Design, synthesis and biological evaluation of some novel diastereoselective β-lactams bearing 2-mercaptobenzothiazole and benzoquinoline

Article abstract of DOI:10.1007/s00044-018-02287-0

We report the synthesis of some novel β-lactam hybrids of 2-mercaptobenzothiazole and benzoquinoline. These compounds were synthesized by a [2 + 2]-cycloaddition reaction of imines 8a-d and ketenes derived from substituted acetic acids. The reaction was totally diastereoselective leading exclusively to the formation of cis-β-lactams 10a-m. All products were obtained in good to excellent yields and their structures were established based on IR, ¹H NMR, ¹³C NMR spectral data and elemental analysis. Schiff bases 8a-d and β-lactam hybrids 10a-m were evaluated for antimicrobial activities against six bacterial species. The minimum inhibitory concentration (MIC) values indicate that two of the β-lactams, 10k and 10m, have good activities against the two Gram-negative bacteria, E. coli and P. aeruginosa, while three of the Schiff bases, 8a-c, are active against P. aeruginosa and the Gram-positive pathogen S. aureus. The molecular and cellular basis for these observed antibacterial properties are not determined. Moreover, the five most active compounds showed acceptably low cytotoxicity (less than 25% cell growth inhibition after 72 h of incubation) against the MCF-7 cell line, and below 10% in vitro hemolytic activity at 50 and 200 μM concentrations. These results suggest a need for further inquiry into the reason for why these compounds are bioactive, and as to what their full biological activities and antibiotic potential may be. The cis stereochemistry of β-lactam 10a was confirmed by X-ray crystallographic studies.

Full text of DOI:10.1007/s00044-018-02287-0

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-018-02287-0
ORIGINAL RESEARCH
Design, synthesis and biological evaluation of some novel
diastereoselective β-lactams bearing 2-mercaptobenzothiazole and
benzoquinoline
Nassim Borazjani1 Aliasghar Jarrahpour1 Javad Ameri Rad1 Milad Mohkam2 Maryam Behzadi2
●
●
●
●
●
Younes Ghasemi3,4 Somayyeh Mirzaeinia5 Hamid Reza Karbalaei-Heidari5 Mohammad Mehdi Ghanbari6
●
●
●
●
Gyula Batta6 Edward Turos7
●
Received: 6 October 2018 / Accepted: 26 December 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
We report the synthesis of some novel β-lactam hybrids of 2-mercaptobenzothiazole and benzoquinoline. These compounds
were synthesized by a [2 + 2]-cycloaddition reaction of imines 8a-d and ketenes derived from substituted acetic acids. The
reaction was totally diastereoselective leading exclusively to the formation of cis-β-lactams 10a-m. All products were
obtained in good to excellent yields and their structures were established based on IR, 1H NMR, 13C NMR spectral data and
elemental analysis. Schiff bases 8a-d and β-lactam hybrids 10a-m were evaluated for antimicrobial activities against six
bacterial species. The minimum inhibitory concentration (MIC) values indicate that two of the β-lactams, 10k and 10m, have
good activities against the two Gram-negative bacteria, E. coli and P. aeruginosa, while three of the Schiff bases, 8a-c, are
active against P. aeruginosa and the Gram-positive pathogen S. aureus. The molecular and cellular basis for these observed
antibacterial properties are not determined. Moreover, the five most active compounds showed acceptably low cytotoxicity
(less than 25% cell growth inhibition after 72 h of incubation) against the MCF-7 cell line, and below 10% in vitro hemolytic
activity at 50 and 200 µM concentrations. These results suggest a need for further inquiry into the reason for why these
compounds are bioactive, and as to what their full biological activities and antibiotic potential may be. The cis
stereochemistry of β-lactam 10a was confirmed by X-ray crystallographic studies.
●
●
●
●
●
●
Keywords β-Lactam Hybrid 2-Mercaptobenzothiazole Benzoquinoline Antimicrobial Hemolysis Mammalian cell
toxicity
Introduction
The β-lactam (or azetidin-2-one) scaffold is an important
strained heterocyclic compound due to its diverse spectrum
of applications in the field of chemistry, biology as well as
in pharmaceutical products. This four-membered ring sys-
doi.org/10.1007/s00044-018-02287-0) contains supplementary
Supplementary information The online version of this article (https://
tem is a key structural unit in a large number of
material, which is available to authorized users.
4
* Aliasghar Jarrahpour
jarahpor@shirazu.ac.ir
Department of Biotechnology, School of Pharmacy, Shiraz
University of Medical Sciences, Shiraz, Iran
aliasghar6683@yahoo.com
5
Molecular Biotechnology Lab., Department of Biology, Faculty of
Sciences, Shiraz University, Shiraz, Iran
1
Department of Chemistry, College of Sciences, Shiraz University,
Shiraz 71946-84795, Iran
6
Department of Chemistry, University of Debrecen, Debrecen,
Egyetem tér 1, 4032 Debrecen, Hungary
2
Biotechnology Research Center, Shiraz University of Medical
Sciences, Shiraz, Iran
7
Center for Molecular Diversity in Drug Design, Discovery, and
Delivery, Department of Chemistry, University of South Florida,
CHE 205, 4202 East Fowler Avenue, Tampa, FL 33620, USA
3
Pharmaceutical Research Center, Shiraz University of Medical
Sciences, Shiraz, Iran

Medicinal Chemistry Research
Fig. 1 Structures of some known
quinoline derivatives with
diverse biological activities
pharmacologically active compounds such as the penicillins
and cephalosporins, and has been identified as crucial for
their bioactivity. Owing to the increasing bacterial resis-
tance against classic antibacterials, it is necessary to search
for new types of β-lactam antibiotics and β-lactamase
inhibitors (Piens et al. 2016; Hosseyni and Jarrahpour
2018). Although β-lactams have been initially introduced
for their renowned antibacterial properties (Chavan and Pai
2007; Bhat et al. 2011; Jarrahpour and Zarei 2006; Cerić
et al. 2010), they have since moved beyond this, showing a
significant use in different therapeutic areas such as inhi-
bition of HIV-1 protease (Kamath and Ojima 2012) and
acyl coenzyme A cholesterol transferases (Indrani et al.
2017) and have also been exhibited antidiabetic activity
(Galletti and Giacomini 2011), antimalarial activity (Alborz
et al. 2018), anticancer activity (Salunkhe and Piste 2014),
antioxidant activity (Nagarajan et al. 2012), anti-
inflammatory (Bhati and Kumar 2008) and antifungal
activity (Jarrahpour et al. 2017). β-Lactams are key mate-
rials for the preparation of various heterocyclic compounds
having biological and medicinal significance, such as the
anticancer drug Taxol (Indrani et al. 2017). Furthermore, 2-
azetidinones have gained an important place in organic
chemistry as versatile building blocks, serving as inter-
mediates for the synthesis of many acyclic and cyclic
nitrogen compounds (Alcaide et al. 2007; D’hooghe et al.
2010; Afzal et al. 2015). Various azacyclic compounds have
been used as antimicrobial agents. Among these, substituted
quinolines are prominent in the pharmaceutical sciences
(Mishra et al. 2007) as antimalarial (Bawa et al. 2010),
antitumor, anti-inflammatory, antibacterial (Kumar et al.
2009; Ahmed and Daneshtalab 2012; El-Gamal et al. 2015),
antiviral (Shipra et al. 2015), antioxidant and cytotoxic
activity (Ramachandran et al. 2012) agents. Some specific
examples, 3,4-dihydro-2H-thiopyrano[2,3-b]quinolone (A)
shows mGlu1 receptor antagonist activity (Zhong et al.
2011),
N′-((2-chlorobenzo[h]quinolin-3-yl)methylene)
methanesulfonohydrazide (B) possesses antibacterial activ-
ity (Baluja and Chanda 2017), ethyl 4-ethoxy-2-((ethox-
ymethyl)thio)benzo[h]quinoline-3-carboxylate (C) has
cytotoxic activity against several cancer cell lines (Bawa
et al. 2010), and N-methyl-2-(4-(2-oxo-1,2-dihydrobenzo[h]
quinolin-3-yl)benzylidene)-hydrazine-1-carbothioamide (D)
showed antioxidant activity (Ramachandran et al. 2012)
(Fig. 1).
2-Mercaptobenzothiazoles are a second important class
of bioactive and industrially important organic compounds.
These compounds have been reported for their anti-
microbial, antifungal, anti-inflammatory, antitumor, anti-
ulcer and chemoprotective activity (Herrera Cano et al.
2015; Wang et al. 2011; Cressier et al. 2009; Zhilitskaya
et al. 2017; Huang and Yang 2006). With the intention to
explore the utility of hybrid compounds, we decided to
prepare structurally unique β-lactams bearing 2-
mercaptobenzothiazole and benzoquinoline, as a means to
explore their potential medicinal properties (Raj et al. 2014;
Vandekerckhove and D’hooghe 2013; Meunier 2007;
Morphy and Rankovic 2006) (Fig. 2).
Results and discussion
Chemistry
In this study, thirteen novel cis-β-lactam hybrids of 2-
mercaptobenzothiazole and benzoquinoline were synthe-
sized by the Staudinger reaction (Rajamäki et al. 2016)
(Scheme 1). In the first step, a mixture of 1-naphthylamine

Medicinal Chemistry Research
(1) and acetic anhydride (2) in methanol containing a small
drop of acetic acid as a catalyst afforded N-(naphthalen-1-
yl)acetamide (3). Then, N-(naphthalen-1-yl)acetamide (3)
was added to a mixture of Vilsmeier-Haack reagent (pre-
pared by dropwise addition of POCl3 in ice-cooled of DMF)
to prepare benzo[h]quinoline-3-carbaldehyde (4) by a
reported procedure (Srivastava and Singh 2005). The chloro
of NaH in DMSO in 80% yield. The structure of the product
6 was confirmed by its spectroscopic data and elemental
analysis. The IR spectrum of compound 6 showed the
characteristic band at υ 1683 cm−1 for the aldehyde car-
1
bonyl group. Its H NMR spectrum displayed a singlet for
the aldehyde carbonyl group at δ = 10.42 ppm. Treatment
of 6 with aniline derivatives 7a-d generated the corre-
sponding imines 8a-d. The IR spectrum of 8a showed the
characteristic band at υ 1592 cm−1 corresponding to the
group in compound
4
was replaced by 2-
mercaptobenzothiazole (5) to yield 2-(benzo[d]thiazol-2-
ylthio)benzo[h]quinoline-3-carbaldehyde (6) in the presence
1
imine (CH=N). The H NMR spectrum of 8a revealed the
signal of an imine proton at δ = 8.89. The E geometry of the
imines reflects its thermodynamic preference under thermal
reaction conditions. Next, imine derivatives 8a-d and var-
ious phenoxyacetic acid derivatives 9a-d were treated in the
presence of triethylamine and tosyl chloride, in molar ratios
of 1:1.5:5:1.5 in anhydrous CH2Cl2 at room temperature,
to give the cis-β-lactams 10a-m in yields varying from
75–90% (Scheme 1).
To confirm the cis structure of the newly synthesized 2-
azetidinones, X-ray single crystal analysis was done on 10a
(Fig. 3). Both bond angles and bond lengths were normal
and analogous with those reported for related compounds
(Westrip 2010; Çelik et al. 2015). Crystal data, data
Fig. 2 Structures of two 2-mercaptobenzothiazole derivatives with
diverse biological activities
Scheme 1 Synthesis of 2-
mercaptobenzothiazole β-
lactams 10a-m

Medicinal Chemistry Research
concentrations (MICs) below 50 µg/ml. Judging from the
structures of these five compounds, the unsubstituted phe-
nyl group on the lactam enhances antibacterial activity
relative to those carrying substituents. The strongest anti-
bacterial activity was observed for 10k and 10m, with MIC
values of 20 µg/ml for P. aeruginosa (a Gram-negative
bacterium). These β-lactams have a phenoxy group on their
position 3 and 10K has a p-N,N-dimethylaminophenyl
group and 10m has a p-methoxyphenyl group on position 1.
It is interesting to note that the Schiff bases 8a-c also are
moderately bioactive, particularly towards P. aeruginosa
and S. aureus. Compounds 8a and 8b have the most potent
anti-pseudomonas and staphylococcal activity, with MIC
values of 42 µg/ml. The mode of antibacterial action has not
yet been identified.
The basis for antibacterial activity, and in particular,
effective inhibition of the Gram-negative microbes, for
these compounds is not yet known and would have to be
investigated further. Most likely, these compounds do not
act upon the penicillin-binding proteins since they do not
carry a requisite ionizable functional group off the β-lactam
ring for binding. Therefore, the finding that some of the
lactams, and imine precursors, possess discernible anti-
bacterial activity is notable.
Fig. 3 ORTEP diagram of diastereomer 10a
Mammalian cell toxicity and hemolytic activity
collection and structure refinement details are presented in
supplementary material.
Since antibacterial compounds should have minimum toxic
effects on human tissue in order to be useful medicinally,
the five best antibacterial compounds (8a-c, 10k, and 10m)
were evaluated against a human breast cancer cell line
(MCF-7) and human red blood cells. As shown in Table 2,
each of these compounds showed negligible cytotoxicity
against the MCF-7 cells after 72 h of exposure. At 200 µM,
over 75% of the cells were alive while at 50 µM more than
90% of the cells were viable. These low cytotoxicity effects
on eukaryotic cells support the potential application of the
compounds as viable antibacterial agents, and certainly
suggest the need for further investigation.
Assignment of the structures of the reaction products was
1
based on their spectral data. The H NMR spectrum of 10a
showed characteristic signals at 5.75 ppm [1H, d, J = 5.0
Hz, H-4 β-lactam] and 6.06 ppm [1H, d, J = 5.0 Hz, H-3
β-lactam]. The IR spectrum of 10a identified the presence of
a β-lactam carbonyl group stretching frequency at υ 1753
cm−1. The cis stereoisomers 10a-m were assigned on the
basis of the observed coupling constant between β-lactam
ring hydrogens H-3 and H-4 (J3,4 < 3.0 Hz for the trans and
J
3,4 > 4.0 Hz for the cis stereoisomer) (Islami et al. 2010;
Bandyopadhyay et al. 2012). Elemental and mass spectral
data of compounds 10a-m provided additional support for
the proposed structures.
A study of the in vitro hemolysis of human red blood
cells of these compounds was conducted at an elevated
compound concentration of 200 µM. As shown in Table 3,
all five compounds revealed less than 10% hemolysis. In
particular, lactam 10m induces only 3.51% hemolysis at
124 µg/ml.
Biological activities
Antibacterial testing
All the newly synthesized β-lactams bearing 2-
mercaptobenzothiazole and benzoquinoline, 10a-m were
evaluated for in vitro antimicrobial activity against six
common bacteria (Table 1). Five of the compounds, 8a, 8b,
8c, 10k and 10m, have respectable bioactivities against one
or more bacterial species, with minimum inhibitory
Conclusion
In this study, for the first time cis-β-lactams 10 bearing 2-
mercaptobenzothiazole and benzoquinoline moieties as ring
substituents have been synthesized and evaluated for
potential in vitro antibacterial activity. The β-lactam

Medicinal Chemistry Research
Table 1 Antimicrobial activities
of 6, 8a-d, and 10a-m
Sample
MIC (µg/ml)
E. coli ATCC P. aeruginosa
S. aureus
S. typhi
E. faecalis
B. subtilis
25922
ATCC 9027
ATCC 25923 ATCC 7251 ATCC 29212
ATCC 6051
6
>200
90
>200
42
>200
42
90
190
90
8a
42
190
>200
>200
>200
190
8b
90
42
42
>200
190
190
190
>200
190
>200
>200
190
>200
90
>200
190
8c
90
42
90
8d
>200
190
190
>200
>200
>200
90
>200
190
>200
>200
>200
>200
90
>200
90
90
10a
10b
10c
10d
10e
10f
>200
190
90
>200
>200
>200
>200
190
>200
>200
>200
>200
190
200
>200
>200
>200
>200
>200
190
10g
10h
10i
190
90
>200
190
190
190
20
>200
>200
190
>200
>200
>200
>200
>200
>200
>200
5
190
>200
42
190
>200
>200
90
10j
>200
>200
190
190
10k
10l
>200
>200
90
90
>200
20
10m
Gentamycin
42
>200
90
90
90
5
5
10
Minimum inhibitory concentration (MIC) values are in µg/ml and are the average from triplicate trials. MIC
values lower than 50 µg/ml are highlighted in bold
Table 2 Cell viability percentage of MCF-7 cells treated with some
selected compounds at 50 and 200 µM (final concentrations) for 72 h
Table 3 Hemolysis percentage of human red blood cells treated with
the selected compounds at 200 µM final concentration
Compound
Concentration
Cell viability (%)
Compound
Hemolysis percentage (%)
8a
50 μM
200 μM
50 μM
200 μM
50 μM
200 μM
50 μM
200 μM
50 μM
200 μM
20 μM
60 μM
96.2 5.6
77.6 1.1
100.6 6.9
85.1 1.9
91.7 3.3
87.39 5.27
100. 6 5.2
77.5 10.0
98.2 10.5
82.34 8.9
73.6 2.2
22.6 3.4
8a
6.45
6.76
8b
8b
8c
5.26
10k
6.32
8c
10m
3.51
Triton X-100 (1%)
100.0
10k
1% Triton X-100 was used as positive control
10m
Cisplatin
for further investigation to assess their full antimicrobial
potential and molecular mechanism of action.
Cisplatin was used as positive control
Materials and methods
General
derivatives 10k and 10m as well as their synthetic pre-
cursors, Schiff bases 8a, 8b and 8c, showed reasonably
good antibacterial activity against either the Gram-negatives
E. coli and P. aeruginosa or the Gram-positive S. aureus.
These five compounds showed very low cytotoxicity
towards MCF-7 human cells at or above the bacterial
minimum inhibitory concentration. These results suggest a
selection of previously unexplored antibacterial candidates
All needed chemicals were purchased from Aldrich, Fluka,
Merck and Acros chemical companies and used without
further purification. CH2Cl2 and Et3N were dried before to
use by distillation over CaH2. All products were char-
acterized by comparison of FT-IR 8300 spectrophotometer
using potassium bromide pellets (ʋ in cm−1). The 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were run in

Medicinal Chemistry Research
CDCl3 using a Bruker Avance DPX instrument. Chemical
shifts were reported in parts per million (δ) downfield from
tetramethylsilane. Coupling constants (J) are reported in
hertz (Hz). Splitting patterns are indicated as s: singlet, d:
doublet, t: triplet, q: quartet, m: multiplet, dd: doublet of
doublet. Melting points were recorded on a Buchi 510
melting point apparatus in open capillary tubes. Elemental
analyses were run on a Thermo Finnigan Flash EA-1112
series. The mass spectra were recorded on a Shimadzu GC-
MS QP 1000 EX instrument. Buchi 510 melting point
apparatus. X-ray data were collected on a Bruker D8
VENTURE diffractometer. Thin-layer chromatography was
carried out on silica gel 254.
121.2; GC-MS m/z = 372 [M+]; Analysis calculated for
C21H12N2OS2: C, 67.72; H, 3.25; N, 7.52; S, 17.22%.
Found: C, 67.25; H, 2.93; N, 7.43; S, 16.97%.
General procedure for preparation of Schiff bases
8a-d
A mixture of compound 6 (1.00 mmol) and one of the
aniline derivatives 7a-d (1.00 mmol) was refluxed in etha-
nol and 2–3 drops of acetic acid for an appropriate time.
The mixture was then cooled to room temperature, filtered
and evaporated under reduced pressure. The precipitate was
then recrystallized from ethanol to give purified Schiff bases
8a-d.
General procedure for the synthesis of 2-(benzo[d]
thiazol-2-ylthio)benzo[h]quinoline-3-carbaldehyde
(6)
1-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-N-(4-
ethoxyphenyl)methanimine (8a)
A mixture of 1-naphthylamine (1) (1.00 mmol) and acetic
anhydride (2) (5 ml) in methanol (20 ml) containing a small
drop of acetic acid as a catalyst was refluxed in a hot water
bath. The crude product was isolated by evaporation, and
crystallized from methanol. N-(naphthalen-1-yl)acetamide
(3) (1.00 mmol) was added to a mixture of Vilsmeier-Haack
reagent (prepared by dropwise addition of 6.5 ml of POCl3
in ice-cooled 2 ml of DMF) and refluxed for 16 h. The
reaction mixture was poured into ice and kept overnight,
followed by neutralization using solid sodium bicarbonate.
The crude product 4 was isolated and crystallized from
ethanol. To a mixture of benzo[d]thiazole-2-thiol (5)
(11 mmol), NaH (20 mmol), and DMSO (20 mL) was added
2-chloro-3-formylquinolines (4) (10 mmol) and the mixture
was heated at 90 °C for the given time. Then the reaction
was quenched with water (60 mL) and extracted with
CH2Cl2 (3 × 50 mL). The combined organic layer was
washed with brine solution, dried over anhydrous Na2SO4,
and concentrated in vacuo. 2-(Benzo[d]thiazol-2-ylthio)
benzo[h]quinoline-3-carbaldehyde (6) was obtained by flash
column chromatography on silica (n-hexane/EtOAc, 10:1/
6:1, v/v).
Yellow solid; Mp. 183–185 °C; IR (KBr, cm−1): 1592 (CH
= N); 1H-NMR (400 MHz, CDCl3): 1.47 (3H, t, J = 4.2 Hz,
CH3), 4.07 (2H, q, J = 4.2 Hz, OCH2), 6.96 (2H, d, J = 5.0
Hz, ArH), 7.37 (2H, d, J = 5.2 Hz, ArH), 7.45 (1H, t, J =
4.5 Hz, ArH), 7.53 (1H, d, J = 5.0 Hz, ArH), 7.57 (1H, d,
J = 5.0 Hz, ArH), 7.56–7.67 (2H, m, ArH), 7.75 (1H, d,
J = 5.2 Hz, ArH), 7.84 (1H, d, J = 4.7 Hz, ArH), 7.92 (1H,
d, J = 4.7 Hz, ArH), 8.11 (1H, d, J = 5.0 Hz, ArH), 8.58
(1H, s, ArH), 8.89 (1H, s, CH = N), 8.98 (1H, d, J = 5.0
Hz, ArH); 13C-NMR (100 MHz, CDCl3) δ 163.2, 158.5,
153.2, 152.7, 152.6, 146.8, 143.2, 137.1, 136.5, 134.4,
130.4, 129.1, 129.0, 128.4, 127.8, 127.3, 126.1, 125.5,
125.1, 125.0, 124.7, 122.7, 121.1, 115.0, 63.7, 14.9; GC-
MS m/z = 491 [M+]; Analysis calculated for C29H21N3OS2:
C, 70.85; H, 4.31; N, 8.55; S, 13.04%. Found: C, 70.58; H,
4.25; N, 8.15, S, 12.65%.
1-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-N-(4-
methoxyphenyl)methanimine (8b)
Cream solid; Mp. 189–191 °C; IR (KBr, cm−1): 1591 (CH
1
= N); H-NMR (400 MHz, CDCl3): 3.86 (3H, s, OCH3),
6.97 (2H, d, J = 5.5 Hz, ArH), 7.37 (2H, d, J = 5.2 Hz,
ArH), 7.45 (1H, t, J = 4.7 Hz, ArH), 7.53 (1H, d, J = 5.0
Hz, ArH), 7.58 (1H, d, J = 5.0 Hz, ArH), 7.64–7.67 (2H, m,
ArH), 7.75 (1H, d, J = 5.5 Hz, ArH), 7.84 (1H, d, J = 5.0
Hz, ArH), 7.92 (1H, d, J = 4.7 Hz, ArH), 8.11 (1H, d, J =
5.0 Hz, ArH), 8.59 (1H, s, ArH), 8.89 (1H, s, CH = N), 8.98
(1H, d, J = 5.0 Hz, ArH); 13C-NMR (100 MHz, CDCl3) δ
163.2, 159.1, 153.2, 152.8, 152.6, 146.8, 143.4, 137.1,
136.5, 134.4, 130.4, 129.0, 128.5, 127.8, 127.3, 126.1,
125.5, 125.1, 125.0, 124.7, 122.7, 121.1, 114.5, 55.5; GC-
MS m/z = 477 [M+]; Analysis calculated for C28H19N3OS2:
C, 70.42; H, 4.01; N, 8.80; S, 13.43%. Found: C, 70.51; H,
4.33; N, 8.15, S, 12.98%.
2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinoline-3-
carbaldehyde (6)
Yellow solid; Mp. 180–182 °C; IR (KBr, cm−1): 1683 (CO
aldehyde); 1H-NMR (400 MHz, CDCl3): 7.52–7.60 (3H, m,
ArH), 7.71–7.77 (2H, m, ArH), 7.86 (1H, d, J = 5.2 Hz,
ArH), 7.90 (1H, d, J = 4.5 Hz, ArH), 7.99 (1H, d, J = 4.7
Hz, ArH), 8.16 (1H, d, J = 4.7 Hz, ArH), 8.63 (1H, s, ArH),
8.77 (1H, d, J = 5.0 Hz, ArH), 10.42 (1H, s, CHO); 13C-
NMR (100 MHz, CDCl3) δ 189.7, 160.6, 154.8, 152.8,
148.7, 141.8, 137.2, 135.2, 130.1, 130.0, 128.9, 127.9,
127.6, 127.3, 126.3, 125.9, 125.5, 124.9, 123.9, 123.2,

Medicinal Chemistry Research
4-(((2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)
methylene)amino)-N,N-dimethylaniline (8c)
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-1-(4-
ethoxyphenyl)-3-phenoxyazetidin-2-one (10a)
Green solid; Mp. 199–201 °C; IR (KBr, cm−1): 1585 (CH
= N); H-NMR (400 MHz, CDCl3): 3.02 (6H, s, NCH3),
White solid; Mp. 198–200 °C; IR (KBr, cm−1): 1753 (CO
β-lactam); H-NMR (250 MHz, CDCl3): 1.37 (3H, t, J =
1
1
6.77 (2H, d, J = 5.2 Hz, ArH), 7.41–7.46 (3H, m, ArH),
7.52–7.61 (2H, m, ArH), 7.66 (1H, d, J = 4.7 Hz, ArH),
7.70 (1H, d, J = 5.5 Hz, ArH), 7.78 (1H, d, J = 5.5 Hz,
ArH), 7.86 (1H, d, J = 5.0 Hz, ArH), 7.92 (1H, d, J = 5.0
Hz, ArH), 8.11 (1H, d, J = 5.0 Hz, ArH), 8.64 (1H, s, ArH),
8.96 (1H, s, CH = N), 9.03 (1H, d, J = 5.0 Hz, ArH); 13C-
NMR (100 MHz, CDCl3) δ 163.6, 153.0, 152.6, 150.1,
149.6, 146.5, 139.2, 136.5, 136.4, 134.3, 130.5, 129.7,
128.8, 128.4, 127.8, 127.3, 126.1, 125.4, 125.1, 125.0,
124.9, 122.9, 122.6, 121.1, 112.5, 40.5; GC-MS m/z = 490
[M+]; Analysis calculated for C29H22N4S2: C, 70.99; H,
4.52; N, 11.42; S, 13.07%. Found: C, 70.64; H, 4.41; N,
11.15, S, 12.82%.
7.0 Hz, CH3), 3.96 (2H, q, J = 7.0 Hz, OCH2), 5.75 (1H, d,
J = 5.0 Hz, H-4), 6.06 (1H, d, J = 5.0 Hz, H-3), 6.83 (5H, d,
J = 8.5 Hz, ArH), 7.06 (2H, t, J = 8.2 Hz, ArH), 7.36–7.41
(3H, m, ArH), 7.49 (1H, t, J = 7.7 Hz, ArH), 7.63 (1H, d,
J = 9.0 Hz, ArH), 7.68–7.75 (2H, m, ArH), 7.83 (2H, d,
J = 8.5 Hz, ArH) 7.89–7.93 (1H, m, ArH), 7.98 (1H, d, J =
8.0 Hz, ArH), 8.19 (1H, s, ArH), 9.22–9.25 (1H, m, ArH);
13C-NMR (100 MHz, CDCl3) δ 162.6, 162.5, 156.8, 156.2,
152.5, 150.9, 146.7, 136.0, 135.8, 134.0, 130.4, 129.8,
129.4, 129.1, 129.0, 127.9, 127.8, 127.6, 126.3, 125.5,
125.2, 125.1, 124.9, 122.6, 122.4, 121.1, 118.8, 115.9,
115.2, 81.7, 63.7, 58.2, 14.8; GC-MS m/z = 625 [M+];
Analysis calculated for C37H27N3O3S2: C, 71.02; H, 4.35;
N, 6.72; S, 10.25. Found: C, 70.51; H, 4.33; N, 7.15, S,
10.58%.
4-(((2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)
methylene)amino)-N,N-diethylaniline (8d)
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-1-(4-
(diethylamino)phenyl)-3-phenoxyazetidin-2-one (10b)
Brown solid; Mp. 210–212 °C; IR (KBr, cm−1): 1588 (CH
= N); 1H-NMR (400 MHz, CDCl3): 1.24 (6H, t, J = 4.5 Hz,
CH3), 3.45 (4H, d, J = 4.5 Hz, NCH2), 6.76 (2H, d, J = 5.5
Hz, ArH), 7.43–7.47 (3H, m, ArH), 7.54 (1H, t, J = 4.5 Hz,
ArH), 7.61 (1H, t, J = 4.5 Hz, ArH), 7.70 (1H, t, J = 4.5 Hz,
ArH), 7.77 (1H, d, J = 5.5 Hz, ArH), 7.84 (1H, d, J = 5.7
Hz, ArH), 7.92 (2H, t, J = 5.5 Hz, ArH), 8.10 (1H, d, J =
5.0 Hz, ArH), 8.75 (1H, s, ArH), 9.05–9.06 (2H, m, CH =
N, ArH); 13C-NMR (100 MHz, CDCl3) δ 163.6, 153.1,
152.7, 148.8, 147.6, 146.6, 138.3, 136.5, 136.2, 134.3,
130.6, 130.0, 128.9, 128.4, 127.8, 127.3, 126.1, 125.4,
125.2, 125.1, 125.0, 123.2, 122.6, 121.1, 111.8, 44.6, 12.7;
GC-MS m/z = 518 [M+]; Analysis calculated for
C31H26N4S2: C, 71.78; H, 5.05; N, 10.80; S, 12.36%.
Found: C, 71.52; H, 5.06; N, 10.72, S, 11.88%.
Yellow solid; Mp. 184–186 °C; IR (KBr, cm−1): 1751 (CO
1
β-lactam); H-NMR (250 MHz, CDCl3): 1.09 (6H, t, J =
7.0 Hz, CH3), 3.27 (4H, q, J = 7.0 Hz, OCH2), 5.71 (1H, d,
J = 5.0 Hz, H-4), 6.02 (1H, d, J = 5.0 Hz, H-3), 6.55 (2H, d,
J = 9.0 Hz, ArH), 6.77–6.86 (3H, m, ArH), 7.04 (2H, t, J =
7.5 Hz, ArH), 7.28 (2H, t, J = 7.5 Hz, ArH), 7.38 (1H, t,
J = 7.2 Hz, ArH), 7.48 (1H, t, J = 7.2 Hz, ArH), 7.64 (1H,
d, J = 8.7 Hz, ArH), 7.68–7.72 (2H, m, ArH), 7.82 (2H, d,
J = 8.5 Hz, ArH), 7.88–7.92 (1H, m, ArH), 7.99 (1H, d,
J = 8.5 Hz, ArH), 8.24 (1H, s, ArH), 9.22–9.25 (1H, m,
ArH); 13C-NMR (100 MHz, CDCl3) δ 162.8, 162.0, 156.9,
152.5, 150.9, 146.6, 145.4, 136.2, 135.9, 134.0, 130.5,
129.4, 128.9, 128.2, 127.9, 127.5, 126.3, 125.6, 125.5,
125.2, 125.1, 125.0, 122.5, 122.4, 121.1, 119.1, 115.9,
112.0, 81.5, 58.1, 44.4, 12.5; GC-MS m/z = 652 [M+];
Analysis calculated for C39H32N4O2S2: C, 71.75; H, 4.94;
N, 8.58; S, 9.82%. Found: C, 71.28; H, 5.05; N, 9.04; S,
9.67%.
General procedure for the synthesis of β-lactams of
2-mercaptobenzothiazole and benzoquinoline, 10a-
m
A mixture of Schiff bases 8a-d (1.00 mmol), triethylamine
(5.00 mmol), one of the substituted acetic acids 9a-d (1.50
mmol) and tosyl chloride (1.50 mmol) in dry CH2Cl2 (15
mL) was stirred overnight at room temperature. Then it was
washed with 1 N HCl (20 mL), saturated NaHCO3 (20 mL)
and brine (20 mL). The organic layer was dried (Na2SO4),
filtered and the solvent was evaporated to give crude pro-
ducts 10a-m that was purified by recrystallization from
ethanol.
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-3-(4-
chlorophenoxy)-1-(4-(dimethylamino)phenyl)azetidin-2-one
(10c)
White solid; Mp. 190–192 °C; IR (KBr, cm−1): 1760 (CO
β-lactam); 1H-NMR (250 MHz, CDCl3): 2.86 (6H, s,
NCH3), 5.67 (1H, d, J = 5.0 Hz, H-4), 6.02 (1H, d, J = 5.0

Medicinal Chemistry Research
Hz, H-3), 6.63 (2H, d, J = 9.0 Hz, ArH), 6.78 (2H, d, J =
9.0 Hz, ArH), 6.97 (2H, d, J = 9.2 Hz, ArH), 7.32 (2H, d,
J = 7.7 Hz, ArH), 7.41 (1H, d, J = 6.5 Hz, ArH), 7.49 (1H,
t, J = 7.7 Hz, ArH), 7.62 (1H, d, J = 9.0 Hz, ArH), 7.71–
7.74 (2H, m, ArH), 7.83 (2H, d, J = 9.0 Hz, ArH), 7.91 (1H,
t, J1 = 5.7 Hz, ArH), 7.98 (1H, d, J = 8.0 Hz, ArH), 8.18
(1H, s, ArH), 9.23–9.27 (1H, m ArH); 13C-NMR (100 MHz,
CDCl3) δ 162.5, 161.7, 155.4, 152.5, 150.8, 148.1, 146.7,
136.1, 135.8, 134.0, 130.4, 129.3, 129.1, 129.0, 127.9,
127.8, 127.7, 127.6, 126.3, 125.5, 125.1, 125.0, 122.4,
121.1, 118.7, 117.3, 112.8, 81.6, 58.0, 40.6; GC-MS m/z =
660 [M+, 37Cl], 658 [M+, 35Cl]; Analysis calculated for
C37H27ClN4O2S2: C, 67.41; H, 4.13; N, 8.50; S, 9.73%.
Found: C, 66.29; H, 4.08; N, 8.56; S, 10.11%.
116.3, 115.2, 81.7, 63.7, 58.0, 14.8; GC-MS m/z = 695 [M
,
C37H25Cl2N3O3S2: C, 63.98; H, 3.63; N, 6.05; S, 9.23%.
Found: C, 63.38; H, 3.55; N, 5.98; S, 9.71%.
+
37Cl], 693 [M+, 35Cl]; Analysis calculated for
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-1-(4-
ethoxyphenyl)-3-(naphthalen-2-yloxy)azetidin-2-one (10f)
White solid; Mp. 170–172 °C; IR (KBr, cm−1): 1760 (CO
1
β-lactam); H-NMR (250 MHz, CDCl3): 1.37 (3H, t, J =
7.0 Hz, CH3), 3.96 (2H, q, J = 7.0 Hz, OCH2), 5.89 (1H, d,
J = 4.7 Hz, H-4), 6.15 (1H, d, J = 4.7 Hz, H-3), 6.82 (3H, d,
J = 8.2 Hz, ArH), 7.13–7.21 (2H, m, ArH), 7.30–7.73
(12H, m, ArH), 7.83 (1H, d, J = 8.7 Hz, ArH), 7.88–7.96
(2H, m, ArH), 8.24 (1H, s, ArH), 9.17 (1H, d, J = 7.8 Hz,
ArH); 13C-NMR (100 MHz, CDCl3) δ 162.7, 162.2, 156.2,
154.4, 152.5, 150.9, 146.7, 136.1, 135.7, 134.0, 133.8,
130.4, 129.7, 129.6, 129.5, 129.1, 129.0, 127.9, 127.6,
127.5, 127.4, 127.0, 126.3, 126.2, 125.4, 125.1, 124.9,
124.8, 124.3, 122.3, 121.0, 118.8, 118.0, 115.2, 109.5,
81.5, 63.7, 58.3, 14.8; GC-MS m/z = 675 [M+]; Analysis
calculated for C41H29N3O3S2: C, 72.87; H, 4.33; N, 6.22; S,
9.49%. Found: C, 72.48; H, 4.23; N, 6.20; S, 9.71%.
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-3-(4-
chlorophenoxy)-1-(4-ethoxyphenyl)azetidin-2-one (10d)
Cream solid; Mp. 205–207 °C; IR (KBr, cm−1): 1761 (CO
1
β-lactam); H-NMR (250 MHz, CDCl3): 1.37 (3H, t, J =
6.7 Hz, CH3), 3.96 (2H, q, J = 6.7 Hz, OCH2), 5.68 (1H, d,
J = 5.0 Hz, H-4), 6.04 (1H, d, J = 5.0 Hz, H-3), 6.77 (2H, d,
J = 9.0 Hz, ArH), 6.83 (2H, d, J = 9.0 Hz, ArH), 6.99 (2H,
d, J = 9.0 Hz, ArH), 7.35–7.42 (3H, m, ArH), 7.49 (1H, t,
J = 7.7 Hz, ArH), 7.62 (1H, d, J = 8.7 Hz, ArH), 7.71–7.75
(2H, m, ArH), 7.84 (2H, d, J = 8.7 Hz, ArH), 7.90–7.93
(1H, m, ArH), 7.97 (1H, d, J = 8.0 Hz, ArH), 8.15 (1H, s,
ArH), 9.23–9.27 (1H, m, ArH); 13C-NMR (100 MHz,
CDCl3) δ 162.4, 162.1, 156.3, 155.3 152.5, 150.7, 146.7,
135.9, 135.8, 134.1, 130.4, 129.7, 129.3, 129.2, 129.1,
128.0, 127.8, 127.7, 127.6, 126.4, 125.5, 125.2, 125.1,
124.9, 122.4, 121.1, 118.8, 117.3, 115.2, 81.7, 63.7, 58.2,
14.8; GC-MS m/z = 661 [M+, 37Cl], 659 [M+, 35Cl]; Ana-
lysis calculated for C37H26ClN3O3S2: C, 67.31; H, 3.97; N,
6.36; S, 9.71%. Found: C, 67.07; H, 3.83; N, 6.28; S,
10.15%.
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-3-(4-
chlorophenoxy)-1-(4-methoxyphenyl)azetidin-2-one (10g)
White solid; Mp. 192–194 °C; IR (KBr, cm−1): 1760 (CO
1
β-lactam); H-NMR (250 MHz, CDCl3): 3.75 (3H, s, CH3),
5.68 (1H, d, J = 5.0 Hz, H-4), 6.05 (1H, d, J = 5.0 Hz, H-3),
6.77 (2H, d J = 8.7 Hz, ArH), 6.83 (2H, d J = 9.0 Hz, ArH),
6.99 (2H, d J = 8.7 Hz, ArH), 7.36–7.42 (3H, m, ArH), 7.49
(1H, t, J = 7.7 Hz, ArH), 7.62 (1H, d, J = 8.7 Hz, ArH),
7.69–7.77 (2H, m, ArH), 7.84 (2H, d, J = 8.5 Hz, ArH),
7.90–7.93 (1H, m, ArH), 7.97 (1H, d, J = 8.0 Hz, ArH),
8.15 (1H, s, ArH), 9.23–9.27 (1H, m, ArH); 13C-NMR (100
MHz, CDCl3) δ 162.4, 162.1, 156.9, 155.3, 152.5, 150.7,
146.7, 135.9, 135.8, 134.1, 130.4, 129.8, 129.3, 129.2,
129.1, 128.0, 127.7, 127.6, 126.4, 125.5, 125.2, 125.1,
124.8, 122.4, 121.1, 118.8, 117.3, 114.7, 81.7, 58.2, 55.5;
GC-MS m/z = 647 [M+, 37Cl], 645 [M+, 35Cl]; Analysis
calculated for C36H24ClN3O3S2: C, 66.92; H, 3.74; N, 6.50;
S, 9.92%. Found: C, 66.88; H, 3.53; N, 6.39; S, 10.21%.
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-3-(2,4-
dichlorophenoxy)-1-(4-ethoxyphenyl)azetidin-2-one (10e)
White solid; Mp. 200–202 °C; IR (KBr, cm−1): 1755 (CO
1
β-lactam); H-NMR (250 MHz, CDCl3): 1.37 (3H, t, J =
6.7 Hz, CH3), 3.96 (2H, q, J = 6.7 Hz, OCH2), 5.72 (1H, d,
J = 5.0 Hz, H-4), 6.08 (1H, d, J = 5.0 Hz, H-3), 6.83 (2H, d,
J = 9.0 Hz, ArH), 7.00–7.05 (1H, m, ArH), 7.18–7.26 (2H,
m, ArH), 7.36–7.41 (3H, m, ArH), 7.48 (1H, t, J = 7.7 Hz,
ArH), 7.63 (1H, d, J = 8.7 Hz, ArH), 7.71–7.75 (2H, m,
ArH), 7.84 (2H, d, J = 8.8 Hz, ArH), 7.90–7.97 (2H, m,
ArH), 8.20 (1H, s, ArH), 9.26–9.29 (1H, m, ArH); 13C-
NMR (100 MHz, CDCl3) δ 162.4, 161.5, 156.3, 152.4,
151.1, 150.7, 146.8, 136.1, 135.9, 134.1, 130.5, 129.9,
129.6, 129.1, 129.0, 127.9, 127.7, 127.6, 127.3, 126.3,
125.5, 125.2, 125.1, 124.9, 123.9, 122.3, 121.1, 118.8,
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-3-(2,4-
dichlorophenoxy)-1-(4-methoxyphenyl)azetidin-2-one (10h)
White solid; Mp. 204–206 °C; IR (KBr, cm−1): 1755 (CO
1
β-lactam); H-NMR (250 MHz, CDCl3): 3.75 (3H, s, CH3),
5.72 (1H, d, J = 5.0 Hz, H-4), 6.07 (1H, d, J = 5.0 Hz, H-3),
6.83 (2H, d, J = 9.0 Hz, ArH), 6.99–7.04 (2H, m, ArH),
7.19 (1H, d, J = 8.5 Hz, ArH), 7.35–7.40 (3H, m, ArH) 7.48
(1H, t, J = 7.7 Hz, ArH), 7.62 (1H, d, J = 8.7 Hz, ArH),

Medicinal Chemistry Research
+
7.71–7.76 (2H, m, ArH), 7.83 (2H, d, J = 8.7 Hz, ArH),
7.89–7.97 (2H, m, ArH), 8.20 (1H, s, ArH), 9.25–9.29 (1H,
m, ArH); 13C-NMR (100 MHz, CDCl3) δ 162.4, 161.5,
156.9, 152.4, 151.1, 150.7, 146.8, 136.2, 135.9, 134.1,
130.5, 129.9, 129.7, 129.2, 129.0, 127.9, 127.7, 127.6,
127.3, 126.3, 125.5, 125.2, 125.1, 124.9, 124.0, 122.4,
121.1, 118.9, 116.3, 114.7, 81.7, 58.0, 55.5; GC-MS m/z =
681 [M+, 37Cl], 679 [M+, 35Cl]; Analysis calculated for
C36H23Cl2N3O3S2: C, 63.53; H, 3.41; N, 6.17; S, 9.42%.
Found: C, 63.18; H, 3.35; N, 6.32; S, 9.71%.
,
37Cl], 720 [M+, 35Cl]; Analysis calculated for
C39H30Cl2N4O2S2: C, 64.90; H, 4.19; N, 7.76; S, 8.88%.
Found: C, 64.66; H, 4.07; N, 7.62; S, 9.10%.
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-1-(4-
(dimethylamino)phenyl)-3-phenoxyazetidin-2-one (10k)
Cream solid; Mp. 196–198 °C; IR (KBr, cm−1): 1740 (CO
β-lactam); 1H-NMR (250 MHz, CDCl3): 2.88 (6H, s,
NCH3), 5.73 (1H, d, J = 4.7 Hz, H-4), 6.03 (1H, d, J = 4.7
Hz, H-3), 6.62 (2H, d, J = 8.7 Hz, ArH), 6.78–6.86 (3H, m,
ArH), 7.05 (2H, t, J = 8.0 Hz, ArH), 7.33 (2H, d, J = 9.0
Hz, ArH), 7.40 (1H, d, J = 7.7 Hz, ArH), 7.49 (1H, t, J =
7.7 Hz, ArH), 7.62 (1H, d, J = 9.0 Hz, ArH), 7.69–7.73
(2H, m, ArH), 7.82 (1H, d, J = 9.5 Hz, ArH), 7.88–7.92
(2H, m, ArH), 7.99 (1H, d, J = 8.0 Hz, ArH), 8.21 (1H, s,
ArH), 9.22–9.25 (1H, m, ArH); 13C-NMR (100 MHz,
CDCl3) δ 162.8, 162.1, 156.9, 152.5, 150.9, 148.0, 146.6,
136.2, 135.8, 134.0, 130.4, 129.4, 128.9, 128.0, 127.9,
127.5, 126.5, 126.3, 125.5, 125.1, 125.0, 122.5, 122.4,
121.1, 118.8, 115.9, 112.8, 81.5, 58.1, 40.6; GC-MS m/z =
624 [M+]; Analysis calculated for C37H28N4O2S2: C, 71.13;
H, 4.52; N, 8.97; S, 10.26%. Found: C, 71.02.; H, 4.19; N,
8.62; S, 10.51%.
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-3-(4-
chlorophenoxy)-1-(4-(diethylamino)phenyl)azetidin-2-one
(10i)
Yellow solid; Mp. 183–185 °C; IR (KBr, cm−1): 1748 (CO
1
β-lactam); H-NMR (250 MHz, CDCl3): 1.10 (6H, t, J =
7.0 Hz, CH3), 3.28 (4H, q, J = 7.0 Hz, NCH2), 5.65 (1H, d,
J = 5.0 Hz, H-4), 6.00 (1H, d, J = 5.0 Hz, H-3), 6.56 (2H, d,
J = 9.0 Hz, ArH), 6.77 (2H, d, J = 9.0 Hz, ArH), 6.97 (2H,
d, J = 9.0 Hz, ArH), 7.29 (2H, d, J = 9.0 Hz, ArH), 7.39
(1H, t, J = 7.2 Hz, ArH), 7.49 (1H, t, J = 7.7 Hz, ArH), 7.64
(1H, d, J = 8.7 Hz, ArH), 7.70–7.74 (2H, m, ArH), 7.83
(2H, d, J = 8.7 Hz, ArH), 7.89–7.93 (1H, m, ArH), 7.98
(1H, d, J = 8.0 Hz, ArH), 8.21 (1H, s, ArH), 9.23–9.27 (1H,
m, ArH); 13C-NMR (100 MHz, CDCl3) δ 162.5, 161.6,
155.4, 152.5, 150.9, 146.6, 145.4, 136.1, 135.8, 134.0,
130.4,129.5, 129.3, 129.0, 128.0, 127.6, 127.5, 126.3,
125.5, 125.4, 125.3, 125.1, 125.0, 122.4, 121.1, 119.1,
117.3, 112.0, 81.5, 58.0, 44.4, 12.5; GC-MS m/z = 688
[M+, 37Cl], 686 [M+, 35Cl]; Analysis calculated for
C39H31ClN4O2S2: C, 68.16; H, 4.55; N, 8.15; S, 9.33%.
Found: C, 68.08; H, 4.38; N, 8.25; S, 9.53%.
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-3-(2,4-
dichlorophenoxy)-1-(4-(dimethylamino)phenyl)azetidin-2-
one (10l)
Cream solid; Mp. 221–223 °C; IR (KBr, cm−1): 1751 (CO
β-lactam); 1H-NMR (250 MHz, CDCl3): 2.89 (6H, s,
NCH3), 5.70 (1H, d, J = 5.0 Hz, H-4), 6.04 (1H, d, J = 5.0
Hz, H-3), 6.62 (2H, d, J = 8.7 Hz, ArH), 7.01 (2H, d, J =
9.7 Hz, ArH), 7.21 (1H, d, J = 8.5 Hz, ArH), 7.32 (2H, d,
J = 9.0 Hz, ArH), 7.39 (1H, d, J = 7.7 Hz, ArH), 7.48 (1H,
t, J = 7.7 Hz, ArH), 7.62 (1H, d, J = 8.7 Hz, ArH), 7.70–
7.74 (2H, m, ArH), 7.82 (2H, d, J = 9.5 Hz, ArH), 7.89–
7.93 (1H, m, ArH), 7.97 (1H, d, J = 8.0 Hz, ArH), 8.23 (1H,
s, ArH), 9.26–9.29 (1H, m, ArH); 13C-NMR (100 MHz,
CDCl3) δ 162.5, 161.1, 152.4, 151.1, 150.8, 148.1, 146.7,
136.2, 135.9, 134.1, 130.5, 129.8, 129.0, 128.9, 127.9,
127.5, 126.3, 126.2, 125.5, 125.2, 125.1, 123.9, 122.3,
121.1, 118.8, 116.3, 112.8, 81.5, 125.0, 57.8, 40.5; GC-MS
m/z = 694 [M+, 37Cl], 692 [M+, 35Cl]; Analysis calculated
for C37H26Cl2N4O2S2: C, 64.07; H, 3.78; N, 8.08; S, 9.24%.
Found: C, 63.98; H, 3.65; N, 7.92; S, 9.69%.
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-3-(2,4-
dichlorophenoxy)-1-(4-(diethylamino)phenyl)azetidin-2-one
(10j)
Cream solid; Mp. 178–180 °C; IR (KBr, cm−1): 1757 (CO
1
β-lactam); H-NMR (250 MHz, CDCl3): 1.10 (6H, t, J =
7.0 Hz, CH3), 3.28 (4H, q, J = 7.0 Hz, NCH2), 5.69 (1H, d,
J = 5.0 Hz, H-4), 6.03 (1H, d, J = 5.0 Hz, H-3), 6.56 (2H, d,
J = 9.0 Hz, ArH), 7.01 (2H, d, J = 10.5 Hz ArH), 7.21 (1H,
d, J = 8.7 Hz, ArH), 7.29 (2H, d, J = 9.0 Hz ArH), 7.38
(1H, t, J = 7.5 Hz, ArH), 7.48 (1H, t, J = 7.7 Hz, ArH), 7.65
(1H, d, J = 8.7 Hz, ArH), 7.70–7.74 (2H, m, ArH), 7.83
(2H, d, J = 8.7 Hz, ArH), 7.90–7.93 (1H, m, ArH), 7.97
(1H, d, J = 8.2 Hz, ArH), 8.25 (1H, s, ArH) 9.26–9.30 (1H,
m, ArH); 13C-NMR (100 MHz, CDCl3) δ 162.5, 160.9,
152.4, 151.2, 150.8, 146.7, 145.5, 136.3, 135.9, 134.1,
130.5, 129.8, 129.0, 128.0, 127.7, 127.6, 127.5, 127.4,
126.3, 125.5, 125.2, 125.1, 123.9, 122.4, 121.1, 119.1,
116.3, 112.0, 81.5, 57.7, 44.4, 12.5; GC-MS m/z = 722 [M
4-(2-(Benzo[d]thiazol-2-ylthio)benzo[h]quinolin-3-yl)-1-(4-
methoxyphenyl)-3-phenoxyazetidin-2-one (10m)
White solid; Mp. 207–209 °C; IR (KBr, cm−1): 1762 (CO
β-lactam); H-NMR (250 MHz, CDCl3): 3.74 (3H, s, CH3),
5.74 (1H, d, J = 4.7 Hz, H-4), 6.05 (1H, d, J = 4.7 Hz, H-3),
1

Medicinal Chemistry Research
6.80–6.86 (5H, m, ArH), 7.06 (2H, t, J = 7.7 Hz, ArH),
7.37–7.40 (3H, m, ArH), 7.48 (1H, t, J = 7.7 Hz, ArH), 7.62
(1H, d, J = 9.0 Hz, ArH), 7.69–7.73 (2H, m, ArH), 7.82
(2H, d, J = 8.5 Hz, ArH), 7.88–7.92 (1H, m, ArH), 7.97
(1H, d, J = 8.0 Hz, ArH), 8.18 (1H, s, ArH), 9.21–9.25 (1H,
m, ArH); 13C-NMR (100 MHz, CDCl3) δ 162.7, 162.5,
156.8, 152.5, 150.9, 146.7, 136.0, 135.8, 134.0, 130.4,
129.9, 129.4, 129.1, 129.0, 128.0, 127.8, 127.6, 126.3,
125.5, 125.1, 124.9, 122.6, 122.4, 121.1, 118.8, 115.9,
114.6, 81.7, 58.2, 55.4; Analysis calculated for
C36H25N3O3S2: C, 70.68; H, 4.12; N, 6.87; S, 10.48%.
Found: C, 70.48; H, 4.09; N, 6.62; S, 10.87%.
4.7) was added to each well to dissolve formazan crystals
and absorbance recorded at 570 nm using SPECTRO-
starNano (BMG Labtech, Germany) microplate reader.
Absorbance at 690 nm was also measured to omit the tur-
bidity. Cell viability percentage calculated as follow:
AT ¼ A570 À A690
Cell viability % ¼ ½AT sample=AT controlŠ  100
Hemolytic activity
General procedure for MIC activity assay
Fresh human red blood cells (RBC) were washed with
phosphate buffer saline (PBS) until the upper phase was
clear after centrifugation. The pellet was resuspended in
PBS to reach an OD600 of 24.0. Stock solutions of the
synthesized compounds (1000×) were prepared in DMSO
and diluted in RBC suspension to achieve a final con-
centration of 200 µM. DMSO and Triton X-100 (1% final
concentration) were used as negative and positive controls,
respectively. After one hour of incubation at 37 °C, the cells
were centrifuged at 1000 × g for 10 min (Ling et al. 2015).
The absorbance of supernatants at A450nm was measured and
hemolysis percentage was calculated as follow:
E. coli ATCC 25922, P. aeruginosa ATCC 9027, S. aureus
ATCC 25923, S. typhi ATCC 7251, E. faecalis ATCC
29212 and B. subtilis ATCC 6051 were used in this study to
test the compounds for antibacterial activity. These bacteria
were cultivated on Brain Heart Infusion (BHI) plates
overnight. Several colonies were suspended into normal
saline and adjusted to OD600nm = 0.07 (0.5 McFarland unit).
The inoculum solution was made by preparing a 1:100
dilution of 0.5 McFarland normal saline suspension using
BHI broth and 100 mL of this suspension was added to 100
mL of BHI broth containing various concentrations of test
antibiotics. The test antibiotic solution was serially diluted
2-fold by automatic pipette in a 96-well microtiter format.
After inoculation with bacterial strains (final density was
approximately 5 × 105 CFU/mL), the microtiter plates were
incubated at 37 °C for 18 h. MIC was determined as the
lowest concentration of the test compound in which the
absorbance at 600 nm is less than or equal to 0.025 (Letavic
et al. 2002).
Hemolysis percentage ¼ ½ðAbsorbance of sample À Absorbance of negative controlÞ
ÄðAbsorbance of positive control À Absorbance of negative controlފ  100
Both hemolysis and cytotoxicity experiments were per-
formed triplicate.
Acknowledgements The authors would like to thank the Shiraz Uni-
versity Research Council for financial support (Grant No. 97-GR-SC-
23) and Dr. Attila Benyei for collecting X-ray data.
Mammalian cytotoxicity
Compliance with ethical standards
MCF-7 (a breast cancer cell line) cells were cultured in a
humidified atmosphere containing 5% CO2 at 37 °C in
DMEM high medium supplemented with 100 U. mL−1
penicillin, 100 μg mL−1 streptomycin and 10% fetal bovine
serum. Cell viability assay was performed using the MTT
method (Riss et al. 2013). Briefly 1 × 104 cells were seeded
in 96 well flat-bottom plates and incubated at 37 oC for 24 h
in the presence of 5% CO2, then the cells exposed to the
synthesized compounds at final concentration of 50 and
200 μM for a period of 72 h. Afterward, MTT (3-(4,5-
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
References
Ahmed A, Daneshtalab M (2012) Polycyclic quinolones (part 1)
thieno [2, 3-b] benzo [h] quinoline derivatives: design, synthesis,
preliminary in vitro and in silico studies. Heterocycles 85:103–
122
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide)
solution was added to each well to achieve a final con-
centration of 0.45 mg/ml and incubated at 37 °C for another
4 h. Finally, equal volume of solubilization solution (40%
(vol/vol) dimethylformamide (DMF) in 2% (vol/vol) glacial
Afzal O, Kumar S, Haider MR, Ali MR, Kumar R, Jaggi M, Bawa S
(2015) A review on anticancer potential of bioactive heterocycle
quinoline. Eur J Med Chem 97:871–910
Alborz M, Jarrahpour A, Pournejati R, Karbalaei-Heidari HR, Sinou
V, Latour C, Brunel JM, Sharghi H, Aberi M, Turos E (2018)
Synthesis and biological evaluation of some novel
acetic acid and 16 % sodium dodecyl sulfate (SDS), pH
̴

Medicinal Chemistry Research
diastereoselective benzothiazole β-lactam conjugates. Eur J Med
Chem 143:283–291
Kumar S, Bawa S, Gupta H (2009) Biological activities of quinoline
derivatives. Mini Rev Med Chem 9:1648–1654
Alcaide B, Almendros P, Aragoncillo C (2007) β-Lactams: versatile
building blocks for the stereoselective synthesis of non-β-lactam
products. Chem Rev 107:4437–4492
Baluja SH, Chanda S (2017) Synthesis and antimicrobial screening of
some novel chloroquinolines in DMF and DMSO. Int J Bioorg
Chem 2:118–124
Bandyopadhyay D, Cruz J, Banik BK (2012) Novel synthesis of 3-
pyrrole substituted β-lactams via microwave-induced bismuth
nitrate-catalyzed reaction. Tetrahedron 68:10686–10695
Bawa S, Kumar S, Drabu S, Kumar R (2010) Structural modifications
of quinoline-based antimalarial agents: Recent developments. J
Pharm Bioallied Sci 2:64–71
Bhat I, Mishra SK, James J, Shastry C (2011) Antimicrobial studies of
synthesized azetidinone derivatives from sulfamethoxazole moi-
ety. J Chem Pharm Res 3:114–118
Bhati SK, Kumar A (2008) Synthesis of new substituted azetidinoyl
and thiazolidinoyl-1, 3, 4-thiadiazino (6,5-b) indoles as promising
anti-inflammatory agents. Eur J Med Chem 43:2323–2330
Çelik I, Akkurt M, Jarrahpour A, Ameri Rad J, Çelik O (2015) Crystal
structure of 2-[(3S,4S)-4-(anthracen-9-yl)-1-(4-methoxyphenyl)-
2-oxoazetidin-3-yl]-2-aza-2H-phenalene-1,3-dione unknown sol-
vate Acta Crystallogr Sect E Struct Rep 71:o184–o185
Cerić H, Šindler-Kulyk M, Kovačević M, Perić M, Živković A (2010)
Azetidinone-isothiazolidinones: Stereoselective synthesis and
antibacterial evaluation of new monocyclic β-lactams. Bioorg
Med Chem 18:3053–3058
Chavan AA, Pai NR (2007) Synthesis and biological activity of N-
substituted-3-chloro-2-azetidinones. Molecules 12:2467–2477
Cressier D, Prouillac C, Hernandez P, Amourette C, Diserbo M, Lion
C, Rima G (2009) Synthesis, antioxidant properties and radio-
protective effects of new benzothiazoles and thiadiazoles. Bioorg
Med Chem 17:5275–5284
Letavic MA, Bronk BS, Bertsche CD, Casavant JM, Cheng H, Daniel
KL, George DM, Hayashi SF, Kamicker BJ, Kolosko NL (2002)
Synthesis and activity of a novel class of tribasic macrocyclic
antibiotics: the triamilides. Bioorg Med Chem Lett 12:2771–2774
Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP,
Mueller A, Schäberle TF, Hughes DE, Epstein S (2015) A new
antibiotic kills pathogens without detectable resistance. Nature
517:455–459
Meunier B (2007) Hybrid molecules with a dual mode of action:
dream or reality? Acc Chem Res 41:69–77
Mishra RK, Coates CM, Revell KD, Turos E (2007) Synthesis of 2-
oxazolidinones from β-lactams: Stereospecific total synthesis of
(−)-cytoxazone and all of its stereoisomers. Org Lett 9:575–578
Morphy R, Rankovic Z (2006) The physicochemical challenges of
designing multiple ligands. J Med Chem 49:4961–4970
Nagarajan S, Arjun P, Raaman N, Shah A, Sobhia ME, Das TM
(2012) Stereoselective synthesis of sugar-based β-lactam deriva-
tives: docking studies and its biological evaluation. Tetrahedron
68:3037–3045
Piens N, De Kimpe N, D'hooghe M (2016) Recent progress in the use
of functionalized á-lactams as building blocks in heterocyclic
chemistry. progress in heterocyclic chemistry 28:27–55
Raj R, Sharma V, Hopper MJ, Patel N, Hall D, Wrischnik LA, Land
KM, Kumar V (2014) Synthesis and preliminary in vitro activity
of mono-and bis-1H-1, 2, 3-triazole-tethered β-lactam–isatin
conjugates against the human protozoal pathogen Trichomonas
vaginalis. Med Chem Res 23:3671–3680
Rajamäki SH, De Luca L, Capitta F, Porcheddu A (2016) A telescopic
one-pot synthesis of β-lactam rings using amines as a convenient
source of imines. RSC Adv 6:38553–38557
Ramachandran E, Thomas SP, Poornima P, Kalaivani P, Prabhakaran
R, Padma VV, Natarajan K (2012) Evaluation of DNA binding,
antioxidant and cytotoxic activity of mononuclear Co (III) com-
plexes of 2-oxo-1, 2-dihydrobenzo[h]quinoline-3-carbaldehyde
thiosemicarbazones. Eur J Med Chem 50:405–415
D’hooghe M, Dekeukeleire S, Leemans E, De Kimpe N (2010) Use of
functionalized β-lactams as building blocks in heterocyclic
chemistry. Pure Appl Chem 82:1749–1759
El-Gamal K, Sherbiny F, El-Morsi A, Abu-El-khair H, Eissa I, El-
Sebaei M (2015) Design, synthesis and antimicrobial evaluation
of some novel quinoline derivatives. Pharm Pharmacol Int J
2:00036
Riss TL, Moravec RA, Niles AL, Benink HA, Worzella TJ, Minor L
(2013) Cell viability assays, assay guidance manual. Eli Lilly &
Company and the National Center for Advancing Translational
Sciences, Bethesda, MD, p 1–23
Galletti P, Giacomini D (2011) Monocyclic β-lactams: new structures
for new biological activities. Curr Med Chem 18:4265–4283
Herrera Cano N, Ballari MS, Lopez AG, Santiago AN (2015) New
synthesis and biological evaluation of benzothiazole derivates as
antifungal agents. J Agric Food Chem 63:3681–3686
Hosseyni S, Jarrahpour A (2018) Org Bimol Chem. https://doi.org/10.
1039/C8OB01833B.
Salunkhe D, Piste P (2014) A brief review on recent synthesis of 2-
azetidinone derivatives. Int J Pharm Life Sci 5:666–689
Shipra H, Baluja H, Kajal H (2015) Biological activities of some novel
quinoline derivatives. Int J Basic Appl Chem Sci 5:45–60.
International
Srivastava A, Singh R (2005) Vilsmeier-Haack reagent: a facile
synthesis of 2-chloro-3-formylquinolines from N-arylacetamides
and transformation into different functionalities. Indian J Chem
44:1868–1875
Huang W, Yang GF (2006) Microwave-assisted, one-pot syntheses
and
fungicidal
activity
of
polyfluorinated
2-
benzylthiobenzothiazoles. Bioorg Med Chem 14:8280–8285
Vandekerckhove S, D’hooghe M (2013) Exploration of aziridine-and
β-lactam-based hybrids as both bioactive substances and synthetic
intermediates in medicinal chemistry. Bioorg Med Chem
21:3643–3647
Indrani B, Fredrick FB, Bimal KB (2017) Microwave-induced
synthesis of enantiopure β-lactams. Mod Chem Appl 5:2329–
6798
Islami MR, Allen AD, Vukovic S, Tidwell TT (2010) N-pyrrolylk-
etene: a nonconjugated heteroarylketene. Org Lett 13:494–497
Jarrahpour A, Zarei M (2006) Synthesis of novel N-sulfonyl mono-
cyclic β-lactams as potential antibacterial agents. Molecules
11:49–58
Jarrahpour A, Rezaei S, Sinou V, Latour C, Brunel JM (2017)
Synthesis of some novel 3-spiro monocyclic b-lactams and their
antibacterial and antifungal investigations. Iran J Sci Technol
Trans A Sci 41:337–342
Wang F, Cai S, Wang Z, Xi C (2011) Synthesis of 2-
mercaptobenzothiazoles via DBU-promoted tandem reaction of
o-haloanilines and carbon disulfide. Org Lett 13:3202–3205
Westrip SP (2010) Document origin: publCIF. J Apply Cryst 43:920–925
Zhilitskaya LV, Yarosh NO, Shagun LG, Dorofeev IA, Larina LI
(2017) Siloxane derivatives of 2-mercaptobenzothiazole. Men-
deleev Commun 27:352–354
Zhong W, Ma W, Liu
Y (2011) First construction of 12H-
thiochromeno [2,3-b] quinolines and 5H-benzo [7,8] thiocino-
[2,3-b] quinolines via intramolecular Friedel–Crafts reaction of
Morita–Baylis–Hillman adducts. Tetrahedron 67:3509–3518
Kamath A, Ojima I (2012) Advances in the chemistry of β-lactam and
its medicinal applications. Tetrahedron 68:10640–10664