Theoretical calculations and experimental verification of the antibacterial potential of some monocyclic β-lactams containing two synergetic buried antibacterial pharmacophore sites

Article abstract of DOI:10.1080/10426500903095556

A new series of N-thiazole, 3-phenyl, 4-substituted phenyl azetidine-2-ones 4(a-h) have been synthesized in good yields starting from 2-aminothiazole 1. In the first step, then Schiff's bases 3(a-h) are prepared by the condensation of 2-aminothiazole 1 with different aryl aldehydes 2(a-h). Finally, monocyclic β-lactams, i.e. substituted azetidinones 4(a-h), were the products formed using three different methods by the dehydrative cyclocondensation of 3(a-h) with phenyl acetyl chloride in dioxane, phenyl acetic acid-thionyl chloride in dichloromethane and phenyl acetic acid-phosphorus oxychloride in dichloromethane in the presence of triethylamine. We found that latter method is the best as compared with the former two methods. The synthesized molecules 4(a-h) were screened for their antibacterial activity against four microorganisms: Staphylococcus aureus (Gram positive), Pseudomonas vulgaris (Gram positive), Pseudomonas aeruginosa (Gram negative), and Escherichia coli (Gram negative). Their antibacterial activities are reported, and on the basis of the screening data available, attempt is also made to elucidate the structure-activity relationship. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

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Theoretical Calculations and
Experimental Verification of the
Antibacterial Potential of Some
Monocyclic β-Lactams Containing
Two Synergetic Buried Antibacterial
Pharmacophore Sites
Ali Parvez a , Meshram Jyotsna a , Moulay Hfid Youssoufi b & Taibi
Ben Hadda b
a Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur
University, Nagpur, India
b Laboratoire de Chimie des Matériaux, Faculté des Sciences,
Université Mohammed Premier, Oujda, Morocco
Version of record first published: 02 Jul 2010.
To cite this article: Ali Parvez , Meshram Jyotsna , Moulay Hfid Youssoufi & Taibi Ben Hadda
(2010): Theoretical Calculations and Experimental Verification of the Antibacterial Potential of
Some Monocyclic β-Lactams Containing Two Synergetic Buried Antibacterial Pharmacophore Sites,
Phosphorus, Sulfur, and Silicon and the Related Elements, 185:7, 1500-1510
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Phosphorus, Sulfur, and Silicon, 185:1500–1510, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903095556
THEORETICAL CALCULATIONS AND EXPERIMENTAL
VERIFICATION OF THE ANTIBACTERIAL POTENTIAL
OF SOME MONOCYCLIC β-LACTAMS CONTAINING
TWO SYNERGETIC BURIED ANTIBACTERIAL
PHARMACOPHORE SITES
Ali Parvez,1 Meshram Jyotsna,1 Moulay Hfid Youssoufi,2
and Taibi Ben Hadda2
1Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University,
Nagpur, India
2Laboratoire de Chimie des Mate´riaux, Faculte´ des Sciences, Universite´
Mohammed Premier, Oujda, Morocco
A new series of N-thiazole, 3-phenyl, 4-substituted phenyl azetidine-2-ones 4(a–h) have been
synthesized in good yields starting from 2-aminothiazole 1. In the first step, then Schiff’s bases
3(a–h) are prepared by the condensation of 2-aminothiazole 1 with different aryl aldehydes
2(a–h). Finally, monocyclic β-lactams, i.e. substituted azetidinones 4(a–h), were the products
formed using three different methods by the dehydrative cyclocondensation of 3(a–h) with
phenyl acetyl chloride in dioxane, phenyl acetic acid–thionyl chloride in dichloromethane
and phenyl acetic acid–phosphorus oxychloride in dichloromethane in the presence of tri-
ethylamine. We found that latter method is the best as compared with the former two methods.
The synthesized molecules 4(a–h) were screened for their antibacterial activity against four
microorganisms: Staphylococcus aureus (Gram positive), Pseudomonas vulgaris (Gram
positive), Pseudomonas aeruginosa (Gram negative), and Escherichia coli (Gram negative).
Their antibacterial activities are reported, and on the basis of the screening data available,
attempt is also made to elucidate the structure–activity relationship.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Antibacterial; β-lactams; Petra/Osiris/Molinspiration (POM) model; SAR; Schiff’s
bases; virtual screening
Received 21 March 2009; accepted 3 June 2009.
This work is dedicated to Prof. Dr. Johann Gasteiger for his bioinformatic multiple services.
Financial support from University Grants Commission, New Delhi, is highly acknowledged. We are grateful
to HEJ Research Institute of Chemistry, University of Karachi, for the help in undertaking NMR spectra and
biological assay. Prof. T. Ben Hadda would like to thank ACTELION, the Biopharmaceutical Company of
Switzerland, and in particular Dr. Johann Gasteiger for the on-line molecular properties calculations and precious
and continuous help and discussion.
Address correspondence to Ali Parvez, Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur
University, Nagpur 440033, India. E-mail: parvezali 81@yahoo.com
1500

ANTIBACTERIAL POTENTIAL OF SOME MONOCYCLIC β-LACTAMS
1501
INTRODUCTION
β-Lactam antibiotics are the most widely used antibiotics in chemotherapy.1 Even
more than 70 years after the discovery of penicillin, β-lactam antibiotics remain as one of
the most targeted contributions of science to humans.1 The first member of this class of
compounds was synthesized by Staudinger in 1907.2 But the importance of β-lactams as
antibiotics was not recognized until the discovery of penicillin by Fleming in 1929.3 An
alarming increase in bacterial resistance to β-lactam antibiotics has pushed pharmaceuti-
cal companies to seek new β-lactam antibiotics.4 Consequently, because of the growing
resistance of bacteria towards β-lactam antibiotics and the need for medicines with a more
specific antibacterial activity, several synthetic and semi-synthetic β-lactam antibiotics have
been developed by the pharmaceutical industry all over the globe.5
Heterocyclic compounds having four-membered heterocyclic ring nucleus with
nitrogen as the heteroatom are generally designated as 2-azetidinone, monobactam,
or, more commonly, β-lactam.6 β-Lactam antibiotics include penicillin, cephalosporin,
cephamycins, carbapenems, nocardicins, monobactams, and beta lactamase inhibitors of
which activity is related to the presence of 2-azetidinone nucleus in the system. Monobac-
tams are monocyclic β-lactam antibiotics, which have been isolated from Gram-negative
bacteria. These compounds show significant antibacterial activity and bind to essential
penicillin-binding proteins (Figures 1 and 2) of susceptible organisms.7 In addition to the
monobactams and nocardicins, some other monocyclic β-lactams, such as functionalized
beta-lactams compounds, have also shown good antibacterial activity.8–10 Thus, contrary to
nocardicins,11 monobactams have biological properties similar to those of bicyclic β-lactam
antibiotics.
Pharmacologically, thiazoles are among the most important classes of organic com-
pounds. These compounds possess versatile types of biological activities; some of these are
well known for their anti-inflammatory activities such as fentiazac and meloxicam, while
compounds like nizatidine possess anti-ulcer activity.12 Some of 2-aminothiazoline deriva-
tives are known for their inhibition of kinurenine-3-hydroxylase,13 and cyclin-dependent
kinase enzymes.14 Thus thiazole derivatives play a vital role in medicinal chemistry.
All these findings led us to develop azetidinones with an N-substituted thiazole moi-
ety. The system of conversion of Schiff’s bases to azetidinones using phenyl acetylchloride
was previously reported.15,16
In continuation of our work on bioactive β-lactams, we describe here a general
synthesis of new β-lactams bearing thiazole moiety (Scheme 1).
Figure 1 3-D structure of protein.

1502
A. PARVEZ ET AL.
Figure 2 Section of a protein structure linked together by peptide bonds.
RESULTS AND DISCUSSION
Synthesis
The Schiff’s bases 3(a–h) were prepared by general method by refluxing 2-amino
thiazole with different aromatic aldehydes. Dehydrative cyclocondensation of Schiff’s
bases with phenylacetyl chloride and in situ prepared phenyl acetyl chloride in the presence
of triethylamine, respectively, afforded azetidinones by different methods as shown in
Scheme 1.
N
R
S
N
4(a-h)
O
PhCH2COCl Et3N
Method A
Dioxane,
12h,RT.
N
R
N
R
N
S
S
N
R
Ethanol
PhCH2COH
CH2Cl2,
+
NH2
O
N
CH
Reflux, 1 hr.
O
S
H
12h,RT.
Et3N,
3(a-h)
(1)
2(a-h)
4(a-h)
Method C
SOCl2
Et3N
12h,RT.
PhCH2COH
CH2Cl2,
Method B
Where e-h are:
Where a-d are:
O2N
CH3
f.
e.
OH
O
N
O
CH3
a.
c.
b.
R
S
N
g.
h.
O
d.
O
HO
CH3
O
NO2
4(a-h)
Scheme 1 Synthesis of mono cyclic β-lactams 4(a–h).

ANTIBACTERIAL POTENTIAL OF SOME MONOCYCLIC β-LACTAMS
1503
The 2-azetidinones 4(a–h) have been synthesized in three different ways, first by
the cyclocondensation of phenylacetyl chloride and Schiff’s bases 3(a–h) in the presence
of triethylamine in dioxane stirred for overnight at room temperature (Method A). The
same products were also synthesized by stirring a mixture of phenylacetic acid, Schiff’s
bases 3(a–h), triethylamine, and thionyl chloride in benzene overnight at room temperature
(Method B). Finally, the same were prepared by dehydrative cyclocondensation of pheny-
lacetic acid, Schiff’s bases 3(a–h), triethylamine, and phosphorus oxychloride overnight at
room temperature (Method C). The yield of the products with Methods A, B, and C was
found to be around 60–65%, 40–50%, and 70–80%, respectively. The authenticity of the
products prepared by all the methods was established by TLC, mp, elemental analysis, 1H
NMR, mass spectrometry, and IR spectroscopy.
1
The selected H NMR data and assignments of the compounds are presented in
Table I. The 1H NMR spectra of the Schiff’s base 3(a–h) in DMSO-d6 at room temperature
using TMS as an internal standard showed the following signals: CH N at 9.6 ppm
(s, 1H), phenyl at 7.0–7.2 ppm as multiplet, OH at 5.0 ppm (s, 1H) and OCH3 at 3.7
ppm, (s, 3H). The 1H NMR spectra of the compounds 4(a–h) showed the following signals:
phenyl as multiplet 7.0–7.2 ppm, OH at 5.0 ppm (s, 1H) and OCH3 at 3.7 (s, 3H). The
absence of a signal for CH N in all the compounds showed that cyclocondensation
was achieved. The 1H NMR showed a cis orientation of the C-3 and C-4 protons of the 2-
azetidinone ring in 4, viz. each proton at C-3 and C-4 appeared as doublet with the coupling
Table I Selected IR and 1H NMR data of compounds 4(a–h)
1H NMR (400 MHz, DMSO-d6) δ ppm & J Hz
IR (KBr) υ cm−1
β-Lactam–
(d,1H,CH,
thiazole)
(d,1H,CH,
thiazole)
Compound
CO
Aromatic H
(d,1H,CH)
(d,1H,CH)
4a
1740
1680
1685
1720
1710
1690
1695
1715
7.54
(d,1H,CH)
J = 3.54 Hz
7.54
(d,1H,CH)
J = 3.54 Hz
7.54
(d,1H,CH)
J = 3.54 Hz
7.54
(d,1H,CH)
J = 3.54 Hz
7.54
(d,1H,CH)
J = 3.54 Hz
7.54
(d,1H,CH)
J = 3.54 Hz
7.54
(1H, d, CH)
J = 3.54 Hz
7.54; 7.23; 7.15
3x(d,1H,CH)
J = 3.54 Hz
7.01–7.26
(10H,m,Arom)
6.52
(d,1H,CH)
5.18
(d,1H,CH)
4.27
(d,1H,CH)
J = 3.54 Hz J = 4.58 Hz J = 5.04 Hz
4b
4c
4d
4e
4f
7.01–7.26
(9H,m,Arom)
6.52
5.18
(d,1H,CH)
4.27
(d,1H,CH)
(d,1H,CH)
J = 3.54 Hz J = 4.58 Hz J = 5.26 Hz
7.01–7.26
(m,10H,Arom)
6.52
5.18
(d,1H,CH)
4.27
(d,1H,CH)
(d,1H,CH)
J = 3.54 Hz J = 4.58 Hz J = 5.26 Hz
7.01–7.26
(m,10H,Arom)
6.52
5.18
(d,1H,CH)
4.27
(d,1H,CH)
(d,1H,CH)
J = 3.54 Hz J = 4.58 Hz J = 5.26 Hz
7.01–7.26
(m,10H,Arom)
6.52
5.18
(d,1H,CH)
4.27
(d,1H,CH)
(d,1H,CH)
J = 3.54 Hz J = 4.58 Hz J = 5.26 Hz
7.01–7.26
(m,10H,Arom)
6.52
5.18
(d,1H,CH)
4.27
(d,1H,CH)
(d,1H,CH)
J = 3.54 Hz J = 4.58 Hz J = 5.26 Hz
4g
4h
7.01–7.26
(m,10H,Arom)
6.52
5.18
(d,1H,CH)
4.27
(d,1H,CH)
(d,1H,CH)
J = 3.54 Hz J = 4.58 Hz J = 5.26 Hz
7.01–7.26
6.52 & 6.14
5.18
4.27
(d,1H,CH)
(m,10H,Arom) 2x(d,1H,CH) (d,1H,CH)
J = 3.54 Hz J = 4.58 Hz J = 5.26 Hz

1504
A. PARVEZ ET AL.
constant of 4.5 to 5.2 Hz needed for cis stereochemistry. There was no appreciable change
in all the other signals of the compounds.
The IR spectrum of compounds 3(a–h) indicates the presence of (-C = N) azomethine
linkage peaks around 1620–1630 cm−1. The absence of azomethine linkage peaks and the
presence of β- lactam, C = O peaks around 1680–1740 cm−1 showed the achievement of
cyclocondensation in compounds 4(a–h).
Antibacterial Activity
The antibacterial activity of the series 4(a–h) been carried out against some strains of
bacteria. To determine the antibacterial activity of these agents, the Agar cup plate method
was used, with ampicillin and streptomycin as the reference antibiotics.17 The prepared
compounds were examined against two strains each of Gram positive and Gram negative
bacteria. The test results, presented in Table S1 (available online in the Supplemental
Materials), suggests that compounds 4g and 4h are highly active against two strains each of
Gram positive and Gram negative bacteria, showing the broadest spectrum of antibacterial
activity. The rest of the compounds were found to be moderately active, slightly active, or
inactive against the tested microorganisms. The results show that the prepared compounds
are toxic against the bacteria.
STRUCTURE–ACTIVITY RELATIONSHIP
A perusal of antibacterial screening data indicates that all the compounds under
investigation were moderately active to the test bacteria.
The structure of synthesized azetidinones 4(a–h) for ease of analysis can be divided
into four parts: azetidinone skeleton, thiazole side chain at N-1 of azetidinone skeleton,
phenyl ring at C-3, and substituted phenyl ring at C-4 of azetidinone skeleton. We have
fixed the former three parts and varied the latter one by attaching the phenyl ring with
several functional groups, such as 2-NO2, 3-NO2, 4-OMe, 3, 4-di-OMe, 2-OH, and 4-OH,
and replacing the phenyl ring by furan one in compound 4h. These modifications in the
azetidinone skeleton followed by the analysis of resulting molecules structure have resulted
in the following findings:
The unsubstituted phenyl ring at C-3 is non-effective against Gram-negative strains
and moderately effective against Gram-positive ones in compound 4a. The introduction of
an electron-withdrawing substituent such as nitro at position 2 and 3 on the C-3 phenyl ring
masked the potency in case of compounds 4b and 4c as compared with 4a.
On the other hand, compounds 4f and 4g had an activity quite comparable to the
commercial antibiotics (ampicillin and streptomycin) tested under similar conditions. This
activity was probably due to the presence of a strong polar substituent -OH at position 2 of
the phenyl ring on the azetidinone moiety as compared to the similar substitution at position
4 in compound 4f, which has shown moderate activity. In both the cases, the oxygen can act
as a hydrogen bond acceptor, and the hydrogen can act as a hydrogen bond donor. One or
all of these interactions may be important in binding the molecules to the binding site. Thus
in both the cases, the hydroxyl group may be involved in some H-bonding, which increases
the affinity of the molecule for the active site of the enzyme. So 2-OH is necessary for high
activity of the compound 4g. Conversion of OH to methyl ether or substitution of 4-OMe
on the ring has reduced the activity as compared to compound 4g. However, substituted
3,4-di-OMe has shown some moderate activity.

ANTIBACTERIAL POTENTIAL OF SOME MONOCYCLIC β-LACTAMS
1505
Further investigation of compound 4g on a wider range of bacteria as well as with
higher dilution is desirable. In compound 4h, there is furan instead of phenyl as a phar-
macophore, i.e. a heterocyclic moiety which can interact through Van der Waals and hy-
drophobic interactions, while the oxygen as a heteroatom can interact by hydrogen bonding
or ionic bonding leading to better potency against the test bacteria. Further investigation
in this case is also desirable. As far as molecular masses of these two compounds 4g and
4h are concerned, both the compounds have masses around 300 Dalton (322 for 4g and
296 for 4h). Optimizing compounds for high activity on a biological target almost often
goes along with increased molecular weights. However, compounds with higher weights
are less likely to be absorbed and therefore to ever reach the place of action and less active.
Although an attempt was made to combine various groups in these molecules with the hope
of achieving compounds of better potency, the results are not very encouraging in all the
cases, except compounds 4g and 4h.
VIRTUAL SCREENINGS AND MOLECULAR PROPERTIES CALCULATIONS
PETRA Calculations
PETRA is a software package comprising various empirical methods for the calcu-
lation of physicochemical properties in organic molecules.18 All methods are empirical
in nature and have been developed over the last 20 years in the research group of Prof.
J. Gasteiger. The following chemical effects can be quantified: heats of formation, bond
dissociation energies, sigma charge distribution, π-charge distribution, inductive effect,
resonance effect and delocalization energies, and polarizability effect.18
The series 4(a–h) of monocyclic β-lactams have been subjected to delocalized-charge
calculations using the PETRA method of the nonhydrogen common atoms (Figure 3), ob-
tained from the partial π-charge of the heteroatoms, have been used to model the bioactivity
against bacteria. We give here, as example, the compounds 4(g–h).
It is found that the negative charges of the oxygen and nitrogen atoms of 1,3-thiazolyl
group and the partial π positive charges of sulfur and supplementary arm 2-OH contribute
positively in favor of an antibacterial activity, and this is in good agreement with the mode
of antibacterial action of the compounds bearing (Xδ−—Y δ+) pharmacophore(s) site(s).
It was hypothesized that difference in charges between two heteroatoms of the same
pharmacophore site (Xδ−—Y δ+) may facilitate the inhibition of bacteria, more than viruses.
It is further found that the activity increases with increase in negative charge of one
heteroatom of the common pharmacophore fragment of the compounds (4g and 4h). This
synergistic and streamlined working procedure led to highly active isomeric/tautomeric
Gram(+/-) receptor ligands.
OSIRIS Calculations19
Structure-based design is now fairly routine, but many potential drugs fail to reach the
clinic because of ADME-Tox liabilities. One very important class of enzymes, responsible
for many ADMET problems, is the cytochromes P450, which is summarized in Table S2
(Supplemental Materials).
Inhibition of these or production of unwanted metabolites can result in many adverse
drug reactions. One of the most important programs, OSIRIS, is available online.19

1506
A. PARVEZ ET AL.
-O
N+
δ−
δ−
N
N
O
δ−
One pharmacophore
O-
N+
S
δ+
N
S
δ+
N
O
δ−
O
O
δ−
4b
4b
δ+
HO
δ−
N
δ−
N
δ+
OH
S
δ+
N
S
δ+
N
Two pharmacophores
δ−
O
δ−
O
4g
4g
δ+
δ−
δ−
N
O
N
δ+
O
S
N
S
δ+
N
δ+
Two pharmacophores
δ−
O
δ−
O
4h
4h
Figure 3 Possible potential antibacterial pharmacophore sites (Xδ−—Y δ+) of compound 4(a–h).
With our recent publication of the drug design combination of various pharmacophore
sites by using spiro-heterocyclic structure, it is now possible to predict activity and/or
inhibition with increasing success in two targets (bacteria and HIV). This was done using
a combined electronic/structure docking procedure, and an example will be given here.
The remarkably well behaved mutagenicity of diverse synthetic molecules classified in the
database of the Celeron Company (Switzerland) can be used to quantify the role played by
various organic groups in promoting or interfering with the way a drug can associate with
DNA.
Molinspiration Calculations20
CLogP (octanol/water partition coefficient) is calculated by the methodology devel-
oped by Molinspiration as a sum of fragment-based contributions and correction factors
(Table S3, Supplemental Materials).
The method is very robust and is able to process practically all organic and most
organometallic molecules. Molecular polar surface area TPSA is calculated based on the
methodology published by Ertl et al.20 as a sum of fragment contributions. O- and N-
centered polar fragments are considered. PSA has been shown to be a very good descriptor
to characterize drug absorption, including intestinal absorption, bioavailability, Caco-2
permeability, and blood–brain barrier penetration. Prediction results of compounds 4(a–h)
molecular properties (TPSA, GPCR ligand, and ICM) are valued (Table S3).

ANTIBACTERIAL POTENTIAL OF SOME MONOCYCLIC β-LACTAMS
1507
A number of important points emerge concerning the electronic and steric factors
that have direct impact on bioactivity properties. The positive results we have recorded,
while encouraging for purposes of new organometallic drug design, confirm that very
likely most of these compounds could be used as potential antibacterial activity after minor
modifications. Based on their structural properties, these compounds may be useful as
chelating agents with higher potential activity.
CONCLUSIONS
The results of the present investigation support the suggested antibacterial pharma-
cophore sites of mono cyclic β-lactams. It has been suggested that some functional groups
such as azomethine or hetero-aromatics present in these compounds displayed roles of
biological activity that may be responsible for the increase of hydrophobic character and
liposolubility of the molecules. This, in turn, enhances activity of the compounds and bio-
logical absorbance, and so all the synthesized cyclic β-lactams containing more than one
antibacterial pharmacophore site have good antibacterial properties (4g and 4h).
These results prompt several pertinent observations: (i) This type of cyclic β-lactam
can furnish an interesting model for studying the interaction of antibiotics with viral target
because of the possible charge modification of substituents and O/N/S of pharmacophore
groups; and (ii) the future flexible pharmacophore site(s) geometric conformation enables
us to prepare molecules for multitherapeutic materials with high selectivity (Figure 4).21
EXPERIMENTAL
The solvents and reagents used in the synthetic work were of laboratory grade and
were purified by distillation or crystallization where necessary. Their boiling or melting
points were compared with the available literature values. Melting points were determined
in open capillaries and are uncorrected. 1H NMR spectra were recorded on a Bruker AM-
400 (400 MHz) instrument using tetramethylsilane (TMS) as an internal standard and
DMSO-d6 as a solvent. Chemical shifts are given in parts per million (ppm). Infrared
spectra were recorded on a Schimadzu-IR Prestige 21. Mass spectra were recorded on a
Varian MAT CH-5 spectrometer. The reactions were monitored and the purity of products
Figure 4 The combinaison of antitubercular and antiviral activities is possible on the basis of β-lactams 4(a–h)
squeleton. The University of Pennsylvania receives US$9.5 million grant as part of an American screening network
to discover of bioactive organometallic ruthenium (II).21

1508
A. PARVEZ ET AL.
was checked on precoated TLC plates (Silica gel 60 F254, Merck), visualizing the spots
under ultraviolet light and iodine chamber. The antimicrobial screening was carried out at
Department of Biochemistry, Saint Francis De Sales College, Nagpur.
Synthesis of N-Substituted Arylidinethiazol-2-amines: 3(a–h)
2-Hydroxy-benzaldehyde (0.01 M) in absolute ethanol (10 mL) was added to a
stirred ethanolic solution (20 mL) of 2-aminothiazole (0.01 M), and the mixture was re-
fluxed for 1 h. Chilled water was added until a slight cloudiness was persisted in the
reaction solution. The reaction mixture was then set aside to cool. The oil which was
separated out was induced to crystallize by rubbing with a glass rod. The resultant solid
deposited was collected by filtration and washed well with cold ethanol. The same method
was applied for the preparation of Schiff bases 3(a–h) by using their respective aldehy-
des: benzaldehyde, 4-hydoxy benzaldehyde, 2-nitro-benzaldehyde, 3-nitro-benzaldehyde,
4-methoxy-benzaldehyde, 3,4-dimethoxy benzaldehyde, and furfuraldehyde. The products
were obtained in 70–75% yield.
Preparation of 4-(Substituted phenyl)-3-phenyl-1-(thiazol-2-yl)-
azetidin-2-ones: 4(a–h)
Method A: To a stirred solution of Schiff base (0.01 M) and Et3N (0.02 M) in dioxane
(50 mL), phenyl acetyl chloride (0.015 M) was added dropwise at 5–10◦C. The mixture was
stirred overnight at room temperature. The reaction progress was checked by TLC. After
completion of the reaction, the contents were poured in stirred ice cold water and stirring
was continued for 1 h. The solid that separated out was filtered, dried, and recrystallized
from ethanol. The purity of the compounds was determined by their melting points and by
thin layer chromatography. It was obtained in 60–65% yield.
Method B: To a stirred solution of Schiff base (0.01 M), Et3N (0.02 M), and phenyl
acetic acid (0.015 M) in anhydrous dichloromethane (50 mL), thionyl chloride (0.015 M)
was added dropwise at 5–10◦C. The mixture was allowed to stir at room temperature
overnight. Reaction progress was monitored by TLC. After completion, the reaction was
quenched in water. The organic layer was separated out, washed with water followed by
washing with NaHCO3 solution, and dried over magnesium sulfate. The products that were
obtained after removing the solvent were recrystallized from ethanol. By this method,
40–50% yield was obtained.
Method C: To a stirred solution of Schiff base (0.01 M), phenyl acetic acid (0.01
M), and Et3N (0.02 M) in anhydrous dichloromethane (50 mL), the solution of phosphorus
oxychloride was added dropwise at 5–10◦C. The mixture was allowed to stir at room
temperature overnight. The reaction monitoring was done by TLC. After completion of
the reaction, it was quenched in water. The organic layer was separated out, washed with
water followed by washing with NaHCO3 solution, and dried over magnesium sulfate. The
products that were obtained after removing the solvent were recrystallized from ethanol.
By this process, we obtained 70–80% yield.
2,3-Diphenyl-4-(1,3-thiazol-2-yl)cyclobutanone (4a). Yield 72%. Mp =
140◦C. MS (FAB < 0, DMSO/MNBA): Calcd for [M]+ C18H14N2OS: 306 (100%),
[M+H]+ (m/z) = 307 (21.5%). Elemental analysis for C18H14N2OS Calcd (Found): C
70.56 (70.6), H 4.61 (4.55), N 9.14 (9.2), S 10.47 (10.45).

ANTIBACTERIAL POTENTIAL OF SOME MONOCYCLIC β-LACTAMS
1509
3-(2-Nitrophenyl)-2-phenyl-4-(1,3-thiazol-2-yl)cyclobutanone (4b). Yield
70%. Mp = 135◦C. MS (FAB < 0, DMSO/MNBA): Calcd for [M]+ C18H13N3O3S:
351 (100%),[M+H]+ (m/z) = 352 (22.0%). Elemental analysis for C18H13N3O3S Calcd
(Found): C 61.53 (61.49), H 3.73 (3.76), N 11.96 (11.94), S 9.13 (9.10).
3-(3-Nitrophenyl)-2-phenyl-4-(1,3-thiazol-2-yl)cyclobutanone (4c). Yield
75%. Mp = 120◦C. MS (FAB < 0, DMSO/MNBA): Calcd for [M]+ C18H13N3O3S: 351
(100%), [M + H]+ (m/z) = 352 (21.5%). Elemental analysis for C18H13N3O3S Calcd
(Found): C 61.53 (61.470), H 3.73 (3.75), N 11.96 (11.88), S 9.13 (9.16).
3-(4-Methoxyphenyl)-2-phenyl-4-(1,3-thiazol-2-yl)cyclobutanone (4d).
Yield 78%. Mp = 170◦C. MS (FAB < 0, DMSO/MNBA): Calcd for [M]+ C19H16N2O2S:
336 (100%), [M+H]+ (m/z) = 337 (22.5%). Elemental analysis for C19H16N2O2S Calcd
(Found): C 67.84 (67.85), H 4.79 (4.80), N 8.33 (8.35), S 9.53 (9.55).
3-(3,4-Dimethoxyphenyl)-2-phenyl-4-(1,3-thiazol-2-yl)cyclobutanone (4e).
Yield 76%. Mp = 150◦C. MS (FAB < 0, DMSO/MNBA): Calcd for [M]+: 366 (100%),
[M+H]+ (m/z) = 337 (23.5%). Elemental analysis for C20H18N2O3S Calcd (Found): C
65.55 (65.50), H 4.95 (4.93), N 7.64 (7.65), 8.75 (8.73).
3-(4-Hydroxyphenyl)-2-phenyl-4-(1,3-thiazol-2-yl)cyclobutanone (4f). Yield
78%. Mp = 115◦C. MS (FAB < 0, DMSO/MNBA): Calcd for [M]+ C18H14N2O2S:
322 (100%), [M+H]+ (m/z) = 323 (25.1%). Elemental analysis for C18H14N2O2S Calcd
(Found): C 67.06 (67.10), H 4.38 (4.35), N8.69 (8.70), S 9.95 (9.90).
3-(2-Hydroxyphenyl)-2-phenyl-4-(1,3-thiazol-2-yl)cyclobutanone (4g).
Yield 80%. Mp = 125◦C. MS (FAB < 0, DMSO/MNBA): Calcd for [M]+ C18H14N2O2S:
322 (100%), [M+H]+ (m/z) = 323 (23.5%). Elemental analysis for C18H14N2O2S Calcd
(Found): C 67.06 (67.10), H 4.38 (4.40), N8.69 (8.700), S 9.95 (9.85).
3-(2-Furyl)-2-phenyl-4-(1,3-thiazol-2-yl)cyclobutanone (4h). Yield 77%.
Mp = 110◦C. MS (FAB < 0, DMSO/MNBA): Calcd for [M]+ C16H12N2O2S: 296 (100%),
[M+H]+ (m/z) = 297 (23.5%). Elemental analysis for C16H12N2O2S Calcd (Found): C
64.85 (64.90), H4.08 (4.10), N9.45 (9.40), S 10.82 (10.80).
REFERENCES
1. (a) R. Southgate, Contemp. Org. Synth., 1, 417 (1994); (b) R. B. Morin and M. Gorman, Chemistry
and Biology of β-Lactam Antibiotics (Academic Press, New York, 1982).
2. H. Staudinger, Liebigs Ann. Chem., 61, 356 (1907).
3. H. T. Clark, J. R. Johnson, and R. Robinson, The Chemistry of Penicillin (Princeton University
Press, Princeton, NJ, 1949).
4. (a) D. Niccolai, L. Trasi, and R. J. Thomas, Chem. Commun., 2233 (1997); (b) D. T. W. Chu, J.
I. Ptattner, and L. Katz, J. Med. Chem., 39, 3853 (1996).
5. F. H. Van Der Steen and G. Van Koten, Tetrahedron, 47, 7503 (1991).
6. I. Bhat, S. Chaitanya, and P. D. Satyanaraya, J. Serb. Chem. Soc., 72(5), 437 (2007).
7. N. H. Georgopapadakou, S. A. Smith, and R. B. Sykes, Antimicrob. Agents Chemother., 23, 98
(1983).
8. A. Jarrahpour, M. Shekarriz, and A. Taslimi, Molecules, 9, 29 (2004).
9. A. Jarrahpour, M. Shekarriz, and A. Taslimi, Molecules, 9, 939 (2004).
10. V. Guner, S. Yildirir, B. Ozcelik, and U. Abbasoglu, Il Farmaco, 55, 147 (2000).
11. H. Aoki, H. Sakai, M. Kohsaka, I. Konomi, J. Hosoda, Y. Tiubochi, R. Iguchi, and H. Imanaka,
J. Antibiotics, 29, 492 (1976).
12. M. P. Knadler, R. F. Bergstrom, J. T. Callaghan, and A. Rubin, Drug Metab. Dispos., 14, 175
(1986).

1510
A. PARVEZ ET AL.
13. S. Rover, M. A. Cesura, P. Huguenin, and A. Szente, J. Med. Chem., 40, 4378 (1997).
14. K. S. Kim, S. D. Kimball, R. N. Misra, D. B. Rawlins, J. T. Hunt, H. Y. Xiao, S. Lu, L. Qian,
W.-C. Han, W. Shan, T. Mitt, Z.-W. Cai, M. A. Poss, H. Zhu, J. S. Sack, J. S. Tokarski, C. J.
Chang, N. Pavletich, A. Kamath, W. G. Humphreys, P. Marathe, J. Bursuker, K. A. Kellar, U.
Roongta, R. Batorsky, J. G. Mulheron, D. Bol, C. R. Fairchild, F. Y. Lee, and K. R. Webster,
J. Med. Chem., 45, 3905 (2002).
15. A. A. Chavan and N. R. Pai, Molecules, 12, 2467 (2007).
16. S. Giri, R. Kumar, and S. Nizamuddin, Agric. Biol. Chem., 52(3), 621 (1988).
17. (a) A. L. Barry, The Antimicrobial Susceptibility Test: Principle and Practices, 4th ed. (Illuslea
and Feger, Philadelphia, PA, 1976), p. 180; (b) A. L. Barry, Biol. Abstr., 64, 25183 (1977).
18. Note: The PETRA molecular properties calculations program is freely available online at the
following site: http://www2.chemie-unierlangen.de/services/.
19. Note: The OSIRIS Property Explorer shown in this page is an integral part of Actelion’s in-house
substance registration system. It lets you draw chemical structures and calculates on-the-fly
various drug-relevant properties whenever a structure is valid. Prediction results are valued
and color-coded. Properties with high risks of undesired effects such as mutagenicity or poor
intestinal absorption are shown in red, whereas a green color indicates drug-conform behavior.
http://www.organic-chemistry.org/prog/peo/
20. P. Ertl, B. Rohde, and P. Selzer, J. Med. Chem., 43(20), 3714 (2000). This program is freely
available online at the following site: http://www.molinspiration.com/services/
21. The University of Pennsylvania receives US$9.5 million grant from NIH as part of a national
screening network to discover active molecules. E. Meggers’ group is involved in this center
with the design of bioactive organometallic ruthenium (II) compounds containing staurosporine
derivatives as ligand. http://www.sas.upenn.edu/∼meggers/