Synthesis, characterization, and antimicrobial evaluation of quinoline-oxadiazole-based azetidinone derivatives

Article abstract of DOI:10.1080/00397911.2011.580199

A series of 3-chloro-1-(aryl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-yl) -1,3,4-oxadiazol-3(2H)-yl)-4-ethyl-azetidin-2-ones (5a-l) have been synthesized and characterized by IR, ¹H NMR, and¹³C NMR. Synthesized compounds were screened for their antimicrobial activity against different strains of bacteria (E. coli, P. aeruginosa, S. aureus, S. pyogenes, C. albicans, A. niger, and A. clavatus). On the basis of statistical analysis, it has been observed that compounds had significant correlations.

Full text of DOI:10.1080/00397911.2011.580199

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Synthesis, Characterization, and
Antimicrobial Evaluation of Quinoline-
Oxadiazole–Based Azetidinone
Derivatives
Amit M. Dodiya a , Niraj R. Shihory a & N. C. Desai a
a Division of Medicinal Chemistry, Department of Chemistry,
Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, India
Accepted author version posted online: 12 Jan 2012.Version of
record first published: 17 Aug 2012.
To cite this article: Amit M. Dodiya, Niraj R. Shihory & N. C. Desai (2012): Synthesis,
Characterization, and Antimicrobial Evaluation of Quinoline-Oxadiazole–Based Azetidinone
Derivatives, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:21, 3230-3241
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Synthetic Communications1, 42: 3230–3241, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.580199
SYNTHESIS, CHARACTERIZATION, AND
ANTIMICROBIAL EVALUATION OF QUINOLINE-
OXADIAZOLE–BASED AZETIDINONE DERIVATIVES
Amit M. Dodiya, Niraj R. Shihory, and N. C. Desai
Division of Medicinal Chemistry, Department of Chemistry, Maharaja
Krishnakumarsinhji Bhavnagar University, Bhavnagar, India
GRAPHICAL ABSTRACT
Abstract A series of 3-chloro-1-(aryl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-
oxadiazol-3(2H)-yl)-4-ethyl-azetidin-2-ones (5a–l) have been synthesized and character-
ized by IR, 1H NMR, and13C NMR. Synthesized compounds were screened for their anti-
microbial activity against different strains of bacteria (E. coli, P. aeruginosa, S. aureus,
S. pyogenes, C. albicans, A. niger, and A. clavatus). On the basis of statistical analysis,
it has been observed that compounds had significant correlations.
Keywords Antimicrobial activity of quinoline; quinoline-oxadiazole-azetidinone;
quinoline-oxadiazole-azetidinone heterocycle
INTRODUCTION
Quinoline-containing drugs such as doxorubicin and mitoxantrone have been
established as one of the most effective classes of anticancer agents in clinical use
Received January 25, 2011.
Address correspondence to N. C. Desai, Division of Medicinal Chemistry, Department of
Chemistry, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364002, India. E-mail:
dnisheeth@rediffmail.com
3230

QUINOLINE-OXADIAZOLE–BASED AZETIDINONE DERIVATIVES
3231
today with broad applications in the treatment of leukaemia and lymphomas as well
as in combination chemotherapy of solid tumors.[1] However, toxic dose-related side
effects such as myelosuppresion and cardiotoxicity have limited their clinical applica-
tions.[2,3] The potent anticancer activity as well as toxic effects described for these
compounds are normally ascribed, at least, to two main mechanisms: one, which is
associated with protein, involves trapping of a protein enzyme–DNA cleavable inter-
mediate, whereas the other, a non-protein-associated mechanism, is related to redox
cycling of the quinone moiety, which produces damaging free-radical species.[3]
In search of more potential bioactive molecules with improved pharmacoki-
netic properties, potency, and lower side effects, a large number of quinoline deriva-
tives and related compounds have been prepared, and several of these are promising
in clinical trials.[4] Regarding structural and chemical modifications of this system,
one of the most interesting modifications has been the introduction of hetero atoms
(N, S) into different positions of the chromophore through incorporation of one or
more of five- or six-membered heterocyclic rings to the basic quinoline system.[5–7]
These bioisosteres would clearly differ from their carbocyclic counterparts in their
interaction with DNA and enzymes, as well as in their reduction potential.
1,3,4-Oxadiazoles are a class of heterocycles that have attracted significant
interest in medicinal chemistry, and they have a wide range of pharmaceutical and
biological activities including antibacterial, antifungal, anti-inflammatory, and anti-
hypertensive activities.[8–10] The widespread use of 1,3,4-oxadiazoles as a scaffold in
medicinal chemistry establishes this moiety as an important bioactive class of hetero-
cycles. These molecules are also utilized as pharmacophores because of their favor-
able metabolic profile and ability to engage in hydrogen bonding. Antihypertensive
agents such as tiodazosin[11] and nesapidil,[12] and antibiotics such as furamizole pos-
sess the oxadiazole nucleus. They are also useful as HIV integrase inhibitors and as
angiogenesis inhibitors.[13] Several methods have been reported in the literature for
the synthesis of 1,3,4-oxadiazoles.[14–17]
The azetidin-2-one (b-lactam) ring is present in several widely used families
of antibiotics such as penicillins, cephalosporins, carbapenems, and monocyclic
b-lactams (for example, aztreonam). Recent discoveries have proved that b-lactams
can serve as mechanism-based inhibitors of serine protease[18,19] and as inhibitors of
acyl-CoA cholesterol acyltransferase (ACAT),[20] which is responsible for athero-
sclerotic coronary heart disease. This has stimulated considerable research efforts
toward stereoselective routes for the synthesis of this important building block.
Moreover, an additional impetus has been provided by the introduction of the
b-lactam synthon methodology,[21–23] according to which enantiomerically pure
b-lactams can be employed as useful intermediates for organic synthesis. One of
the most popular methods for the preparation of b-lactam ring involves venerable
[2 þ 2] cycloaddition of ketenes and imines.[24,25]
In this article, we have reported the synthesis of a new series of quinoline,
1,3,4-oxadiazole, and azetidinone heterocycle derivatives. We report herein synthesis
of new class of heterocyclic molecules in which all of these moieties are present, and
we tried to develop potential bioactive molecules. The structures of synthesized
1
compounds were assigned on the basis of infrared (IR), H NMR, 13C NMR, and
mass spectral data. These compounds were evaluated for their antimicrobial activi-
ties with different strains of bacteria and fungi.

3232
A. M. DODIYA, N. R. SHIHORY, AND N. C. DESAI
RESULTS AND DISCUSSION
We have described the synthesis, characterization, and biological evaluation of
3-chloro-1-(aryl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-
yl)-4-ethyl-azetidin-2-ones (5a–l). In the first step, 2-chloroquinoline-3-carbaldehyde
(1) was reacted with isoniazide using 1,4-dioxane as a solvent to furnish aroyl hydra-
zone (2) as an intermediate. Then, compound 2 was reacted with acetic anhydride,
which yielded intermediate 3, which on further treatment with different amines using
ethanol (95%) in the presence of glacial acetic acid as a catalyst produced intermedi-
ate 4. Compound 4, when reacted with equal amounts of triethylamine and chloroa-
cetyl chloride in 1,4-dioxane as a solvent, yielded product 5. The solvent system used
for thin-layer chromatography (TLC) was n-hexane-ethyl acetate (7:3).
The IR spectrum of the compound 5c (molecular formula C26H18ClN5O2, MW
537.05) has given vibrations at 3060 cmꢀ1 over the range, which showed multiple
weak absorption peaks corresponding to Qu-H and Ar-H stretching vibration
absorption peaks. The absorption peak at 2885 cmꢀ1 is due to the stretching
vibration of the methyl group. The strong absorption at 1710 cmꢀ1 is due to the
stretching vibration of C¼O, which is present in b-lactam ring. The moderate inten-
sity absorption at 1615 cmꢀ1 corresponds to a C¼N stretching vibration, and the
stretching vibration of C¼C linkage appeared at 1605 cmꢀ1. The absorption peak
at 1465 cmꢀ1 is due to the bending vibration of the methyl group, while in oxadiazole
nucleus the C-O-C linkage appeared at the range of 1210 cmꢀ1. The absorption
peaks at 754 cmꢀ1 and 768 cmꢀ1 arise because of C-Cl groups present in the moiety.
It can be seen from the chemical structure of compound 5c that different
pairs of carbons (e.g., C-13 and C-16, C-14 and C-15) are attached to chemically
equivalent protons. The protons that are attached to C-13 and C-16 appeared at
d ¼ 7.98 ppm, whereas the protons that are attached to C-14 and C-15 appeared
at d ¼ 8.66 ppm. The proton attached at the C-6 position appeared as a multiplet
at d ¼ 7.59 ppm because of mutual coupling with protons attached to C-5 and C-7,
which appeared at d ¼ 8.03 and 7.74 ppm respectively. The proton attached at the
C-7 position appeared as a multiplet at d ¼ 7.74 ppm because of mutual coupling
with protons attached to C-6 and C-8, which appeared at d ¼ 7.59 and 7.99 ppm
respectively. The proton attached to C-3 and present in quinoline nucleus appeared
as a singlet at d ¼ 8.27 ppm, whereas the C-10 (–CH group) present in the oxadiazole
nucleus appeared as a singlet at d ¼ 5.64 ppm. The proton of C-19 of the b-lactam
ring, which is directly attached to the chlorine atom, appeared as a singlet at
d ¼ 5.28 ppm. The proton of the methyl group at C-18 gives a singlet and appeared
at d ¼ 1.70 ppm, because of the vicinity of carbonyl group at C-20 and the chlorine
atom at C-19 present in the b-lactam ring. The other four protons attached to
carbons in phenyl ring are chemically equivalent protons; C-22 and C-26 appeared
at d ¼ 7.34 ppm, whereas the other equivalent protons that are attached at C-23
and C-25 appeared at d ¼ 7.54 ppm respectively.
The chemical shifts of the final compound 5c carbons vary from d ¼ 161.0
to 17.0 ppm. The carbon nuclei under the influence of a strong electronegative
environment appeared downfield (e.g., the C-20 carbonyl present in b-lactam
ring and directly linked to the nitrogen in ring has a chemical shift value of d ¼
161.0 ppm, whereas C-1, linked to one chlorine and one nitrogen atom, appeared

QUINOLINE-OXADIAZOLE–BASED AZETIDINONE DERIVATIVES
3233
at d ¼ 151.9 ppm). The chemical shift of the ring carbon at C-9 is affected by the
presence of the directly attached ring nitrogen atom and appeared at d ¼ 145.4 ppm.
ppm. The alkane carbon at C-18 is directly attached to a carbon of the b-lactam ring
and appeared at d ¼ 17.0 ppm, whereas the carbon at C-19 directly attached to the
chlorine atom present in the b-lactam ring records a downfield chemical shift at
d ¼ 65.9 ppm. The carbons of the phenyl ring, which are attached to nitrogen atoms,
of the azetidinone ring having equivalent carbons C-22 and C-26, appeared at
d ¼ 125.6 ppm. Other equivalent carbons C-23 and C-25 appeared at d ¼ 129.0 ppm,
ppm, whereas the carbon C-21 directly attached to the nitrogen atom of the azetidi-
none ring appeared at d ¼ 139.8 ppm and C-24 directly attached to the chlorine atom
appeared at d ¼ 133.3 ppm. The carbons present in oxadiazole nuclei C-10 and C-11
both are on one side directly attached to oxygen atoms, and on the other side C-10 is
attached to nitrogen by a single bond. Because of this, it gives a chemical shift at
d ¼ 77.4 ppm, whereas on the other side C-11 attached to the nitrogen atom by a
double bond gives a chemical shift at d ¼ 157.0 ppm. The carbons of the quinoline
ring (C-2 to C-8) appeared between d ¼ 127.0 to 136.2 ppm respectively. The equiva-
lent carbons C-13 and C-16 appeared at d ¼ 124.1 ppm, whereas other equivalent
carbons C-14 and C-15, which are directly attached to nitrogen atom of the pyridine,
appeared at 149.4 ppm respectively. The carbon numbering is described in Fig. 1.
Antibacterial Activity
From screening results, it has been observed that final compounds 5b, 5g, and 5l
possess good activity compound 5e possesses very good activity, and compound 5f
possesses excellent activity against E. coli as compared to the standard drug ampicil-
lin. Final compounds 5a, 5f, 5h, and 5l possess good activity, compound 5d possesses
very good activity, and compound 5e possesses excellent activity against P. aeruginosa
as compared to ampicillin. Final compounds 5j and 5k possess good activity
Figure 1. Carbon numbering of the final compound 5c.

3234

QUINOLINE-OXADIAZOLE–BASED AZETIDINONE DERIVATIVES
3235
compounds 5c, 5e, and 5i possess very good activity, and compound 5b possesses
excellent activity against S. aureus as compared to the standard drug ampicillin. Com-
pounds 5f and 5i were shown to possess good activity against S. pyogenes as com-
pared to the standard drug ampicillin. The remaining compounds of the entire
series possess moderate to poor antibacterial activity. The antibacterial activity is
described in Table 1.
Antifungal Activity
Antifungal screening data showed that final compounds 5b, 5d, 5f, 5g, 5i, and 5k
possess good activity, and compounds 5a, 5e, and 5j possess very good activity against
C. albicans as compared to the standard drug griseofulvin. Compounds 5c and 5j pos-
sess good activity against A. niger as compared to the standard drug griseofulvin.
Compounds 5d and 5e possess good activity against A. clavatus as compared to the
standard drug griseofulvin. The remaining compounds of the entire series possess
moderate antifungal activity. The antifungal activity is described in Table 1.
Statistical Analysis
The standard deviation value is expressed in terms of ꢁstandard deviation
(SD). On the basis of the calculated value using analysis of varience (ANOVA),
it has been observed that differences below the 0.0001 level (p ꢃ 0.0001) were
considered statistically significant.
EXPERIMENTAL
The percentage composition of elements (CHN) for the compounds was deter-
mined using an elemental analyzer CHN Model Fison EA 1108. IR spectra were
recorded on potassium bromide disks using Perkin–Elmer spectrophotometer GX.
1
The H and 13C nuclear magnetic resonance spectra were recorded using a Jeol
JNM-ECP 400 spectrometer. Mass spectra were recorded on a Shimadzu
GCMSQP5050A spectrometer, DB-1 glass column 30 m, 0.25 mm, ionization energy
70 eV. The purity of the synthesized compounds were checked by TLC silica gel–
coated plates obtained from Merck as stationary phase and solvent mixture of
n-hexane=ethyl acetate used as mobile phase at 25 ꢄC. 2-Chloroquinoline-3-carbalde-
hyde (1) was synthesized by following the procedure given by Meth-Cohn et al.[26]
The progress of the reaction and the purity of compounds were routinely checked
on TLC aluminium-sheet silica gel 60 F245 (E. Merck) using benzene–acetonitrile
(4:1 v=v) as an irrigator and developed in an iodine chamber.
N’-((2-Chloroquinolin-3-yl)methylene)isonicotinohydrazide (2)
A mixture of equal amounts of 2-chloroquinoline-3-carbaldehyde and isonia-
zide dissolved in 1,4-dioxane and refluxed for 5–6 h. After cooling, the crystals were
filtered off and recrystallized from alcohol (95%) to give compound 2. Yield 70%,
mp: 132–134 ꢄC. Anal. for C18H13ClN4O3 calcd: C, 58.62%; H, 3.55%; N, 15.19%.
Found: C, 58.69%; H, 3.61%; N, 15.24%.

3236
A. M. DODIYA, N. R. SHIHORY, AND N. C. DESAI
1-(2-(2-Chloroquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-
3(2H)-yl)ethanone (3)
Acetic anhydride was added to aroylhydrazone (2), and the mixture was
refluxed for 2 h. After cooling, the reaction mixture was poured into ice water.
The precipitate was filtered off, washed with water, dried, and recrystallized from
mixed solvents dimethyl formamide and ethanol (95%) to give compound 3. Yield
75%, mp 210–211 ꢄC. Anal. for C20H15ClN4O4 calcd: C, 58.47%; H, 3.68%; N,
13.63%. Found: C, 58.53%; H, 3.72%; N, 13.69%.
4-Chloro-N-(1-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-
oxadiazol-3(2H)-yl)ethylidene)aniline (4c)
A mixture of 3 (0.01 mol) and p-chloroaniline (0.01 mol) in ethanol (30 ml)
containing a catalytic amount of glacial acetic acid was refluxed for 8 h at 80 ꢄC.
The solid that separated out on cooling was filtered, washed with water, and recrys-
tallized from alcohol (95%) to afford compound 4c. Yield 72%, mp 215–217 ꢄC.
Anal. for C24H17Cl2N5O calcd: C, 62.34%; H, 3.70%;, N, 15.14%. Found: C,
62.38%; H, 3.74%; N, 15.19%.
3-Chloro-1-(4-chlorophenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-
4-yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5c)
A mixture of compound 4c (0.01 mol) and triethylamine (TEA) (1.02 ml,
0.01 mol) was dissolved in 1,4-dioxane (30 ml), kept in an ice bath, and stirred for
half an hour. To this, a cold solution of chloroacetyl chloride (0.72 ml, 0.01 mol)
was added slowly at 0–5 ꢄC, further stirred for half an hour, refluxed, and stirred
again for 10–12 h at 95 ꢄC. It was left for 2–3 h. The precipitated triethylammonium
chloride was filtered off, and 1,4-dioxane was removed by distillation. Residue was
poured into cold water, and the resulting solid was washed well with water, dried,
and crystallized from alcohol (95%) to afford final product 5c.
All other compounds of this series were prepared using the same method.
3-Chloro-1-(2-chlorophenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-
yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5a). Yield: 73%, mp
278–280 ꢄC. IR (KBr): 3065, 2880, 1712, 1611, 1602, 1461, 1215, 751, 762 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 1.69 (s, 3H, CH3), 5.64 (s, 1H, -N-CH-O link-
age), 5.28 (s, 1H, -CH-Cl azetidinone ring), 7.32–8.66 (m, 13H, Qu-H and ph-H)
ppm; 13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 65.9, 77.4, 90.2, 124.1, 123.0,
126.6, 127.0, 127.3, 127.0, 129.9, 130.1, 130.9, 131.2, 136.2, 138.4, 140.2, 141.1,
145.4, 149.4, 151.9, 157.0, 161.2 ppm; MS: m=z ¼ 537.05. Anal. for C26H18Cl3N5O2
calcd: C, 57.95; H, 3.36; N, 12.99. Found: C, 57.89; H, 3.42; N, 12.94%.
3-Chloro-1-(3-chlorophenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-
4-yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5b). Yield: 65%,
mp 187–188 ꢄC. IR (KBr): 3069, 2878, 1706, 1616, 1601, 1461, 1213 and 757,
769 cmꢀ1
.
-N-CH-O linkage), 5.26 (s, 1H, -CH-Cl azetidinone ring), 7.15–8.66 (m, 13H,
1H NMR (400 MHz, DMSO-d6): d ¼ 1.64 (s, 3H, CH3), 5.65 (s, 1H,

QUINOLINE-OXADIAZOLE–BASED AZETIDINONE DERIVATIVES
3237
Qu-H and ph-H) ppm; 13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 65.9, 77.4, 90.2,
124.1, 125.6, 126.6, 127.0, 127.3, 127.9, 129.9, 130.3, 130.9, 134.5, 135.8, 136.2,
138.4, 143.1, 145.4, 149.4, 151.9, 157.0, 161.4 ppm; MS: m=z ¼ 537.05. Anal. for
C26H18Cl3N5O2 calcd: C, 57.95; H, 3.36; N, 12.99. Found: C, 57.99; H, 3.41; N,
12.93%.
3-Chloro-1-(4-chlorophenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-
yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5c). Yield: 67%, mp
201–203 ꢄC. IR (KBr): 3060, 2885, 1710, 1615, 1605, 1465, 1210, 768, 754 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 1.70 (s, 3H, CH3), 5.64 (s, 1H, -N-CH-O link-
age), 5.28 (s, 1H, -CH-Cl azetidinone ring), 7.34–8.66 (m, 13H, Qu-H and ph-H)
ppm; 13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 65.9, 77.4, 90.2, 124.1, 125.6,
126.6, 127.0, 127.3, 129.0, 129.9, 130.9, 133.3, 136.2, 138.4, 139.8, 145.4, 149.4,
151.9, 157.0, 161.0 ppm; MS: m=z ¼ 537.05. Anal. for C26H18Cl3N5O2 calcd: C,
57.95; H, 3.36; N, 12.99. Found: C, 57.90; H, 3.41; N, 12.99%.
3-Chloro-1-(2-nitrophenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-
yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5d). Yield: 60%, mp
137–138 ꢄC. IR (KBr): 3060, 2885, 1715, 1615, 1605, 1487, 1465, 1295, 1210, 768,
754 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 1.65 (s, 3H, CH3), 5.64 (s, 1H,
-N-CH-O linkage), 5.28 (s, 1H, -CH-Cl azetidinone ring), 7.58–8.64 (m, 13H,
Qu-H and ph-H) ppm; 13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 65.9, 77.4, 90.2,
113.3, 124.1, 126.6, 127.0, 127.3, 125.4, 129.9, 130.9, 125.2, 136.2, 137.7, 138.4,
136.9, 142.4, 145.4, 149.4, 151.9, 157.0, 161.2 ppm; MS: m=z ¼ 549.36. Anal. for
C26H18Cl2N6O4 calcd: C, 56.84; H, 3.30; N, 15.29. Found: C, 56.90; H, 3.36; N,
15.35%.
3-Chloro-1-(3-nitrophenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-
yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5e). Yield: 69%, mp
176–178 ꢄC. IR (KBr): 3060, 2889, 1712, 1611, 1606, 1492, 1465, 1305, 1208, 763,
752 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 1.62 (s, 3H, CH3), 5.63 (s, 1H,
-N-CH-O linkage), 5.26 (s, 1H, -CH-Cl azetidinone ring), 7.58–8.67 (m, 13H,
Qu-H and ph-H) ppm; 13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 65.9, 77.4, 90.2,
119.5, 123.1, 124.1, 126.6, 127.0, 127.3, 129.8, 129.9, 130.9, 133.6, 136.2, 138.4,
142.6, 145.4, 148.1, 149.4, 151.9, 157.0, 161.1 ppm; MS: m=z ¼ 549.36. Anal. for
C26H18Cl2N6O4 calcd: C, 56.84; H, 3.30; N, 15.29. Found: C, 56.89; H, 3.37; N,
15.36%.
3-Chloro-1-(4-nitrophenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-
yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5f). Yield: 73%, mp
280–281 ꢄC. IR (KBr): 3060, 2882, 1718, 1616, 1605, 1487, 1462, 1298, 1210, 786,
754 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 1.69 (s, 3H, CH3), 5.66 (s, 1H,
-N-CH-O linkage), 5.27 (s, 1H, -CH-Cl azetidinone ring), 6.86–8.68 (m, 13H,
Qu-H and ph-H) ppm; 13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 65.9, 77.4, 90.2,
124.1, 124.4, 124.7, 131.1, 131.3, 126.6, 127.0, 127.3, 129.9, 130.9, 136.2, 138.4,
143.5, 145.4, 147.6, 149.4, 151.9, 157.0, 161.3 ppm; MS: m=z ¼ 549.36. Anal. for
C26H18Cl2N6O4 calcd: C, 56.84; H, 3.30; N, 15.29. Found: C5, 6.90; H, 3.36; N,
15.35%.

3238
A. M. DODIYA, N. R. SHIHORY, AND N. C. DESAI
3-Chloro-1-(2-methoxyphenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-
yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5g). Yield: 57%, mp
212–214 ꢄC. IR (KBr): 3060, 2970, 2885, 1706, 1615, 1605, 1480, 1465, 1210, 768,
754 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 1.64 (s, 3H, CH3), 3.73 (s, 3H,
-OCH3), 5.64 (s, 1H, -N-CH-O linkage), 5.28 (s, 1H, -CH-Cl azetidinone ring),
6.97–8.66 (m, 13H, Qu-H and ph-H) ppm; 13C NMR (100 MHz, DMSO-d6):
d ¼ 17.0, 17.8, 65.9, 77.4, 90.2, 116.9, 124.1, 125.9, 126.6, 127.0, 127.3, 130.7,
129.3, 129.9, 130.9, 134.3, 136.2, 138.4, 138.6, 145.4, 149.4, 151.9, 157.0,
161.4 ppm; MS: m=z ¼ 533.10. Anal. for C27H21Cl2N5O3 calcd: C, 60.68; H, 3.96;
N, 13.10. Found: C, 60.74; H, 3.90; N, 13.16%.
3-Chloro-1-(3-methoxyphenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-
yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5h). Yield: 50%, mp
209–210 ꢄC. IR (KBr): 3060, 2975, 2885, 1713, 1615, 1605, 1487, 1465, 1210, 768,
754 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 1.66 (s, 3H, CH3), 3.73 (s, 3H,
-OCH3), 5.64 (s, 1H, -N-CH-O linkage), 5.26 (s, 1H, -CH-Cl azetidinone ring),
6.97–8.68 (m, 13H, Qu-H and ph-H) ppm; 13C NMR (100 MHz, DMSO-d6):
d ¼ 17.0, 55.8, 65.9, 77.4, 90.2, 116.4, 119.8, 124.1, 125.4, 126.6, 127.0, 127.3,
124.0, 129.9, 130.9, 136.2, 138.4, 142.7, 145.4, 149.4, 151.9, 157.0, 160.3,
161.0 ppm; MS: m=z ¼ 533.10. Anal. for C27H21Cl2N5O3 calcd: C, 60.68; H, 3.96;
N, 13.10. Found: C, 60.74; H, 3.91; N, 13.16%.
3-Chloro-1-(4-methoxyphenyl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-yl)-
1,3,4-oxadiazol-3(2H)-yl)-4-methylazetidin-2-one (5i). Yield: 61%, mp 189–
191 ꢄC. IR (KBr): 3060, 2983, 2885, 1716, 1615, 1605, 1492, 1465, 1210, 754,
768 cmꢀ1
.
1H NMR (400 MHz, DMSO-d6): d ¼ 1.66 (s, 3H, CH3), 3.73 (s, 3H,
-OCH3), 5.64 (s, 1H, -N-CH-O linkage), 5.27 (s, 1H, -CH-Cl azetidinone ring),
7.04–8.68 (m, 13H, Qu-H and ph-H) ppm; 13C NMR (100 MHz, DMSO-d6):
d ¼ 17.0, 55.8, 65.9, 77.4, 90.2, 124.1, 122.6, 114.5, 126.6, 127.0, 127.3, 129.9,
130.9, 134.0, 136.2, 138.4, 145.4, 149.4, 151.9, 157.0, 158.9, 161.0 ppm; MS:
m=z ¼ 533.10. Anal. for C27H21Cl2N5O3 calcd: C, 60.68; H, 3.96; N, 13.10. Found:
C, 60.73; H, 3.90; N, 13.17%.
3-Chloro-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-
3(2H)-yl)-4-methyl-1-2-tolylazetidin-2-one (5j). Yield: 69%, mp 202–204ꢄC. IR
(KBr): 3060, 2885, 2894, 1719, 1615, 1605, 1465, 1482, 1210, 768, 754 cmꢀ1. 1H NMR
(400 MHz, DMSO-d6): d ¼ 1.66 (s, 3H, CH3), 2.09 (s, 3H, phe-CH3), 5.64 (s, 1H,
-N-CH-O linkage), 5.28 (s, 1H, -CH-Cl azetidinone ring), 6.86–8.66 (m, 13H, Qu-H
and ph-H) ppm; 13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 17.5, 65.9, 77.4, 90.2,
116.9, 124.1, 125.7, 126.6, 127.0, 127.3, 129.3, 129.9, 130.7, 130.9, 136.2, 138.4, 138.6,
145.4, 149.4, 151.9, 157.0, 161.5 ppm; MS: m=z ¼ 517.11. Anal. for C27H21Cl2N5O2
calcd: C, 62.55; H, 4.08; N, 13.50. Found: C, 62.61; H, 4.13; N, 13.58%.
3-Chloro-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-
3(2H)-yl)-1-(2-fluorophenyl)-4-methylazetidin-2-one (5k). Yield: 68%, mꢀp
198–200 ꢄC. IR (KBr): 3060, 2885, 1710, 1615, 1605, 1465, 1210, 768, 754, 722 cm
1
1. H NMR (400 MHz, DMSO-d6): d ¼ 1.66 (s, 3H, CH3), 5.64 (s, 1H, -N-CH-O
linkage), 5.28 (s, 1H, -CH-Cl azetidinone ring), 7.22–8.67 (m, 13H, Qu-H and
ph-H) ppm; 13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 65.9, 77.4, 90.2, 115.7,

QUINOLINE-OXADIAZOLE–BASED AZETIDINONE DERIVATIVES
3239
124.1, 123.2, 124.5, 126.6, 127.0, 127.3, 127.8, 129.0, 129.9, 130.9, 136.2, 138.4, 145.4,
149.4, 151.9, 157.0, 161.0, 162.8 ppm; MS: m=z ¼ 522.36. Anal. for C26H18Cl2FN5O2
calcd: C, 59.78; H, 3.47; N, 13.40. Found: C, 59.83; H, 3.53; N, 13.45%.
3-Chloro-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-
3(2H)-yl)-1-(4-fluorophenyl)-4-methylazetidin-2-one (5l). Yield: 72%, mꢀp
221–223 ꢄC. IR (KBr): 3060, 2885, 1719, 1615, 1605, 1465, 1210, 768, 754, 725 cm
1. 1H NMR (400 MHz, DMSO-d6): d ¼ 1.66 (s, 3H, CH3), 5.64 (s, 1H, -N-CH-O link-
age), 5.28 (s, 1H, -CH-Cl azetidinone ring), 7.25–8.66 (m, 13H, Qu-H and ph-H) ppm;
13C NMR (100 MHz, DMSO-d6): d ¼ 17.0, 65.9, 77.4, 90.2, 115.1, 115.7, 123.2, 123.5,
124.1, 126.6, 127.0, 127.3, 129.9, 130.9, 136.2, 137.3, 138.4, 145.4, 149.4, 151.9, 157.0,
161.0, 162.9 ppm; MS: m=z ¼ 522.36. Anal. for C26H18Cl2FN5O2 calcd: C, 59.78; H,
3.47; N, 13.40. Found: C, 59.85; H, 3.52; N, 13.46%.
Biological Activity
We have synthesized 3-chloro-1-(aryl)-4-(2-(2-chloroquinolin-3-yl)-5-(pyridin-
4-yl)-1,3,4-oxadiazol-3(2H)-yl)-4-methyl- azetidin-2-ones (5a–l) derivatives. Mini-
mum inhibitory concentration (MIC) for bacteria of all the synthesized compounds
was determined against four different strains, two Gram-positive bacteria (S. aureus
and S. pyogenes) and two Gram-negative bacteria (E. coli and P. aeruginosa)
as compared to the standard drug ampicillin by the broth dilution method.[27]
Minimum inhibitory concentration (MIC) measurements for antifungal activity were
carried out against C. albicans, A. niger, and A. clavatus organisms, and results
were compared with the standard drug griseofulvin by the same method.
CONCLUSION
We have provided a practical, efficient, and an inexpensive method for the syn-
thesis of quinoline-oxadiazole-azetidinone derivatives. These compounds constitute
a new class of in vitro antimicrobial agents. An extension of this work is currently
under investigation.
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