
| LOG P VALUES AND
ANTIBACTERIAL ACTIVITY
6.37
6.09
1
0
Lipophilicity is one of the most interesting physicochemi-
cal properties for biological activity of drugs. Positive
value of log P denotes the lipophilic behaviour of the
drugs. Table 2 shows the predicted log P values from
chemaxon for the synthesized compounds. From the
table, we have observed that compared to substituted
acetic acid product 6, log P values are higher for other
four compounds (7-10). This fact reveals better penetrat-
ing ability of the newly synthesised compounds through
a polar cell membranes and hence enhanced antibacterial
activity than the parent compound. As compound 7 pos-
sess the highest log P value, therefore apparently it can
be claimed to have highest zone of inhibition, which we
practically observed. However, compounds with same log
P values may have different levels of antibacterial activity
depending on the nature and position of substituents on
the molecule. In our case, although compounds 7 and
9 possess the same log P values, but compound 7 exhibit
more antimicrobial activity compared to compound 9.
Both the molecules are identical and possess same type of
substituents in the aromatic ring of the imine unit, but
the positions of substituents are different in both which
eventually causes the differences in their antimicrobial
activities.
respective inductive effect generated by the chlorine sub-
stituents creates the differences in their antimicrobial
activities for the two azetidinones, compounds 7 and 10.
Another important observation from the histogram is
that azetidinones with no substituents in the aromatic
ring also possess significant antimicrobial activity. How-
ever, compared to substituted azetidinones (compounds
7, 8, and 10), their zone of inhibition was less. Therefore,
substituents in the azetidinones markedly influence the
biological activities of the compounds.
For the gram-positive bacteria, B. Subtilis, compared
to chloro substituents (─Cl), the methoxy (─OCH ) sub-
3
stituent has a more positive influence on the biological
activity of azetidinones while reverse observation was
noted for the case of gram-negative bacteria, E. coli. For
E. coli, the maximum inhibition zone was recorded for
2
, 4-dichloro azetidinone. This fact indicates that the
inductive effect of the chlorine group is more prominent
than that of methoxy (─OCH ) group. On the mechanis-
3
tic front, the azetidinone derivatives interfere with the
enzymes that are actively involved in the synthesis pro-
cess of the bacteria cell walls. They interfere with the
enzymes, which are required for the synthesis of the
peptidoglycan layer that binds to the terminal D-alanine
5 | MINIMUM INHIBITORY
CONCENTRATION (MIC)
[
35]
residues of the nascent peptidoglycan chain,
thereby
preventing the cross-linking steps required for stable
cell wall synthesis. Azetidinones are also taking advan-
tage of the bacterial ribosomes that differ in structure
from their counterparts in eukaryotic cells. Therefore,
MICs of the extracts were determined for the bacterial
strains which were sensitive to the extracts in the well
diffusion assay. A broth macro-dilution method was used

BARUAH ET AL.
7
TABLE 3 MIC and MBC values of different compounds against bacterial strain B. subtilis (MTCC 441) and E. Coli
Tested organism
7 (μg/ml)
15.62
15.62
1
8 (μg/ml)
31.25
62.50
2
9 (μg/ml)
31.25l
62.50
2
10 (μg/ml)
31.25
62.50
2
Bacillus subtilis (441)
MIC
MBC
MBC/MIC
MIC
Escherichia coli (MTCC 739)
15.62
15.62
1
15.62
15.62
1
31.25
62.50
2
15.62
15.62
1
MBC
MBC/MIC
Values represented in the table confirm the fact that
the reported compounds exhibit significant antimicrobial
activity against the bacterial strains of B. subtilis and
E. coli. For B. subtilis, MIC value for compound 7 is quite
good (15.62 μg/mL) compared to the other three products
8, 9, and 10. MIC value for these three products is
31.25 μg/mL. This fact reflects the superiority of com-
pound 7 over the other three molecules with respect to
B. subtilis. Similarly, considering the case of E. coli, from
the MIC value it can be stated that Compounds 7, 8, and
10 showed highest activities compared to 9. Available lit-
erature data indicates that disulfonamide, which is a very
FIGURE 4 UV-visible spectra of compound 7 (0.01 M) in the
important antimicrobial agent, shows minimum activity
2
+
2+
2+
absence and presence of Cu , Ni , and Zn ions in MeOH-H
1/1, vol/vol) solutions
2
O
[38]
at 100 μg/mL against E. coli.
From Table 2, we can
(
also observe that the minimum bactericidal concentra-
tion (MBC) ranges from 15.62 to 62.50 μg/mL.
According to Fauchère and Avril (2002), an antibiotic
is described as bactericidal when the MBC value of an
antibiotic on a given strain is close to the MIC (1 ≤ MBC/
MIC ≤2. As the MBC/MIC of our products are well
within this range, we can strongly argue that they possess
significant bactericidal property.
[
37]
with a slight modification.
The broth dilution method
is a simple procedure for testing a small number of iso-
lates, even for a single isolate. Stock solution of 2 mg/mL
of the plant extract was prepared by mixing with DMSO.
A row of sterile screw capped tubes containing 2 mL of
nutrient broth each was arranged. Plant extract (2 mL)
from appropriate stock solution was mixed with the
nutrient broth. The content was mixed using a pipette
and 2 mL was transferred to the second tube. The content
of the second tube was mixed well and 2 mL of it was
transferred to the next tube. The dilution was continu-
ously prepared by following the same procedure as men-
tioned above.
Similarly another important drug tetracycline shows
[39]
minimum activity at 25 μg/mL against B. Subtilis.
Therefore, if we compare the values for the reported com-
pounds with that of the standard ones referred above, we
can certainly conclude that products reported in this work
has promising antimicrobial activity which in other words
reflects the novelty of the work. The compounds can be a
better alternative as antimicrobial drug against broad spec-
trum of gram-negative and gram-positive bacteria. Work
presented in this article increases the hope of discovering
new bioactive molecules based on (S)-4-Aminobenzyl-
2-oxazolidinone, which are potent antimicrobial agents.
Thus, concentrations of 1000, 500, 250, 125, 62.5, 31.25,
5.62, 7.8, and 3.9 μg/mL were prepared. The last tube with-
out plant extract was used as control. The tubes were then
inoculated with 50 μL of broth culture of the test organism.
1
ꢀ
After incubation of the cultures at 37 C for 18 hours, the
MIC value was determined. MIC is expressed as the lowest
dilution that can inhibit the growth of an organism and is
determined by the absence of turbidity in the tube. MIC
values determined for the reported compounds against bac-
terial strain B. subtilis (MTCC 441) and E. coli (MTCC 739)
are tabulated in Table 3.
6 | ION SENSING PROPERTIES
β-Lactum compounds also possess the scope for using as
a receptor molecule for important guest molecules or
[
40]
ions,
which unveils the possibility of their application

8
BARUAH ET AL.
FIGURE 5 Change of
emission spectra of compound
in the presence of varying
7
2
+
2+
concentrations of Cu , Zn , and
2
+
Ni ions (.01 M) in MeOH-H
1/1,vol/vol) solutions at 360 nm
excitation wavelength
2
O
(
2+
n ! π* transition. On addition of Zn ion to compound
solution, the band at 250 nm disappeared and a new
significant band appeared with a red shift at 300 nm. Cor-
7
2+
2+
respondingly, by addition of Cu ion and Ni ion, a red
shift was noticed for the band at 250 nm. It can be obvi-
ous to find that the interaction with the metal ion stabi-
lize the electronic excited state relative to the ground
state of the compound 7 (and hence decreased the energy
gap between the excited and ground state) resulting in
red-shift. Again the observed red shift of the n ! π* band
can be attributed to the interaction between carbonyl
oxygen of Oxazolidinone unit and metal ions. Thus, UV-
visible experiment revealed effective interaction of com-
pound 7 with the metal cations.
FIGURE 6 Job's plot for stoichiometry of binding between
compound 7 and Cu
2
+
Fluorescence active compounds often used as a sensor
to identify metal ions in biological, environmental, and
in the field of molecular recognition, host-guest chemistry
and for ion sensing. Therefore, with the hope of unambig-
uously establishing the interaction between the metal ion
guest and the azetidinone host, we have examined the
sensing property of compound 7 by UV-Visible spectros-
copy and fluorescence titration, in which the intensity of
the sample was measured by immersing different concen-
[
41]
sewage testing
and usually response in fluorescence
spectroscopy is generally considered more sensitive than
[
42]
UV-visible spectroscopy.
Due to fluorescence
quenching effects of biologically active ions, development
of new molecules as fluorescence turn-on sensors has
[
43]
become an important research area.
Being encouraged
2+
2+
2+
tration of the metal ions (Cu , Ni , and Zn ) with fixed
concentration of the host azetidinone (7).
by the responses in UV-Visible spectroscopy, we also
studied the sensing properties of compound 7 as a repre-
sentative case for the new series of compounds. The sens-
ing property of the compound 7 was monitored
by florescence titrations with varying concentrations of
Compound 7 displayed specific interaction pattern
2+
2+
2+
with divalent metal cations such as Cu , Zn , and Ni
ion, as manifested in Figure 4. It has been observed that
UV-visible spectra of compound 7 exhibits an intense
absorption band at 220 nm due to π ! π* transition and
two mild absorption bands at 250 and 290 nm due to an
2+
2+
2+
Cu , Zn , and Ni ions (.01 M). All the titrations were
attained in MeOH-H O (1/1, vol/vol) solutions. The fluo-
2
rescence spectra of compound 7 (.01 M) exhibit an

BARUAH ET AL.
9
TABLE 4 The LOD and LOQ calculation of compound 7 for the three metal cations
Metal
SD (S
9.44
a
)
Slope (b)
0.149
Limit of detection (mg/L)
Limit of quantitation (mg/L)
Copper (Cu)
Nickel (Ni)
Zinc (Zn)
0.756
0.748
1.725
0.402
0.317
0.337
7.92
0.143
4.07
0.0789
The limit of detection (LOD) and limit of quantitation
2+
2+
2+
(
LOQ) of Cu , Zn , and Ni ions with compound 7 was
calculated from the plot of emission intensities vs metal ion
concentrations and using the formula 3S / b & 10S /b,
a
a
where “S ” is the SD and “b” is the slope of the straight
a
[45]
line.
Table 4). According to World Health Organisation (WHO)
report 2003, the permissible limit of copper, nickel, and zinc
The concentration was found to be at ppm level
(
[46]
in drinking water is 1, .05, and 3.0 mg/L, respectively.
The result obtained from the LOD and LOQ are found to
be very close to permissible limit and therefore, compound
7
can be used as a chemosensor for the detection of heavy
metals in drinking water. Same justification can be believed
to hold true for the other three reported compounds.
7
| HOMO-LUMO ENERGY GAP
AND CHEMICAL HARDNESS: A DFT
STUDY
All the calculations were performed by DFT method with
6-311G(d,p) basis set using Gaussian 09 W software pack-
age. HOMO-LUMO energies were studied at time-
dependent TD-SCF based on the optimized structure.
The molecular HOMO/LUMO picture of the ligands
compounds 7, 8, and 9 as well as the complex of 7 with
2+
Cu is depicted in Figure 7.
FIGURE 7 Frontier HOMO-LUMO energy gap of
A) compounds 7, 8, 9, and (B) and Compound 7-Complex with Cu
From the figure there is a clear observation of conjuga-
tion and delocalisation of charge over the entire framework.
For all the azetidinones, zero charge delocalization was
observed on the ring. After formation of the complex, the
charge density moved towards the azetidinone ring. This fact
confirms the coordination of the azetidinone ring with Cu .
The chemical hardness generally rationalizes the rela-
tive stability and reactivity of chemical compounds. And
2+
(
emission band at 458 nm. As illustrated in Figure 5, fluo-
rescence intensity of emission band of the compound
2+
7
gradually declined upon progressive addition of metal
ions in all the cases. This dramatic fluorescence
quenching of emission band is attributed to the forma-
tion of a charge-transfer complex between compound
large HOMO-LUMO gap is associated with hard and
2
+
[47]
7
and M . Thus, compound 7 may be used as a turn-off
more stable compounds.
The definitions of universal
[44]
fluorescent probe towards divalent metal ions.
concepts of molecular structure stability and reactivity
can be provided using DFT method. For definition of
For the binding mode study the Job's method was
utilised to find out the stoichiometry of binding between
the receptor and the metals. For that we have taken a
constant total concentration of the ligand and the metal
with a continuous variable mole fraction of guest. This
study confirms 1:1 stoichiometry for Cu, Ni, and
Zn. Figure 6 shows the Job's plot for 1:1 stoichiometry of
[
48]
hardness ç, following equation is developed
:
η = 1/ 2 (I − A),where I and A are the vertical ioniza-
tion energy and the vertical electron affinity, respectively.
According to Koopman theorem, the ionization
energy and electron affinity can be equalized through
HOMO and LUMO orbital energies (EA = −E HOMO
and IP = −E LUMO). So, the hardness depends on the
2+
compound 7 with Cu .

10
BARUAH ET AL.
TABLE 5 HOMO-LUMO energy
gap and chemical hardness data
Compound
HOMO/eV
−6.41
LUMO/eV
−2.12
Gap/eV
4.29
Hardness
2.14
7
8
9
−5.95
−1.99
3.76
1.88
−6.35
−2.04
4.31
2.15
2
+
7
+ Cu complex
−11.40
−7.34
4.06
2.03
FIGURE 8 X-ray diffraction
pattern for compound 5 and 7
energy gap between HOMO and LUMO orbital. Larger
the HOMO-LUMO energy gap, the harder molecule is.
As observed from Table 5 HOMO-LUMO energy gap
of compounds 7, 8, and 9 were found as 4.29, 3.76, and
9 | XRD ANALYSIS
Linezolid or other oxazolidinone derivatives are known
to exhibit polymorphism and two crystalline forms are so
[
50]
4
.31 eV, respectively. On the other hand, the energy gap
far known.
X-ray powder diffraction patterns of crystal
2+
for 7-Complex with Cu
was found 4.06 eV. Indeed
form of compounds 5 and 7 are illustrated in Figure 8.
From the figure, we have observed that compound 5 pos-
sess crystalline behaviour contrary to compound 7 (after
formation of the azetidinone) which shows semi-
crystalline behaviour. As polymorphism is a common
characteristics of oxazolidinone, therefore, we have noted
the observed changes in crystal behaviour of compound
7. For compound 5, the diffraction peaks 2θ were
observed at 12.04, 16.12, 17.18, 18.71, 20.82, 21.42, 24.43,
25.82, and 27.62. On the other hand, for azetidinone
(compound 7) peaks were observed at 12.22, 17.34, 21.27,
24.59, and 27.63. The analogy observed for few of the 2θ
values of the two compounds provides clear indication
about the formation of the compound.
chemical hardness data also confirms the fact that the
hardness of the complex is lesser than the ligand
azetidinone. This fact reveals that the metal chelation
reduces the stability of the independent medium.
8
| CONCLUSIONS
Successfully synthesized a series of 2-azetidinones based on
S)-4-Aminobenzyl-2 oxazolidinone and evaluated their
(
antibacterial activities against gram-positive and gram-
negative bacteria like B. Subtilis and E. Coli. Results of zone
of inhibition and MIC values strongly indicates that these
molecules have much wider scope for using as
antibacterial drugs for broad spectrum of microorgan-
isms. Even there are scopes of using such molecules as
an alternative for known antibacterial drugs like chlor-
amphenicol. Fluorescence study reveals that molecules
show excellent sensing capabilities for divalent metal
cations, especially for copper (Cu), zinc (Zn) and nickel
10 | EXPERIMENTAL SECTION
10.1 | Materials
2,4-dichlorobenzaldehyde,
3,4-dichlorobenzaldehyde,
(
Ni), with detection limit in ppm level. Most interest-
Benzaldehyde, (S)-4-(4-Aminobenzyl-2-oxazolidone,-
ingly, we have noted that the limit of detection (LOD)
and limit of quantitation (LOQ) for the respective
metal cations are closer to the reported permissible
limit of World Health Organization (WHO, 2011),
which in other words reflects the novelty of the work.
chloro acetic acid, n-propyl amine, n-butyl amine,
sodium ethoxide, and triethylamine were procured from
Sigma-Aldrich and TCI, Japan and were used as received,
without further purification. Methanol, diethylether, dic-
hloromethane solvents were used after drying by
[
49]

BARUAH ET AL.
11
standard procedure. Reported literature procedure was
used for the synthesis of the Imines. Carry 630 FT-IR
spectrophotometer was used to record the Infrared
bottom flask, followed by addition of equimolar amount
of benzaldehyde at room temperature for 5 minutes.
After formation of the crystal it was extracted with dic-
hloromethane (3 × 10.0 mL) and further purified by pass-
ing through a small column using 10% Ethyl acetate
solution in hexane as the eluent.
(IR) spectra and expressed as νmax/cm. Bruker AvIII HD-
4
00 MHz FTNMR spectrometer was used for the nuclear
magnetic resonance (NMR) spectra using tetra-
methylsilane (TMS) as internal standard. Mass spectral
data were recorded on Waters UPLC- TQD (ESI-MS) and
Triple Quadrupole (LC-MS/MS) mass spectrometer. Ele-
mental analysis was performed in Thermo finnigan
FLASH EA 1112 CHN/CHNS/O analyser and Perkin
Elmer PR 2400 series II elemental analyser.
10.5 | Synthesis procedure of 2-((S)-
4-((E)-4-(benzylideneamino) benzyl)-
2-oxooxazolidin-3-yl) acetic acid (6)
Compound 5 was dissolved in 3 mL of methanol taken in
a 50.0 mL round bottom flask followed by addition of
equimolar amount of chloroacetic acid. Sodium ethoxide
1
0.2 | Antimicrobial study
(
20 mg, 3 mmol) was used as a base in the reaction mix-
ꢀ
The Mueller Hinton agar plates were inoculated with
.0 mL of inoculum by spreading the swab over the plate.
ture and the mixture was stirred at 40 C for 24 hours.
2
Progress of the reaction was monitored with thin layer
chromatography. Product of the reaction was extracted
with diethyl ether (3 × 10 mL) and was dried using anhy-
drous sodium sulphite. Finally, solvent was removed
under reduced pressure to obtain the product.
With the help of sterile borer, wells of 8 mm diameter
were cut on the agar plates and loaded with sample solu-
tion of different concentrations. Tetracycline of 1 mg/mL,
concentration was used as a control antibacterial agent.
All plates were incubated at 37 C for 24 hours. After
ꢀ
incubation period, the inhibition diameters were mea-
[51]
sured with Hi-Media scale.
10.6 | Synthesis procedure for (S)-4-((E)-
4
2
-(benzylideneamino) benzyl) oxazolidin-
-one based azeditinone(7-10)
1
0.3 | General procedure for synthesis of
imines
Compound 6(2.0 mmol) was dissolved in 3 mL of metha-
nol taken in a 250.0 mL round bottom flask followed by
Synthesis of imines (1-4) was performed using literature
procedure. Aromatic aldehyde (2.0 mmol) was dissolved
in 1.0 mL methanol in a test tube. An equimolar amount
of amine was dissolved separately in another test tube
containing 1.0 mL of 0.018 M H SO acid solution. The
addition of thionyl chloride (2.5 mmol). The reaction
mixture was stirred at 40 for 1 hour. Then equimolar
amount of imine (compounds 1-4) was added.
ꢀ
Triethylamine was used as a base for the reaction. The
ꢀ
reaction mixture was again stirred for 4 hours at 40 . Pro-
2
4
solutions were then mixed properly in a 25.0 mL round
gress of the reaction was monitored with thin layer chro-
matography. Product of the reaction was extracted with
diethyl ether (3 × 10 mL) and was dried using anhydrous
sodium sulphite. Finally, solvent was removed under
bottom flask. The reaction mixture was then transferred
ꢀ
into a microwave oven maintained at 40 C. The reaction
was allowed to continue for 15 minutes under microwave
irradiation. Product of the reaction was extracted with
dichloromethane (2 × 10.0 mL). The solvent was
removed under reduced pressure to obtain the product.
Products were further purified by passing through a small
column using 10% Ethyl acetate solution in hexane as the
[
53]
reduced pressure to obtain the product.
0
10.7 | Analytical data for 2,4 -
dichlorobenzyliminepropane (1)
[52]
eluent.
Yield: 78%. IR (νmax/cm): 3089(C─H),1578(CH═N),
1
1
461,1386, 1032,915, 831, 713, 553. H NMR
1
4
2
0.4 | Synthesis procedure of (S)-4-((E)-
-(benzylideneamino) benzyl) oxazolidin-
-one (5)
(CDCl ,400 MHz),δ: 8.23(s, 1H, 1CH imine), 7.23
3
7.34 7.45(m, 3H, 3 CH arom), 3.53(t, 2H, 1CH ),
2
1
3
1
1.74(m,2H,1CH ),.96(t, 3H, 1CH ). C{ H} NMR
2
3
(
CDCl , 400 MHz),δ:158.00(CH═N),130.56127.11129.5
3
(S)-4-Aminobenzyl-2-oxazolidone (2.0 mmol) was dis-
(aromatic),134.38133.01(C─Cl),63.43(─CH ─N), 23.94
2
solved in 3 mL of methanol taken in a 50.0 mL round
(─CH2), 11.82(─CH3). Mass-216(M), 218(M + 2).

12
BARUAH ET AL.
Elemental Anal. Calcd. for C H NCl - C-55.56, H-
136.15, 131.11, 129.90, 128.98, 125.52,69.75,52.19, 45.01.
Mass − 194.1 (C14 H12 N). Elemental analysis for
C H N O Calculated., C- 72.84, H- 5.75, N-9.99, Found
1
0
11
2
5
.09, N-6.48%. Found-C54.94, H-5.23, N-6.56%.
17
16 2 2
C- 72.00, H-5.33, N- 9.11%.
0
10.8 | Analytical data for 3,4 -
dimethoxybenzyliminepropane (2)
1
0.12 | Analytical data for 2-((S)-4-((E)-
Yield: 79.5%.IR (νmax/cm): 3175(C─H), 2951, 28 34, 1585
4-(benzylideneamino)benzy- l)-
2-oxooxazolidin-3-yl) acetic acid (6)
1
(
(
CH═N), 1280, 1152, 1014, 738, 532. HNMR
400 MHz,CD Cl ), δ: 8.22(s,1H, CH imine), 3.59(d, 6H,
3
2
3
OCH ), 4.00 (t, 2 H, 1 CH ),1.35(m, 2H, 1CH ), .96 (t,
Yield: 65%.IR (νmax/cm): 3350(OH), 1705, 1640, 1578
(CH═N), 1500, 1430, 1400, 1360, 1260, 1020, 905. H
3
2
2
13
1
1
H, 1CH ). C { H} NMR (CDCl , 400 MHz), δ: 160.02
3
3
(
1
CH═N), 129.72, 126.37, 122. 53, 62.98, 55.74, 23.79, 23.75,
1.51, 11.4. Mass-208(M + 1), 209(M + 2). Elemental
Anal. Calcd. for C H NO C- 69.56, H- 8.21, N-6.76%.
NMR (CDCl , 400 MHz),δ: 11.0(-OH), 8.08(CH=N), 7.62,
7.4, 7.3, 7.2, 7.1 (Aro matic), 4. 53, 4.42, 4.19, 3.97, 2.87,
3
13
1
2.64.
(C═O),160.7, 157.6, 143.9143.7, 134.4, 133.6, 130.23,
29.12, 128.5, 128.4, 77.5, 69.8, 54.3, 41.6, 40.5. Mass
340.4(M + 2). Elemental analysis for C19H18N2O4
C
{ H} NMR (CDCl3, 400 MHz),δ:170.9
12
17
2
Found-C-69.2, H-8.93, N-6.46%.
1
−
0
1
0.9 | Analytical data for 3, 4 -
Calculated, C- 67.44, H- 5.36, N-8.28, Found C- 66.96,
H- 5.22, N- 8, 32.
dichlorobenzyliminepropane (3)
Yield:81%. IR(νmax/cm):3089(C─H),1578 (CH═N), 1461,
1
1
386, 1035, 918, 833, 717, 557. H NMR (CDCl , 400 MHz)
10.13 | Analytical data for (S)-4-((E)-
4-(benzylideneamino) benzyl)-3-(2-[2,4 -
dichlorophenyl]-4-oxo-1-propylazetidin-
3-yl) oxazolidin-2-one (7)
3
0
δ = 8.25(s,1H,1CH imine), 7.22, 7.36, 7.44(m,3H,3 CH
arom), 3.5(t, 2H, 1CH ), 1.72(m, 2H, 1CH ), .96(t,-
H,1CH ) C { H} NMR (CDCl ,400 MHz),δ:158.19
CH═N),130.56134.38133.01,129.58, 127.11, 63.43, 23.94,
1.88. Mass-216(M), 218(M + 2). Elemental Anal. Calcd. for
C H NCl - C-55.56, H- 5.09, N-6.48%. Found-C-54.94,
2
2
13
1
3
(
1
3
3
Yield: 68%. IR (νmax/cm): 1710(C═O), 1700, 1600, 1587
1
(C═N), 1450, 1400, 1250, 1200, 1100, 1050. H NMR
10
11
2
H-5.23, N-6.56%.
(CDCl , 400 MHz), δ: 8.49(CH, imine), 7.57, 7.29, 7.23,
3
7.21 (Aromatic CH) 5.32, 4.83, 4.43 (s, 1H, 1CH,
azetidinone), 3.62(s, 1H, 1CH, azetidinone), 3.31
1
3
1
1
0.10 | Analytical data for benzylidene-
(t,2H,1CH ), 1.7(m,2H,1CH ), .98 (t,3H,1CH ). C{ H}
2 2 3
phenyl-amine (4)
NMR (CDCl , 400 MHz), δ:168.32 (C═O, azetidinone),
59.00(C═O, oxazolidinone), 156.94(C═N, imine),
3
1
Yield: 82.5%. IR (νmax/cm): 2685, 2538, 1588
138.40, 130.76, 130.60, 129.10, 128.96, 122.61, 70.81,
64.39, 49.58, 49.37, 48.94, 22.09, 12.14. Mass.
C H Cl N O 523.0(C H Cl N O ). Elemental analy-
1
(
CH═N),1280, 11 75, 850. H NMR (CDCl , 400 MHz),
3
13
δ:8.5(s, 1H, 1CH), 6.7, 7.3, 8.4(m, 10H, 10 CH arom). C
29
27
2
2
3,
28 25
2 3 3
1
{
H} NMR (CDCl , 400 MHz), δ: 160.65(CH═N), 131.42,
sis for C H Cl N O Calculated, C- 64.93, H- 5.07,
29 27 2 3 3
3
1
1
8
29.17, 128.77, 128.39, 127.81, 120.97, Mass-181(M + 1),
N-7.83, Found C- 65.16, H- 5.02, N- 7.77.
82(M + 2). Elemental Anal. Calcd. for C H N - C-
13
11
6.19, H-6.08, N-7.73. Found-C-86.34, H-6.19, N-7.52%.
1
4
0.14 | Analytical data for (S)-4-((E)-
-(benzylideneamino) benzyl)-3-(1-butyl-
0
10.11 | Analytical data for (S)-4-((E)-
4-(benzylideneamino) benzyl) oxazolidin-
2-one (5)
2-[3,4 -dimethoxyphenyl]-4-oxoazetidin-
3-yl) oxazolidin-2-one (8)
Yield: 67%. IR (νmax/cm): 2958 (─OCH ), 2610, 2500,
3
Yield: 77.5%.IR(νmax/cm): 3240, 1740, 1680(C = 0),1578
1740, 17 25(C = 0), 1578(C=N), 1475, 1428, 1410, 1155,
1
1
(
CH═N), 1410, 1300,1180, 1080, 924. HNMR (CDCl ,
1018. HNMR (CD Cl , 400 MHz) δ: 8.26(CH═N), 7.50,
3
3
4
00 MHz),δ: 8.43(CH═N), 8.06(NH),7.62,7.29, 7.21,7.12
7.50, 7.29, 7.12 (Aromatic CH), 5.31, 5.12, 4.48 (s, 1H,
13
(Aromaic) 4.58, 4.45,4.17,2.89,2.70. C NMR (CDCl3,
1CH, azetidinone), 3.98(s, 1CH, azetidinone), 3.22(t,
1
3
4
00 MHz), δ: 160.75(C═N) 160.09(C═O), 151.15(C─N),
2H,1CH ),1.78(m, 2H, 1CH ), .95(t, 3H, 1CH ). CNMR
2 2 3

BARUAH ET AL.
1
13
{
H}(CDCl ,400 MHz),δ:168.32(C═O,azetidinone),160.19
ORCID
3
(
1
5
C═O,Oxazolidinone),154.46(C═N,
imine),
30.77, 130.0, 126.82, 110.45, 108.95, 77.65, 77.23, 76.80,
6.16, 55.95, 46.07, 22.79, 8.71. Mass-526.7(M-OCH ). Ele-
149.53,
Amrit Puzari https://orcid.org/0000-0001-9485-6237
REFERENCES
3
mental analysis for C H N O Calculated, C- 70.57,
H- 6.30, N-7.96, Found C- 71.11, H- 6.12, N- 7.82.
[1] R. W. Scott, W. F. De Grado, G. N. Tew, Curr. Opin. Biotechnol.
2018, 19, 620.
31
33 3 5
[2] G. N. Tew, R. W. Scott, M. L. Klein, W. F. Degrado, Acc. Chem.
Res. 2010, 43, 30.
[
3] C. L. Friedrich, D. Moyles, T. J. Beveridge, R. E. Hancock,
Antimicrob. Agents. Chemother. 2000, 44, 2086.
1
4
0.15 | Analytical data for (S)-4-((E)-
-(benzylideneamino) benzyl)-3-(2-[3,4 -
0
[
[
[
4] R. E. Hancock, H. G. Sahl, Nat. Biotechnol. 2006, 24, 155.
5] P. Méndez-Samperio, Peptides. 2008, 29, 155.
6] B. M. Peters, M. E. Shirtliff, M. A. Jabra-Rizk, PLoS. Pathog.
dichlorophenyl]-4-oxo-1-propylazetidin-
-yl) oxazolidin-2-one (9)
3
2010, 6, 1001.
Yield: 66.5%. IR (νmax/cm): 2980, 2960, 2610, 2500,
[7] A. J. Karlsson, W. C. Pomerantz, B. Weisblum, S. H. Gellman,
S. P. Palecek, J. Am, Chem. Soc., 2006, 128, 12630.
[8] R. Kapoor, P. R. Eimerman, J. W. Hardy, J. D. Cirillo,
C. H. Contag, A. E. Barron, Antimicrob. Agent. Chemother.
1
1
8
7
740, 1710(C═O), 1575(C═N), 1470, 1430, 1400, 1170,
1
020. H NMR (CDCl , 400 MHz) δ = 8.39(C═N), 8.11,
3
.05, 8.02, 7.97, 7.77, 7.74, 7.67, 7.64, 7.57, 7.55, 7.53,
.50, 7.45, 7.43, 7.06 7.02 (Aromatic-CH),4.71,4.61,
2011, 55, 3058.
[9] Y. Niu, Y. Hu, H. Wu, J. Cai, J. Mol. Biol. 2013, 35, 1081.
(
s,1H,1CH, azetidinone),3.92(s,1H,1CH, azetidinone),
[
10] P. Claudon, A. Violette, K. Lamour, Angew. Chem. Int.
3
9
.44, 3.38, 3.16 (t,2H,1CH ), 1.81(m, 2H,1 C H ),
2 2
Ed. Engl. 2010, 49, 333.
[11] W. Guijun, AntiInfective. Agents. 2008, 7, 32.
1
3
1
6(t,3H,1CH ). CNMR{ H}(CDCl ,400 MHz),δ:167.22
3
3
[
12] A. C. L. Leite, R. F. Vieira, A. R. Faria, A. G. Wanderley,
P. Afiatpour, E. Camelo, P. A. Ximenes, R. M. Srivastava,
C. F. Oliveira, M. V. Medeiros, E. Antunes, D. J. Brondani,
Farmaco. 2000, 55, 719.
13] H. Wenker, J.Am. Chem. Soc. 1935, 57, 1079.
14] J. Ilaš, P. S. Anderluh, M. S. Dolenc, D. Kikelj, Tetrahedron.
(
(
7
(
C═O, azetidinone),160.20(C═O, oxazolidinone),157.84
C═N, imine),137.30, 131.66, 130.42, 129.32128.50, 77.66,
7.23, 76.81, 46.19, 39.76, 29.22, 19.83, 13.45. Mass 536.15
M + 1). Elemental analysis for C H Cl N O Calculated,
29
27
2 3 3
[
[
C- 64.93, H- 5.07, N-7.83, Found C- 64.89, H- 5.00, N-7.72.
2005, 61, 7325.
[15] M. R. Barbachyn, C. W. Ford, Angew. Chem. Int. E. 2003, 42, 2010.
1
0.16 | Analytical data for (S)-4-((E)-
-(benzylideneamino) benzyl)-3-(2-oxo-1,4 -
[16] S. J. Brickner, Curr. Pharm. Des. 1996, 2, 175.
0
[
17] M. B. Gravestock, Curr. Opin. Drug. Discov. Devel. 2005, 8, 469.
18] A. R. Renslo, G. W. Luehr, M. F. Gordeev, Bioorg. Med. Chem.
Lett. 2006, 14, 4227.
4
[
diphenylazetidin-3-yl) oxazolidin-2-one (10)
[
[
19] E. Wong, S. Rab, P. T. 2014, 39, 555.
20] P. Koomanachai, J. L. C. JL, D. P. Nicolau, Expert. Opin.
Pharmacother. 2009, 10, 2829.
Yield: 68%.IR (νmax/cm): 2990, 2940, 2600, 2500, 1740,
1
8
7
710(C = 0), 1578(C═N), 1495, 1400, 1180, 1020,
1
40, 810. H NMR(CDCl ,400 MHz), δ: 8.06(C═N), 7.65,
3
[21] B. E. Murray, Agents. Chemother. 1992, 36, 2355.
[22] P. C. Applebaum, Eur. J. Clin. Microbiol. 1987, 6, 367.
[23] A. M. Slee, M. A. Wuonola, R. J. McRipley, I. Zajac,
M. J. Zawada, P. T. Bartholomew, W. A. Gregory, M. Forbes,
Antimicrob. Agents. Chemother. 1987, 31, 1791.
.45, 7.44, 7.43, 7.42, 7.41,7.40 (Aromatic CH), 4.55, 4.13
(
s, 1H, 1CH, azetidinone), 3.92 (s, 1H, 1CH,
13
1
azetidinone). CNMR{ H}(CDCl ,400 MHz),δ:168.79
3
(
(
C═O, azetidinone),160.12 (C═O, oxazolidinone),157.32
C═N, imine),133.05, 130.96, 130.40, 129.97, 129.66,
[
[
24] A. L. Barry, Antimicrob. Agents. Chemother. 1988, 32, 150.
25] K. Michalska, I. Karpiuk, M. Król, S. Tyski, Bioorg. Med. Chem.
1
29.09, 128.53, 128.37, 127.00, 123.93, 77.65, 77.43, 77.23,
2012, 21, 577.
7
6.80, 46.1. Mass-500.8(M). Elemental analysis for
[
26] G. W. B. GW, W. J. Langston, Environ. Pollut. 1962, 76, 89.
C H Cl N O Calculated, C- 76.63, H- 5.43, N-8.38,
[27] J. B. Willis, Anal. Chem. 1962, 34, 614.
29
27
2 3 3
Found C- 77.69, H- 5.21, N- 8.44.
[28] L. A. Hutton, G. D. O. Neil, T. L. Read, Z. J. Ayres,
M. E. Newton, J. V. Macpherson, Anal. Chem. 2014, 86,
4
566.
29] S. Li, C. Zhang, S. Wang, Q. Liu, H. Feng, X. Ma, Analyst.
018, 143, 4230.
ACKNOWLEDGEMENTS
[
[
Authors gracefully acknowledge Department of Science and
Technology, Government of India for the financial assistance
received under the DST-RFBR collaborative project grant
with the project ID: INT/RUS/RFBR/P-221. Authors also
sincerely acknowledge Dr. Soumya Chattergee, Head of
the bio-degradation Division, Defence Research Labo-
ratory, Tezpur, for the antibacterial study.
2
30] B. V. Bonifácio, D. S. P. Bento, R. M. A. Santos,
N. K. M. Silveira, T. M. Bauab, M. Chorilli, Int.
J. Nanomedicine. 2014, 9, 1.
[31] M. Mon, R. Bruno, J. F. Soria, D. Armentano, E. Pardo,
J. Mater. Chem. A. 2018, 6, 4912.
32] R. J. F. RJ, Y. Tor, Per. Med. Chem. 2014, 6, 25.
[

14
BARUAH ET AL.
[
[
[
33] B. K. Hordern, Chem. Soc. Rev. 2010, 39, 4466.
[48] R. G. Pearson, J. Chem. Ed. 1987, 64, 561.
[49] World Health Organization, Guidelines for drinking-water
quality, 4th ed., Geneva, 2011.
[50] J. Frelek, M. Górecki, M. Laszcz, A. Suszczy nꢀ ska, E. Vass,
W. J. Szczepek, Chem. Commun. 2012, 28, 5295.
[51] S. G. Davies, P. M. Roberts, J. E. Thomson, A. M. Fletcher,
Org. Biomol. Chem. 2018, 17, 1322.
[52] S. Baruah, A. Fiyuk, I. Kulakov, A. Puzari, Asian. J. Chem. 2017,
2, 13.
34] G. L. Furtado, A. A. Medeiros, J. Clin. Microbiol. 1980, 12, 550.
35] M. J. Cheesman, A. Ilanko, B. Blonk, I. E. Cock, J. Pharmacogn.
Rev. 2017, 11, 57.
36] M. D. Lebar, J. M. May, A. J. Meeske, S. A. Leiman,
T. J. Lupoli, H. Tsukamoto, R. Losick, D. Z. Rudner,
S. Walker, D. Kahne, J. Am. Chem. Soc. 2014, 136, 10874.
37] S. Yadav, N. A. Trivedi, J. D. Bhatt, Ayu. 2015, 36, 203.
38] C. V. Nakamura, T. Ueda-Nakamura, E. Bando,
A. F. Melo, D. A. Cortez, B. P. Filho, Inst. Oswaldo. Cruz.
[
[
[
[53] S. Baruah, F. Sultana, J. Barman, A. Puzari, Anti- Infective
Agents. 2018, 16, 104.
1
999, 94, 675.
39] S. Alyar, N. Karacan, J. Enzyme. Inhib. Med. Chem. 2009,
4, 986.
40] T. H. Grossman, Cold. Spring. Harb. Perspect. Med. 2016, 6,
25387.
41] A. Brandi, S. Cicchi, F. M. Cordero, Chem. Rev. 2018, 108,
988.
[
[
[
2
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
0
3
[
[
42] K. P. Carter, A. M. Young, A. E. Palmer, Chem. Rev. 2014, 114, 4564.
43] N. A. Villegas, A. A. Morales, R. A. Posada, Perfusion Fluids
J. Pharm. Sci. 1983, 72, 1221.
44] J.F. Chen, Q. Lin, Y.M. Zhang, H. Yao, T.B. Wei, Chem.
Commun.. 2017, 53, 13296-13311.
45] X. M. Li, R. R. Zhao, Y. Yang, X. W. Lv, Y. L. Wei, R. Tan,
J. F. Zhang, Y. Zhou, Chin.Chem. Lett. 2017, 28, 1258.
46] M. Kumar, A. Puri, Ind. J. Occup. Environ. Med. 2012, 16, 40.
47] N. Özbek, G. Kavak, Y. Özcan, S. Ide, S. S. Karacan, J. Mol.
Struct. 2009, 919, 154.
How to cite this article: Baruah S, Aier M,
Puzari A. (S)-4-(4-aminobenzyl)-2-oxazolidinone
based 2-azetidinones for antimicrobial application
and luminescent sensing of divalent metal cations.
J Heterocyclic Chem. 2020;1–14. https://doi.org/10.
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1002/jhet.3965